Article

Decreased expression of ICAM‐1 and its induction by tumor necrosis factor on breast‐cancer cells in vitro

International Journal of Cancer

June 1997
71(6):1086 - 1090

DOI:10.1002/(SICI)1097-0215(19970611)71:6<1086::AID-IJC27>3.0.CO;2-A

Authors:

Alexandra C Budinsky

Medical University of Vienna

Show all 7 authorsHide

In order to study adhesion-molecule expression and its consequences for cellular recognition, the presence of adhesion molecules ICAM-1, VCAM-1, VLA-4, LFA-1, alpha, LFA-1 beta, LFA-3, β1-integrin and β3-integrin was studied on specimens from breast tissue by immunohistochemistry and on cells from breast cell lines propagated in vitro. Breast-cancer tissue and the breast-cancer cell lines MCF-7, SK-BR-3 and ZR-75-1 showed expression of ICAM-1 and VLA-4 significantly lower than that of benign breast cells or normal breast epithelium. Of various cytokines tested, including recombinant human (rh) interleukin-6 (IL-6), rh tumor necrosis factor alpha (TNF-α), interleukin 2 (IL-2), granulocyte/macrophage-colony-stimulating-factor (GM-CSF), interferon-alpha (IFN-α) and interferon-gamma (IFN-γ), only TNF was able to re-induce expression of ICAM-1 on cells from MCF-7, SK-BR-3 and ZR-75-1. Further, the ability of either unstimulated or lymphokine-stimulated killer (LAK) cells to recognize and lyse native or TNF-stimulated breast-cancer cells was studied. Whereas neither unstimulated lymphocytes or LAK cells were able to lyse untreated breast-cancer cells deficient for ICAM-1 expression, pre-treatment of tumor cells with TNF led to increased tumor-cell lysis. Anti-ICAM-1 antibodies, and pre-treatment of tumor cells with anti-TNF-receptor antibodies, abrogated these findings, corroborating their specificity. We thus conclude that the defective expression of ICAM-1 in our model might constitute a mechanism by which breast-cancer cells escape immunologic recognition and lysis by appropriate effector cells. Int. J. Cancer 71: 1086-1090, 1997. © 1997 Wiley-Liss Inc.

Defective antigen presentation resulting from impaired expression of costimulatory molecules in breast cancer

Article

Oct 2000
INT J CANCER

Previous experiments from our laboratory have shown that immune mechanisms aiming at the destruction of tumour cells including the recognition of target cells and their elimination via the expression of intercellular adhesion molecule‐1 (ICAM‐1; CD54), the production of tumour necrosis factor‐α (TNF‐α) by monocytes and appropriate function of lymphocyte subpopulations were defective in breast cancer. Previous observations were extended to assess expression levels and regulatory mechanisms of costimulatory molecules CD54, CD80 and CD86 on monocytes derived from patients with early breast cancer (EBC). In addition, antigen presentation by antigen‐presenting cells (APC) was analyzed within this context. We report that monocytes derived from patients with EBC exhibited significantly decreased expression levels of CD54 (p = 0.0002), CD80 (p = 0.009) and CD 86 (p = 0.002) compared with monocytes derived from healthy females. Simultaneously, lipopolysaccharide (LPS)‐induced TNF‐α production of monocytes was found to be defective in patients with EBC. Finally, T‐cell proliferation in response to tetanus toxoid (TT) was significantly decreased in patients with EBC compared with healthy control females (p < 0.0001). Furthermore, T‐cell proliferation in response to TT‐pulsed APC derived from healthy controls was significantly inhibited in the presence of anti‐CD54 and/or anti‐CD80 antibodies in a dose‐dependent manner, thus corroborating the necessity of the presence of CD54 and CD80 as costimulatory molecules in the present setting. We conclude that monocytes derived from patients with EBC showed a simultaneous defect of expression of CD54 and its regulation via TNF‐α, CD80 and CD86 as well as T‐cell proliferation following exposure to TT‐pulsed APC. Based upon these findings, it is speculated that defects in costimulatory molecule expression might contribute to tolerance of the immune system towards the presence of malignant cells in patients with EBC. Int. J. Cancer 88:239–244, 2000. © 2000 Wiley‐Liss, Inc.

Defective antigen presentation resulting from impaired expression of costimulatory molecules in breast cancer

Article

Oct 2000
INT J CANCER

Previous experiments from our laboratory have shown that immune mechanisms aiming at the destruction of tumour cells including the recognition of target cells and their elimination via the expression of intercellular adhesion molecule-1 (ICAM-1; CD54), the production of tumour necrosis factor-α (TNF-α) by monocytes and appropriate function of lymphocyte subpopulations were defective in breast cancer. Previous observations were extended to assess expression levels and regulatory mechanisms of costimulatory molecules CD54, CD80 and CD86 on monocytes derived from patients with early breast cancer (EBC). In addition, antigen presentation by antigen-presenting cells (APC) was analyzed within this context. We report that monocytes derived from patients with EBC exhibited significantly decreased expression levels of CD54 (p = 0.0002), CD80 (p = 0.009) and CD 86 (p = 0.002) compared with monocytes derived from healthy females. Simultaneously, lipopolysaccharide (LPS)-induced TNF-α production of monocytes was found to be defective in patients with EBC. Finally, T-cell proliferation in response to tetanus toxoid (TT) was significantly decreased in patients with EBC compared with healthy control females (p < 0.0001). Furthermore, T-cell proliferation in response to TT-pulsed APC derived from healthy controls was significantly inhibited in the presence of anti-CD54 and/or anti-CD80 antibodies in a dose-dependent manner, thus corroborating the necessity of the presence of CD54 and CD80 as costimulatory molecules in the present setting. We conclude that monocytes derived from patients with EBC showed a simultaneous defect of expression of CD54 and its regulation via TNF-α, CD80 and CD86 as well as T-cell proliferation following exposure to TT-pulsed APC. Based upon these findings, it is speculated that defects in costimulatory molecule expression might contribute to tolerance of the immune system towards the presence of malignant cells in patients with EBC. Int. J. Cancer 88:239–244, 2000. © 2000 Wiley-Liss, Inc.

Soluble ICAM-1 in breast cancer: Clinical significance and biological implications

Article

Jan 2001

Objectives: In previous experiments, we demonstrated a decreased expression of intercellular adhesion molecule I (ICAM-1) on both tumour cells and antigen-presenting cells derived from patients with breast cancer, resulting in an abrogation of antigen presentation and tumour cell lysis. Recently, increased levels of a soluble isoform of ICAM-1 (sICAM-1) have been detected in the sera of breast cancer patients. The present investigation was performed in order to investigate the biological relevance of serum concentrations and the effects of sICAM-1 in patients with breast cancer. Patients and methods: sICAM-1 was determined using a sandwich enzyme immunoassay on sera from 88 patients with various stages of breast cancer and correlated with clinical parameters. The effect of sICAM-1 present in the sera of patients with breast cancer upon unspecific and anti-Her-21/neu antibody-mediated cytotoxicity (ADCC), as well as upon antigen presentation, was determined using a 51Cr-release assay and [3H]thymidine-uptake of T cells after co-incubation with tetanus-toxoid-pulsed antigen-presenting cells. Results: In patients with early breast cancer, serum levels of sICAM-1 were significantly lower compared to patients with metastatic disease, but did not correlate with usual clinical parameters. In patients with metastatic breast cancer, a significant correlation of sICAM-1 with tumour markers CEA and CA 15-3 was observed. No influence of sICAM-1 upon unspecific cytotoxicity, ADCC, or the ability to present antigen was observed. Discussion: The origin of sICAM-1 in the sera of patients with breast cancer remains unknown. In contrast to its membrane-bound isoform, sICAM-1 was increased in the sera of patients with various stages of breast cancer, but its presence did not influence unspecific cytotoxicity, ADCC, or antigen-induced T cell proliferation.

Serum levels of soluble intercellular adhesion molecule-1 and E-selectin in metastatic breast carcinoma: Correlations with clinicopathological features and prognosis

Article

Full-text available

Feb 1999

Cellular adhesion molecules have been demonstrated to play an important role in the progression and metastasis of malignancies. We determined the serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and E-selectin (sE-selectin) by enzyme-linked immunosorbent assay in 49 Japanese patients with metastatic breast cancer. Significantly high concentrations of sICAM-1 and sE-selectin were found in the patients with liver and/or bone metastases (both P<0.05). The mean serum sICAM-1 levels were significantly higher in patients with two or more metastatic sites compared to those with one metastatic site (P=0.001). A significant correlation was found between serum sICAM-1 (P=0.0001) and sE-selectin (P<0.0001) and the interleukin (IL)-6 levels. The patients who did not respond to chemo/ endocrine therapy showed significantly higher sICAM-1 and sE-selectin levels compared with those who responded to therapy (P=0.0004, P=0.02, respectively). Moreover, high sICAM-1 levels predicted a significantly poorer overall survival in both univariate and multivariate analyses. Our results suggest that the shedding of sICAM-1 or sE-selectin may enhance the metastatic process by escaping from host immune surveillance. The serum sICAM-1 level may help to predict the patient response to chemo/endocrine therapy and may be of prognostic significance in metastatic breast cancer patients.

Contribution of reactive oxygen species and caspase-3 to apoptosis and attenuated ICAM-1 expression by paclitaxel-treated MDA-MB-435 breast carcinoma cells

Article

Jan 2006

Paclitaxel is a microtubule-stabilizing and apoptosis-inducing drug that is commonly used to treat metastatic breast cancer, although the mechanism of paclitaxel-induced apoptosis remains incompletely understood. Furthermore, adhesion molecule expression is attenuated on mouse mastocytoma and human leukemia cells that survive short-term culture in the presence of paclitaxel. In the present study we show that MDA-MB-435 human breast carcinoma cells that survived culture for 72 h in the presence of submaximal cytotoxic concentrations of paclitaxel (0.02 and 0.01 microg/ml) showed decreased expression of the adhesion molecule ICAM-1. Paclitaxel treatment of MDA-MB-435 cells was associated with the generation of reactive oxygen species (ROS), dissipation of mitochondrial transmembrane potential, and the activation of caspase-3. The antioxidant glutathione protected MDA-MB-435 cells from paclitaxel-induced cytotoxicity and reduced ICAM-1 expression. In addition, a selective inhibitor of caspase-3 (Z-DEVD-FMK), as well as a pan-caspase inhibitor (Z-VAD-FMK), partially prevented the decrease in ICAM-1 expression observed following paclitaxel treatment, but did not protect against paclitaxel-induced cytotoxicity. We conclude that the paclitaxel-induced reduction in ICAM-1 expression by MDA-MB-435 breast carcinoma cells is both ROS- and caspase-dependent, whereas paclitaxel-induced cytotoxicity is ROS-dependent and does not involve caspases. Decreased ICAM-1 expression by breast carcinoma cells that survive paclitaxel treatment may negatively impact on cytotoxic lymphocyte-mediated destruction of paclitaxel-resistant breast cancer cells in the context of chemo-immunotherapy or chemo-adoptive immunotherapy.

TGF-beta1 down-regulates ICAM-1 expression and enhances liver metastasis of pancreatic cancer

Article

Full-text available

Feb 2006

In order to study the regulation of adhesion-molecule expression by cytokines, we have investigated the effect of transforming growth factor-beta1. (TGF-beta1) on the expression of intercellular adhesion molecule-1 (ICAM-1) in human pancreatic cancer cell lines. By using three pancreatic cancer cell lines, SW1990, CAPAN-2 and PANC-1, the effect of TGF-beta1 on expression of ICAM-1, cancer cell immunogenicity and liver metastasis were investigated. Cell surface ICAM-1 expression by ELISA on three cell lines were all reduced significantly by following incubation with various concentrations of TGF-beta1 and down-regulation of ICAM-1 expression was also observed at the mRNA level. Corresponding to the down expression of ICAM-1, the adhesion of peripheral blood mononuclear lymphocytes (PBMLs) to cancer cells and cancer cell cytotoxicity during co-culture with PBMLs were remarkably decreased by treatment with TGF-beta1. Furthermore, enhanced liver metastatic potential by in vivo splenic injection was observed in CAPAN-2 cells pretreated with TGF-beta1. Since decreased expression of ICAM-1 has been known to contribute to cancer cell escape from immunologic recognition and cytotoxicity by effector cells, the present results indicate that unknown function of TGF-beta1 in the tumor progression and metastasis of pancreatic cancer.

ChemInform Abstract: Inhibition of LFA-1/ICAM-1 and VLA4/VCAM-1 as a Therapeutic Approach to Inflammation and Autoimmune Diseases

Article

May 2010
ChemInform

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Inhibiton of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune disease

Article

Mar 2002

This review focuses on providing insights into the structural basis and clinical relevance of LFA-1 and VLA-4 inhibition by peptides and small molecules as adhesion-based therapeutic strategies for inflammation and autoimmune diseases. Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses. Leukocyte function-associated antigen (LFA-1, alpha(L)beta(2), and CD11a/CD18) and very late antigen (VLA-4, alpha(4)beta(1), and CD49d/CD29) are members of integrin-type CAM that are predominantly involved in leukocyte trafficking and extravasation. LFA-1 is exclusively expressed on leukocytes and interacts with its ligands ICAM-1, -2, and -3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune systems. VLA-4 is expressed mainly on lymphocyte, monocytes, and eosinophils, but is not found on neutrophils. VLA-4 interacts with its ligands VCAM-1 and fibronectin (FN) CS1 during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, psoriasis, transplant-rejection, and allergy. Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression. LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases. The therapeutic intervention of mostly mAb-based has been extensively studied. However, due to the challenging relative efficacy/safety ratio of mAb-based therapy application, especially in terms of systemic administration and immunogenic potential, strategic alternatives in the forms of peptide, peptide mimetic inhibitors, and small molecule non-peptide antagonists are being sought. Linear and cyclic peptides derived from the sequences of LFA-1, ICAM-1, ICAM-2, VCAM-1, and FN C1 have been shown to have inhibitory effects in vitro and in vivo. Finally, understanding the mechanism of LFA-1 and VLA-4 binding to their ligands has become a fundamental basis in developing therapeutic agents for inflammation and autoimmune diseases.

Deficiences in phenotype expression and function of dentritic cells from patients with early breast cancer

Article

Full-text available

Feb 2006
EUR J MED RES

Monocytes derived from patients with early breast cancer (EBC) have shown functional deficiencies. These functional deficiencies are characterized by changes in phenotype and morphology. We have expanded these investigations to dendritic cells generated from monocytes from patients with early breast cancer. - Peripheral blood from 36 patients with EBC and from 26 healthy age-matched women was drawn and prepared for ex vivo generation of dendritic cells (DC) by incubation with granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL4). The phenotype of DC was examined by flow-cytometry. T cell - proliferation was induced with tetanus toxoid pulsed autologous dendritic cell. - Dendritic cells generated from monocytes from EBC-patients showed a significantly lower expression of the phenotype-associated antigens CD1a, CD83, CD80, CD86 and CD54 than the dendritic cells from healthy controls. T cell - proliferation in response to TT-pulsed autologous dendritic cells was significantly decreased when induced with dendritic cells from patients with early breast cancer, when compared to healthy controls. Morphologically, only dendritic cells from healthy women possessed prominent dendrites indicating maturity. - These findings indicate that dendritic cells generated from monocytes from patients with early breast cancer express an immature phenotype, exhibit immature morphology and show functional deficits when compared to the cells derived from healthy age-matched controls. Whether these findings offer a potential target for therapeutic interventions remains to be elucidated.

Tumor microenvironment (Part I): Tissue integrity in a rat model of peripheral neural cancer

Preprint

Full-text available

Mar 2025

ICAM-1 (intercellular adhesion molecule 1) and MPZ (myelin protein zero) are thought to be a factor in the integrity of nerve tissues. In this report, we attempted to trace the expression of ICAM-1, responsible for cell-to-cell adhesion, and of MPZ, the main constituent of myelin sheath, in malignant tissues of the sciatic nerve (SN) in inbred male Copenhagen rats. AT-1 Cells (anaplastic tumor 1) were injected in the perineurial sheath, and tissues of the SNs were collected after 7, 14 and 21 days and compared to a sham-operated group of rats (n = 6 each). Tissues were sectioned and histologically examined, under light microscope, and stained for measuring the immunoreactivity of ICAM-1 and MPZ under laser scanning microscope. The cancer model was established, and the tumor growth was confirmed. ICAM-1 showed severe decreases, proportional to the growing anaplastic cells, as compared to the sham group. MPZ revealed, however, a distinct defensive pattern before substantially decreasing in a comparison with sham. These results support the notion that malignancies damage peripheral nerves and cause severe axonal injury and loss of neuronal integrity, and clearly define the role of ICAM-1 and MPZ in safeguarding the nerve tissues.

Differentiation induction of human breast cancer cells by arsenite in combination with tetrandrine

Article

Full-text available

Dec 2019

Background: To provide novel insight into the development of new therapeutic strategies to combat breast cancer, differentiation-inducing activity of clinically achievable concentrations of arsenite (AsIII) and tetrandrine (Tetra) was investigated in breast cancer cell lines MDA-MB-231 and MCF-7. Methods: Differentiation induction of cancer cells was analyzed by flow cytometer. Alterations of genes related to differentiation, and proliferation of human normal peripheral blood mononuclear cells (PBMCs) were analyzed using western blotting and cell viability assay, respectively. Results: Exposure to Tetra alone or in combination with AsIII induced differentiation of both cells characterized by upregulation of ICAM-1, downregulation of Her2/neu. In comparison with MCF-7, the combination of lower concentrations of AsIII and Tetra induced differentiation of MDA-MB-231, indicating that MDA-MB-231 cells were highly susceptible to differentiation. The differentiation occurred in parallel with activation of Erk signaling pathway, and was abolished by PD98059, a potent Erk inhibitor. Consistent with in vitro experimental results, the upregulation of ICAM-1 and the activation of Erk signaling pathway were also observed in MDA-MB-231 breast tumors in xenograft mouse obtained from our previous study. No obvious proliferation inhibition of PBMCs was observed following the exposure to AsIII combined with Tetra at the concentrations capable of inducing differentiation of MDA-MB-231 cells. Conclusion: The Erk signaling pathway may be crucially involved in the differentiation induction of breast cancer cells in vitro and in vivo. Collectively, our results suggest that the combination can probably serve as promising candidates for the development of novel therapeutic approaches for different types of breast cancer.

CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes

Article

Full-text available

Sep 2016

Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fc? receptors (Fc?Rs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the Fc?RIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16- expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated ?2-integrins and induced TNF? secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNF?-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFN?, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.

Downregulation of human intercellular adhesion molecule-1 attenuates the metastatic ability in human breast cancer cell lines

Article

Jan 2016

Intercellular adhesion molecule-1 (ICAM-1) is a cell surface glycoprotein that belongs to immunoglobulin superfamily and plays an important role in tumor cell expansion or metastasis. However, the detailed mechanisms of ICAM-1 in breast cancer remain unclear. In this study, we evaluated the expression level of ICAM-1 in breast cancer using tissue microarray and clinical tissue specimens by immunohistochemical method, and the results revealed that ICAM-1 is highly expressed in the breast cancer tissues. To investigate whether ICAM-1 can affect the metastasis ability in breast cancer, we knocked down ICAM-1 expression in breast cancer cell line MCF-7 by using lentivirus-mediated RNA interference (RNAi). As a result, we stably silenced ICAM-1 expression in MCF-7 cells by infection with lentivirus expressing green fluorescent protein (GFP), the change of metastatic ability of MCF-7 cells was assessed by wound-healing assay, Transwell assay or clone formation assay. Our results showed that silencing of ICAM-1 can inhibit the metastatic ability of MCF-7 cell lines in vitro significantly, and the decreased migration and invasion was accompanied by a reduction of MMP-14. These results implying that ICAM-1 might be involved in the progression of breast cancer metastasis and lentivirus-mediated silencing of ICAM-1 might be a potential therapeutic approach for the treatment of breast cancer.

A Quantitative Perspective on Surface Marker Selection for the Isolation of Functional Tumor Cells

Article

Full-text available

Jul 2015
Breast Canc Basic Clin Res

Much effort has gone into developing fluid biopsies of patient peripheral blood for the monitoring of metastatic cancers. One common approach is to isolate and analyze tumor cells in the peripheral blood. Widespread clinical implementation of this approach has been hindered by the current choice of targeting epithelial markers known to be highly variable in primary tumor sites. Here, we review current antigen-based tumor cell isolation strategies and offer biological context for commonly studied cancer surface markers. Expression levels of the most common markers are quantitated for three breast cancer and two non-small cell lung cancer (NSCLC) lineage models. These levels are contrasted with that present on healthy peripheral blood mononuclear cells (PBMC) for comparison to expected background levels in a fluid biopsy setting. A key feature of this work is establishing a metric of markers per square micrometer. This describes an average marker density on the cell membrane surface, which is a critical metric for emerging isolation strategies. These results serve to extend expression of key tumor markers in a sensitive and dynamic manner beyond traditional positive/negative immunohistochemical staining to guide future fluid biopsy targeting strategies.

Bay11-7082 inhibits the disintegration of the lymphendothelial barrier triggered by MCF-7 breast cancer spheroids; The role of ICAM-1 and adhesion

Article

Full-text available

Oct 2012
BRIT J CANCER

Background: Many cancers spread through lymphatic routes, and mechanistic insights of tumour intravasation into the lymphatic vasculature and targets for intervention are limited. The major emphasis of research focuses currently on the molecular biology of tumour cells, while still little is known regarding the contribution of lymphatics. Methods: Breast cancer cell spheroids attached to lymphendothelial cell (LEC) monolayers were used to investigate the process of intravasation by measuring the areas of ‘circular chemorepellent-induced defects' (CCID), which can be considered as entry gates for bulky tumour intravasation. Aspects of tumour cell intravasation were furthermore studied by adhesion assay, and siRNA-mediated knockdown of intracellular adhesion molecule-1 (ICAM-1). Replacing cancer spheroids with the CCID-triggering compound 12(S)-hydroxyeicosatetraenoic acid (HETE) facilitated western blot analyses of Bay11-7082- and baicalein-treated LECs. Results: Binding of LECs to MCF-7 spheroids, which is a prerequisite for CCID formation, was mediated by ICAM-1 expression, and this depended on NF-κB and correlated with the expression of the prometastatic factor S100A4. Simultaneous inhibition of NF-κB with Bay11-7082 and of arachidonate lipoxygenase (ALOX)-15 with baicalein prevented CCID formation additively. Conclusion: Two mechanisms contribute to CCID formation: ALOX15 via the generation of 12(S)-HETE by MCF-7 cells, which induces directional migration of LECs, and ICAM-1 in LECs under control of NF-κB, which facilitates adhesion of MCF-7 cells to LECs.

Autologous T lymphocytes may specifically recognize leukaemic B cells in patients with chronic lymphocytic leukaemia

Article

Nov 2000
BRIT J HAEMATOL

This study analysed a naturally occurring specific cellular immunity against tumour cells in chronic lymphocytic leukaemia (CLL) patients. Five out of eight patients had blood T lymphocytes able to recognize spontaneously and specifically the autologous tumour B cells (proliferation assay). In these five patients, detection of cytokines by real-time reverse transcription polymerase chain reaction (RT-PCR) revealed that granulocyte–macrophage colony-stimulating factor (GM-CSF) was the most abundant cytokine gene expressed by the T cells that recognized the autologous tumour B cells. Other activated cytokine genes were -interferon (IFN), interleukin (IL)-2 and tumour necrosis factor (TNF)-, but not IL-4. This profile suggests a type 1 anti-B-CLL T-cell response. CD80 and CD54 were relatively downregulated on the native tumour B cells compared with control normal B cells. Upregulation of CD80 on the leukaemic cells was mandatory for the induction of such a specific T-cell response. CD80 and CD54 monoclonal antibodies inhibited the specific T-cell DNA synthesis proliferation. The proliferative T-cell response was either MHC class I or class II restricted (inhibition by monoclonal antibodies). The specific cytokine gene expression could be found in isolated CD4, as well as CD8, T-cell subsets. This study demonstrated the presence of a potential natural specific CD4, as well as a CD8 type 1 T-cell immunity against the leukaemic CLL tumour B cells in CLL. A further detailed analysis of the spontaneous anti-CLL T-cell immunity is warranted that may facilitate the development of effective anti-tumour vaccines in CLL.

Expression Profiling after Induction of Demethylation in MCF-7 Breast Cancer Cells Identifies Involvement of TNF-α Mediated Cancer Pathways

Article

Full-text available

Feb 2012
MOL CELLS

Epigenetic methylation change is a major process that occurs during cancer development. Even though many tumor-related genes have been identified based on their relationship between methylation and expression, few studies have been conducted to investigate the relevant biological pathways involved in these changes. To identify essential pathways likely to be affected by methylation in breast cancer, we examined a pool of genes in which expression was upregulated after induction of demethylation by 5-Aza-2'-deoxycytidine (Aza) in the MCF-7 breast cancer cell line. Genome-wide demethylation was confirmed by monitoring the demethylation of a previously known gene, SULT1A1. Overall, 210 and 213 genes were found to be upregulated and downregulated (fold change ≥ 2), respectively, in common in cells treated with 5 and 10 μM of Aza. Network analysis of these 423 genes with altered expression patterns identified the involvement of a cancer related network of genes that were heavily regulated by TNF-α in breast tumorigenesis. Our results suggest that epigenetic dysregulation of cellular processes relevant to TNF-α-dependent apoptosis may be intimately involved in tumorigenesis in MCF-7 cells.

Arsenic Trioxide and Breast Cancer: Analysis of the Apoptotic, Differentiative and Immunomodulatory Effects

Article

Full-text available

May 2002

Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia and has activity in vitro against several solid tumour cell lines, where induction of differentiation and apoptosis are the prime effects. To investigate the potential therapeutic application of As2O3 to breast cancer, we analysed the effects of As2O3 on the growth of four human breast cancer cell lines: MCF7, MDA-MB-231, T-47D and BT-20. Cells were cultured in 0.5, 2 and 5 microM AS2O3, a range of pharmacologically achievable concentrations of AS2O3. At > or = 2 microM, AS2O3 rapidly induced cell death by apoptosis in MCF7 and MDA-MB-231 while T-47D and BT-20 were partially resistant. At 0.5 microM, As2O3 was subapoptotic but induced features of differentiation consisting in upregulation of ICAM-1 (CD54), a marker of mammary epithelial differentiation, and cell cultures appeared morphologically more organized. Furthermore, we demonstrate by standard cytotoxicity assays that As2O3 treatment can augment breast cancer cell lysis by lymphokine-activated killer cells and demonstrate an important role of the ICAM-1/LFA-1 interaction in this process. This additional activity of As2O3 could translate into improved antitumour immunosurveillance in vivo. In conclusion, As2O3 induced varying degrees of differentiation, apoptosis and lysis in these model cell lines, and may be a promising adjuvant to current treatments of breast cancer by virtue of its triple apoptotic, differentiative and immunomodulatory effects.

Cytotoxic and anti-migratory effects of polyphenolic compounds on breast cancer cells by altering Jam-A, LFA-1, and VLA-4 gene expression

Article

Apr 2025
NAT PROD RES

This study represents the initial research of the effects of a combination of the largest number (13) of different polyphenic substances (PFK5120), formulated based on the propolis content on cell viability, migration and expression of lymphocyte function-associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and junction adhesion molecule A (Jam-A) in breast cancer (BC) cells. PFK5120 negatively affected cell viability at a 5% concentration as compared with unexposed ones (p < 0.001). Treatment with 20% PFK5120 for 48h down-regulated Jam-A in MCF-7 and MCF-10A, up-regulated LFA-1 in MCF-10A and MDA-MB-231, and down-regulated VLA-4 in MCF-10A and MDA-MB-231 (p < 0.001). Furthermore, migration was found to be inhibited by PFK5120 at varying doses and times. Migration was completely inhibited by 35% PFK5120 treatment in MDA-MB-231, while even lower concentrations (10%) were effective in MCF-7. Current findings indicate that PFK5120 represents a valuable natural component of BC therapy through its cytotoxic and anti-migratory effects.

Tumor Microenvironment (Part I): Tissue Integrity in a Rat Model of Peripheral Neural Cancer

Article

Jul 2024

ICAM–1 (intercellular adhesion molecule 1) and MPZ (myelin protein zero) are thought to be a factor in the integrity of nerve tissues. In this report, we attempted to trace the expression of ICAM–1, responsible for cell-to-cell adhesion, and of MPZ, the main constituent of myelin sheath, in malignant tissues of the sciatic nerve (SN) in inbred male Copenhagen rats. AT–1 Cells (anaplastic tumor 1) were injected in the perineurial sheath, and tissues of the SNs were collected after 7, 14 and 21 days and compared to a sham-operated group of rats (n = 6 each). Tissues were sectioned and histologically examined, under light microscope, and stained for measuring the immunoreactivity of ICAM–1 and MPZ under laser scanning microscope. The cancer model was established, and the tumor growth was confirmed. ICAM–1 showed severe decreases, proportional to the growing anaplastic cells, as compared to the sham group. MPZ revealed, however, a distinct defensive pattern before substantially decreasing in a comparison with sham. These results support the notion that malignancies damage peripheral nerves and cause severe axonal injury and loss of neuronal integrity, and clearly define the role of ICAM–1 and MPZ in safeguarding the nerve tissues.

The Immunomodulatory Activity of Some Maltese Medicinal Plants: Tradition, Science and Future Prospects

Chapter

Apr 2020

Aims: To review previous studies conducted on some Maltese medicinal plants for their immunomodulatory effects on lymphocytes. Methodology: Human peripheral lymphocytes were obtained from the whole blood of human healthy volunteers. Several extracts were obtained from Olea europea L., Ephedra fragilis Desf., Aster squamatus (Sprengel) Hieron., Glebionis coronaria (L.) Tzvelev, Calendula arvensis L., Carlina involucrata Poir., Dittrichia viscosa (L.) Greuter, Galactites tomentosa Moench, Inula crithmoides L., Leontodon tuberosus L., Reichardia picroides (L.) Roth, Sonchus oleraceus L. and Ecballium elaterium (L.) A. Rich. These extracts, pure metabolites and phytohaemagglutinin were tested on both resting and stimulated lymphocytes. The blastogenic transformation was monitored by morphological observations and biochemical tests using the WST-1 tetrazolium reagent and the LDH cytotoxicity assay. Results: This current study collates all previous studies. Most of the extracts tested exhibited lymphocyte activation, with the blastogenic transformation. Some extracts exhibited comparable activity to that of PHA. Metabolites showing such effects include oleuropein, ephedrine, cucurbitacin E and flavonoids. Extensive research on cucurbitacin E reveals that, in lymphocyte-cancer cell co-cultures, this metabolite induces lymphocyte activation, which in turn provokes cytotoxic effect on cancer cells. Conclusion: The effects of extracts on the lymphocytes was exhibited by several extracts. In the case of oleuropein, ephedrine and cucurbitacin E, the relationship between structure and function can be deduced. However, the extracts from the Asteraceae family contained flavonoids, but no further chemical characterization was carried out. This review recommends further chemical characterization of the extracts and in depth analysis of the mechanisms for lymphocyte activation by plant metabolites. On the other hand, this study shows the potential use of these extracts to boost the immune system, alongside chemotherapeutic agents.

Tumor mechanisms of resistance to immune attack

Chapter

Jan 2019

The immune system plays a key role in the interactions between host and tumor. Immune selection pressure is a driving force behind the sculpting and evolution of malignant cancer cells to escape this immune attack. Several common tumor cell-based mechanisms of resistance to immune attack have been identified and can be broadly categorized into three main classes: loss of antigenicity, loss of immunogenicity, and creation of an immunosuppressive microenvironment. In this review, we will discuss in detail the relevant literature associated with each class of resistance and will describe the relevance of these mechanisms to human cancer patients. To conclude, we will outline the implications these mechanisms have for the treatment of cancer using currently available therapeutic approaches. Immunotherapy has been a successful addition to current treatment approaches, but many patients either do not respond or quickly become resistant. This reflects the ability of tumors to continue to adapt to immune selection pressure at all stages of development. Additional study of immune escape mechanisms and immunotherapy resistance mechanisms will be needed to inform future treatment approaches.

Mammakarzinom

Chapter

Jan 2004

Das Mammakarzinom stellt mit etwa 23% aller malignen Erkrankungen den häufigsten Tumor der Frau dar, an dem in der westlichen Zivilisation derzeit jede achte bis jede zehnte Frau im Lauf ihres Lebens erkrankt. In den Jahren 1978–1982 sind in den 12 Ländern der EU 135.403 Frauen am Mammakarzinom erkrankt (Cancer in Europe). Die Inzidenz variiert innerhalb Europas deutlich zwischen ca. 70–100 Erkrankungenhoo.000 Frauen in den west- und nordeuropäischen und 25–40 Erkrankungenhoo.000 Frauen in den ost- und südeuropäischenden Ländern. Das mittlere Erkrankungsalter liegt zwischen 50 und 60 Jahren mit einer Kumulation zwischen dem 45. und 64. Lebensjahr und jenseits des 65. Lebensjahrs. 9% der Zunahme des Mammakarzinoms sind auf die höhere Lebenserwartung und eine Reduktion der allgemeinen Mortalität zurückzuführen (Helzlsauer 1994).Insgesamt nimmt die Inzidenz weltweit zu, zum Beispiel von 1973 bis 1990 um etwa 21% (Miller et al.1993). Die Gründe hierfür sind letztlich unklar, und können hypothetisch mit Änderungen der Risikoprofile (z. B. späte Schwangerschaften, veränderte Lebens- und Essgewohnheiten) in Verbindung gebracht werden. In enger Korrelation mit der erhöhten Inzidenz steht die Tatsache, dass seit dem Jahr 198o eine deutliche Zunahme an früh diagnostizierten Mammakarzinomen zu beobachten ist, während große (T3) Tumoren in der Häufigkeit bei Erstdiagnose zurückgegangen sind: In Österreich ist zum Beispiel der Anteil der Fälle im Stadium I von 198o bis 1991 von 40 % auf 46% gestiegen, hingegen der Fälle im Stadium II von 40 % auf 37% und der Fälle im Stadium III von 15% auf 10% zurückgegangen.

Influence on invasion ability of MDA-MB-231 by ectopic expression of BCSC-1 gene and its mechanism

Article

Jan 2014

OBJECTIVE: To transfect human breast cancer cell MDA-MB-231 with BCSC-1 (Breast cancer suppressor candidate 1) gene eukaryotic expression vector, study the influence on invasion ability of MDA-MB-231 cells by ectopic expression of BCSC-1 gene in vitro and explore its mechanisms. METHODS: pcDNA3.1/v5-HisB-BCSC-1 and pcDNA3.1/v5-HisB were transfected into wild type MDA-MB-231 cells by liposomes. pcDNA3.1/v5-HisB transfected cells group were the control group, the wild type MDA-MB-231 cells were the blank controls. The stable cell line expressing BCSC-1 protein was successfully established. Cell scratch and transwell methods were used to detect the invasion ability, real-time fluorescence quantitative PCR and immunohistochemistry method were used to detect the expressions of BCSC-1 and ICAM-1(Intercellular cell adhesion molecule 1). RESULTS: The stable cell line expressing BCSC-1 protein was successfully established. Cell scratch assay showed that the average migration distance of blank control group, control group and transgenic group were (225±18.02) μm, (236±16.46) μm and (105.33±13.61) μm respectively. The migration ability of transgenic group was significantly lower than that of the other two groups (F=60.50, P=0.002). Cell invasion experiment showed that the average number of transwell cells of bank control group, control group and transgenic group were 56.66±2.08, 63.33±4.16 and 34.67±2.52 respectively, the invasive ability of transgenic group was lower significantly than that of the other two groups (F=72.33, P=0.005). Real-time fluorescence PCR showed that BCSC-1 expression level were 2.33±1.52 and 32.66±2.51 in control group and transgenic group respectively compared with the blank control group (F=333.12, P=0.001). ICAM-1 expression level were 3.33±1.53 and 28.67±3.79 respectively, the BCSC-1 and ICAM-1expression levels in transgenic group were higher significantly compared with the other two groups (F=127.14, P=0.003). Immunohistochemistry results also indicated that the BCSC-1 and ICAM-1 expression levels were higher in cells with ectopic expression of BCSC-1. CONCLUSION: Ectopic expression of BCSC-1 gene in MDA-MB-231 cells can attenuate the invasion ability in vitro, this may be related to ICAM-1 expression.

Serum levels of adhesion molecules ICAM-1, VCAM-1, and E-selectin in Egyptian patients with metastatic breast cancer: Clinical and biological correlations

Article

Jan 2002

Background: Cellular adhesion molecules mediating homotypic and heterotypic cellular interactions have been implicated in various stages of tumor progression and metastases. Soluble variants-detected in the serum of the cellular adhesion molecules intercellular adhesion molecule ICAM-1, Vascular cell adhesion molecule VCAM-1, and E-Selectin have recently been described in various malignancies including breast cancer. Patients and Methods: Serum levels of ICAM-1, VCAM-1, and E-Selectin were determined in 50 consecutive metastatic breast cancer patients (32 cases with recurrent disease and 18 presenting with metastatic disease at the start) before treatment as well as in 30, age matched healthy controls using an (ELISA). Correlation with clinical characteristics and prognostic factors had been attempted. Results: For the patients group (50 cases), the mean value for E-selectin (38.1+14.8 ng/ml) and ICAM (442.5+68.2 ng/ml) but not VCAM (162+71.3 ng/ml) were higher than the control group and the difference was statistically significant (P = 0.008, P = 0.00003, P = 0.9 respectively). E-selectin levels were higher in patients with more than one site of disease, lung metastases, bone metastases, previous DFI of less than 12 month duration, those with progressive disease (P = 0.04, 0.4, 0.4, 0.2, 0.8, 0.06 respectively). ICAM-1 level were higher in those with soft tissue metastases rather than visceral metastases, and in those, who do not respond to treatment but the increases did not reach statistical significance. Conclusion: High serum levels of ICAM-1, E-Selectin are further documented in patients with metastatic breast cancer. Elevation of E-Selectin in patients with multiple metastatic sites might be a reflection of high tumor burden or aggressive tumor behavior. The prognostic significance of these molecules and relation to other prognostic factors remains to be determined through larger prospective studies together with correlation of serum level and expression in histological specimen, measuring expression on primary and metastatic deposits, and with longer patients follow up.

Defect of tumour necrosis factor-α (TNF-α) production and TNF-α-induced ICAM-1 - Expression in BRCA1 mutations carriers

Article

Sep 2003

Tumour necrosis factor-alpha (TNF-alpha) is a potent cytokine secreted primarily by activated cells from the monocyte/macrophage lineage which exhibits various antitumoral effects including the induction of apoptosis, necrosis, activation of lytic effector cells as well as upregulation of the expression of intercellular adhesion molecule-1 (ICAM-1) which is of decisive importance in the interaction with lymphokine activated killer cells. Previous studies from our laboratory have indicated impaired production of TNF-alpha by monocytes as well as decreased expression of ICAM-1 on monocytes derived from patients with various stages of breast cancer. In the present experiments, we have assessed spontaneous as well as lipopolysaccharide (LPS)-induced production of TNF-alpha by as well as expression of ICAM-1 on monocytes derived from healthy females with germline mutations of BRCA1 and from healthy age-matched control females. We report that monocytes derived from healthy women with various germline mutations of BRCA1 had significantly decreased spontaneous (p = 0.03) and LPS-induced (p < 0.001) production of TNF-alpha, as compared to monocytes derived from healthy age-matched control females. In contrast, no difference in LPS- or TNF-alpha-induced production of interleukin-6 was found. Whereas unstimulated monocytes derived from healthy women with germline mutations of BRCA1 and from healthy control women had similar expression of ICAM-1, stimulation with cytokines TNF-alpha and/or interleukin-1 led to a significant increase of ICAM-1 expression on monocytes derived from control females only, but not from BRCA1 germline mutation carriers (p < 0.001). We conclude that the presence of germline mutations of BRCA1 was associated with a selective deficiency in spontaneous and LPS-induced production of TNF-alpha and of TNF-alpha-induced ICAM-1 expression on peripheral blood monocytes.

Apoptotic responsiveness of the Ewing's sarcoma family of tumours to tumour necrosis factor–related apoptosis‐inducing ligand (TRAIL)

Article

Oct 2000
INT J CANCER

We investigated the cytotoxic responsiveness of 40 cell lines derived from representatives of the Ewing's sarcoma family of tumours (ESFT), i.e., Ewing's sarcoma (ES), peripheral primitive neuroectodermal tumour (pPNET) and Askin tumour (AT), to tumour necrosis factor–related apoptosis-inducing ligand (TRAIL). Incubation with TRAIL at 100 ng/ml induced cell death at 24 hr in 19 of 26 ES, 11 of 12 pPNET and 2 of 2 AT cell lines. Half-maximal cell death concentrations (IC50 values) varied from 0.1 to 20 ng/ml. TRAIL displayed potent cytotoxic activity against freshly derived ESFT cell isolates. Cytotoxicity was associated with phosphatidylserine expression and internucleosomal DNA fragmentation, features characteristic of apoptosis. The apoptotic programme in the sensitive ESFT VH-64 cell line revealed TRAIL-induced activation of FLICE/MACH1 (caspase-8) and CPP32/Yama/apopain (caspase-3) and processing of the prototype caspase substrate poly(ADP-ribose) polymerase. In addition, TRAIL provoked a collapse of the mitochondrial transmembrane potential (ΔΨm), parallelled by a reduction in ATP levels and release of cytochrome c from mitochondria into the cytosol. Inhibition of caspase-8 and caspase-3 by zIETDfmk and zDEVDfmk, respectively, substantially prevented TRAIL-induced apoptosis. However, zIETDfmk, but not zDEVDfmk, reduced TRAIL-mediated ΔΨm dissipation, indicating that TRAIL causes mitochondrial dysfunction through caspase-8 acting upstream of mitochondria. While macromolecule synthesis inhibitors (actinomycin D, cycloheximide) augmented susceptibility to TRAIL in TRAIL-responsive cell lines, these agents did not render TRAIL-resistant cell lines susceptible to TRAIL. However, the proteasome inhibitor MG132 sensitised to TRAIL in resistant cell lines. Collectively, these results show that TRAIL initiates effective death in the vast majority (80%) of cell lines derived from ESFT. Since TRAIL provoked cell death in ESFT ex vivo, this cytokine may be a promising drug for the treatment of ESFT in vivo.Int. J. Cancer 88:252–259, 2000. © 2000 Wiley-Liss, Inc.

Breast Cancer Progression: A “Vicious Cycle” of Pro-Malignancy Activities is Mediated by Inflammatory Cells, Chemokines and Cytokines

Chapter

Mar 2006

Adit Ben-Baruch

Breast cancer progression is a multi-step process, affected by intrinsic, as well as by microenvironmental factors. The inflammatory milieu of breast tumors, comprising of cells, chemokines and cytokines, was recently suggested to have a major role in this process. The current chapter addresses the presence of these elements in breast tumors, and their roles in the malignancy and metastatic fate of breast cancer. First, the presence of Tumor-Associated Macrophages (TAM), and the array of tumor-promoting activities that they exert in breast tumors, is described. Thereafter, the inflammatory chemokines CCL2 (MCP-1), CCL5 (RANTES) and CXCL8 (Interleukin 8) are addressed, followed by description of the expression and roles of inflammatory cytokines, which are monocyte/macrophage-derived, namely Interleukin 1 (IL-1), Tumor Necrosis Factor α (TNFα) and Interleukin 6 (IL-6). Throughout the chapter, major emphasis is put on the manner by which the different inflammatory mediators cross-interact with each other, as well as with the tumor cells, together establishing an inflammatory microenvironment that consists of an extensive network of pro-malignancy activities.

Gossypol decreases tumor necrosis factor-??-induced intercellular adhesion molecule-1 expression via suppression of NF-??B activity

Article

Apr 2011

Gossypol is a yellowish polyphenolic compound originally from cotton plant, which has been shown to exert a potential for anti-cancer and anti-inflammatory effects. However, its molecular mechanism is not thoroughly understood on breast cancer cells known to highly express intercellular adhesion molecule-1 (ICAM-1) for their adhesion and metastasis. This study aims to investigate the effect of gossypol on tumor necrosis factor (TNF)-α-stimulated ICAM-1 via nuclear factor-kappa B (NF-κB) activity. Gossypol was shown to inhibit TNF-α-induced ICAM-1 expression and U937 cell adhesion to MDA-MB-231 and MCF-7 cells. Additionally, TNF-α-induced MDA-MB-231 cell invasion was blocked in the presence of gossypol. Chromatin immunoprecipitation analysis demonstrated that gossypol blocks NF-κB binding on the ICAM-1 promoter regions. Additionally, TNF-α-induced NF-κB activation was completely suppressed in the presence of gossypol. Gossypol did not directly suppress the binding of NF-κB to the DNA but rather inhibited the nuclear translocation of p65 and p50 via phosphorylation and degradation of IκB. We also found that gossypol suppresses NF-κB activation induced by a wide variety of agents, including taxol, okadaic acid, and phorbol myristate acetate. Taken together, gossypol effectively inhibited TNF-α-induced ICAM-1 expression via the suppression of NF-κB activation and in vitro adhesion and invasion in human breast cancer cells.

Expression of intercellular adhesion molecule (ICAM)-1 or ICAM-2 is critical in determining sensitivity of pancreatic cancer cells to cytolysis by human γδ-T cells: Implications in the design of γδ-T- cell-based immunotherapies for pancreatic cancer

Article

Nov 2008
J GASTROEN HEPATOL

gammadelta-T cells can recognize and kill malignant cells, particularly those of epithelial origin, through mechanisms which do not require the recognition of tumor-specific antigens (innate immune response). This natural ability of gammadelta-T cells to kill tumor cells in a tumor antigen-independent manner provides a strong rationale for developing clinical trials designed to exploit the innate antitumor properties of gammadelta-T cells. In vitro studies were carried out to asses the sensitivity of pancreatic cancer cells (MIA PaCa2, BxPC-3, PANC-1) to killing by ex vivo expanded human gammadelta-T cells. The capacity of gammadelta-T cells to bind to as well as to kill pancreatic cancer cells correlated with the degree of surface expression of key intercellular adhesion molecules (ICAM) present on pancreatic cancer cells. Moreover, pancreatic cancer cells expressing neither ICAM-1 nor ICAM-2 were bound poorly by gammadelta-T cells and were found to be resistant to gammadelta-T-cell killing. However, upon transfection of resistant cells with ICAM-1 or ICAM-2, gammadelta-T cells were then able to bind to and subsequently kill these cells. In vitro, the expression of ICAM-1 or ICAM-2 on human pancreatic cancer cells is critically important in determining the extent to which these cells are sensitive to killing by human gammadelta-T cells. Accordingly, in ongoing and future clinical studies using gammadelta-T cells for the treatment of a variety of epithelial-derived solid tumors-including pancreatic cancer-interventions intended to modulate ICAM expression on tumor cells may become important adjuncts to gammadelta-T-cell-based immunotherapies.

Cytocidal activity of PBL, LAK, and IDEC-C2B8 and expression of HLA class 1, ICAM-1, and CD20 in vincristine-resistant hematologic cell lines

Article

Jun 1999
J IMMUNOTHER

This study was designed to determine whether the cytocidal activity of immunotherapy such as cytotoxic peripheral blood lymphocytes (PBL), lymphokine-activated killer (LAK) cells, and chimeric anti-CD20 mouse/human monoclonal antibody, IDEC-C2B8, overcome vincristine (VCR) resistance in cultured cell lines derived from human leukemia/lymphoma. In addition, the relation between the susceptibility to these immunotherapies and the expression levels of HLA class 1 and ICAM-1 as well as CD20 on the cell surface was analyzed. Three of six VCR-resistant cell lines were less susceptible to PBL cytotoxicity compared with wild-type cells, whereas the susceptibility was kept in the other three VCR-resistant cell lines. Four of six VCR-resistant cell lines were less susceptible to LAK activity and the other two cell lines were as sensitive to LAK cells as their wild-type counterparts. There was no correlation between the susceptibility for PBL cytotoxicity and the expression of HLA class 1 in both wild and VCR-resistant cells. In contrast, ICAM-1 in the two cell lines that showed decreased susceptibility for LAK cytotoxicity disappeared, although that in one cell line increased. IDEC-C2B8 was effective only against B-cell lines expressing CD20. One cell line in which the expression of CD20 increased was nearly six times more sensitive to IDEC-C2B8 than wild type. Thus, we concluded that the resistance to VCR in some tumor cell lines is associated with modified susceptibility for immunotherapies by the different expression of target molecules from those of wild-type counterparts.

All-trans retinoic acid inhibits the growth of breast cancer cells by up-regulating ICAM-1 expression

Article

Apr 1999
J BIOL REG HOMEOS AG

All-trans retinoic acid (ATRA) is currently used in clinical trials for breast cancer, in virtue of its ability to inhibit cell growth and to promote cell differentiation. Elucidation of the molecular mechanism(s) underlying the pleiotropic pharmacological activity of ATRA is of fundamental relevance for an effective use of the compound in clinics. This paper reports on the effects of ATRA treatment on the cell surface expression of a panel of adhesion molecules known to regulate the interactions between the effectors of the immune system and tumor targets. Results indicate that breast cancer (BC) cell lines exposed to ATRA selectively up-modulate the surface expression of ICAM-1/CD54, a molecule regulating cell/cell contacts. Such effect could be reproduced in all the BC cell lines analyzed, independently of their hormone receptor status, indicating that estrogens and progesterone are irrelevant in this process. The regulatory effects on ICAM-1 expression are time- and dose-dependent and reversible. Moreover, other differentiating and proliferating agents comparatively tested, e.g. dimethyl sulfoxide, estradiol or dexamethas one, are ineffective, indicating that ICAM-1 up-modulation is uniquely featured by ATRA. A second observation is that ATRA treated cells are, only apparently, less sensitive to lysis by lymphocytes activated by IL-2, as determined by means of a standard 51Cr release assay. In fact, notwithstanding this effect, a marked reduction in the ability to form colonies was highlighted in ATRA treated versus control lines after incubation with LAK. Finally, the clonogenic killing effect could be reversed using anti-CD54 mAbs as blocking tools, indicating that ICAM-1 plays a key role in the phenomena.

Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu

Article

Nov 1999
EXP HEMATOL

Treatment of advanced breast cancer with autologous stem cell transplantation is limited by a high probability of disease relapse. In clinical trials, interleukin 2 (IL-2) alone can expand natural killer (NK) cells in vivo and increase their cytotoxic activity against breast cancer cell lines, but this increase is modest. Understanding the mechanisms that mediate NK cell lysis of breast cancer targets may lead to improvements of current immunotherapy strategies. NK cells from normal donors or patients receiving subcutaneous IL-2 were tested in cytotoxicity assays against five breast cancer cell lines. The role of adhesion molecules and antibodies that interact through Fc receptors on NK cells was explored. NK cell lysis of breast cancer targets is variable and is partially dependent on recognition through ICAM-1 and CD18. While blocking CD2 slightly decreased cytotoxicity, contrary to expectations, an antibody against CD58 (the ligand for CD2), failed to block killing and instead mediated an increased cytotoxicity that correlated with target density of CD58. The CD58 antibody-enhanced killing was dependent not only on FcRgammaIII but also on CD2 and ICAM-1/CD18. To further elucidate the mechanism of this CD58 antibody-dependent cellular cytotoxicity (ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized antibody against HER2/neu, mediated potent ADCC against all the HER2/neu positive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin ADCC was minimally affected by blocking antibodies to CD2 or ICAM-1/CD18, which suggests a different mechanism of action. This study shows that multiple mechanisms are involved in NK cell lysis of breast cancer targets, that none of the targets are inherently resistant to killing, and that two distinct mechanisms of ADCC can target immunotherapy to breast cancer cells.

Marincola, F.M., Jaffee, E.M., Hicklin, D.J. & Ferrone, S. Escape of human solid tumors from T-cell recognition: Molecular mechanisms and functional significance. Adv. Immunol. 74, 181-273

Article

Feb 2000
ADV IMMUNOL

Publisher Summary It is known for some time that malignant transformation of human cells may be associated with the appearance of tumor associated antigens (TAA). Decades of research have been aimed at the identification of TAA that can serve as targets for the immunotherapy of malignant diseases. The dramatic progress in the understanding of molecular basis of target cell recognition by cytotoxic T lymphocytes (CTL) has provided the background to design effective strategies to identify TAA recognized by CTL on tumor cells. The extensive application of these strategies by a number of investigators has resulted in the identification of various families of TAA on various types of solid tumors. Mouse tumor models have played an important role in elucidating the mechanisms by which the immune system interacts with tumor cells and eradicates cancer. The second line of evidence is represented by the phenomenon of a “mixed response.” A mixed response occurs rather frequently in patients with metastases, although its actual frequency is not documented. Mixed responses are characterized by the different behavior of synchronous metastases in response to T cell-based immunotherapy. This important finding suggests that TAA-specific CTL may be present in some cancer patients but are unable to attack tumor cells due to the presence of inhibitory receptors.

Differential levels of soluble intercellular adhesion molecule-1 (sICAM-1) in early breast cancer and benign breast lesions

Article

Dec 1999

To date, no soluble markers can discriminate benign from malignant breast lesions; therefore, to assess the diagnostic potential of circulating intercellular adhesion molecule-1 (sICAM-1), serum concentrations of sICAM-1 were quantitated in 230 consecutive patients that underwent surgery for breast neoplasias, utilizing an enzyme-linked immunosorbent assay. Histological diagnosis revealed that 177 patients had breast cancer and 53 had a benign breast disease. In the cancer patient group, 90 subjects had pT1 tumors without (pT1N0M0, n = 46) or with (pT1N1M0, n = 41; pT1N2M0, n = 3) regional lymph node metastases. Mean levels of serum sICAM-1 of patients with pT1 breast cancer, without or with regional lymph node involvement, were significantly (P < 0.05) higher than those of patients with benign breast lesions and of 49 age-matched control subjects. Elevated levels of serum sICAM-1 were detected in 27/90 (30%) pT1 breast tumors and in 1/53 (2%) benign breast lesions; thus, among subjects with high levels of sICAM-1, 96% had breast cancer. No significant correlation was found between levels of serum sICAM-1 and breast cancer progression. These observations, altogether, suggest that in the presence of a suspicious breast neoplasm the quantitative analysis of serum sICAM-1 can orient clinical diagnosis towards malignancy.

Intercellular Cell Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, and Regulated on Activation Normal T Cell Expressed and Secreted Are Expressed by Human Breast Carcinoma Cells and Support Eosinophil Adhesion and Activation

Article

Aug 2000

Eosinophils are usually associated with parasitic and allergic diseases; however, eosinophilia is also observed in several types of human tumors, including breast carcinomas. In this study we examined several human breast carcinoma cell lines for adhesion molecule expression and the ability to bind and activate eosinophils. MDA-MB-435S and MDA-MB-468 cells constitutively expressed both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and this expression was enhanced by treatment with tumor necrosis factor-alpha (TNF-alpha). BT-20 and SK-BR-3 cells only expressed ICAM-1 or VCAM-1 after stimulation with TNF-alpha. Eosinophils constitutively bound to MDA-MB-435S cells, but not to BT-20 cells. Stimulation with TNF-alpha slightly enhanced eosinophil adhesion to MDA-MB-435S cells and dramatically increased adhesion to BT-20 cells. Greater than 80% of eosinophil adhesion to these cell lines was blocked with an anti-alpha4-integrin monoclonal antibody. Both MDA-MB-435S and BT-20 cells also released eosinophil activator(s). Supernatants from TNF-alpha-treated, but not control-treated, cell lines increased eosinophil adhesion to fibronectin and increased eosinophil transmigration across fibronectin-coated transwell plates. Enzyme-linked immunosorbent assays showed that TNF-alpha-stimulated breast carcinoma cells released the chemokine regulated on activation, T cell expressed and secreted (RANTES). Addition of an anti-RANTES antibody to breast carcinoma cell supernatants partially blocked eosinophil activation suggesting that RANTES in these supernatants was participating in eosinophil activation. These data show that TNF-alpha-stimulated breast carcinoma cells express mediators that can both bind and activate eosinophils, suggesting a mechanism for eosinophil localization to breast carcinoma sites.

Defective Antigen Presentation Resulting from Impaired Expression of Costimulatory Molecules in Breast Cancer

Article

Nov 2000

Previous experiments from our laboratory have shown that immune mechanisms aiming at the destruction of tumour cells including the recognition of target cells and their elimination via the expression of intercellular adhesion molecule-1 (ICAM-1; CD54), the production of tumour necrosis factor-alpha (TNF-alpha) by monocytes and appropriate function of lymphocyte subpopulations were defective in breast cancer. Previous observations were extended to assess expression levels and regulatory mechanisms of costimulatory molecules CD54, CD80 and CD86 on monocytes derived from patients with early breast cancer (EBC). In addition, antigen presentation by antigen-presenting cells (APC) was analyzed within this context. We report that monocytes derived from patients with EBC exhibited significantly decreased expression levels of CD54 (p = 0.0002), CD80 (p = 0.009) and CD 86 (p = 0.002) compared with monocytes derived from healthy females. Simultaneously, lipopolysaccharide (LPS)-induced TNF-alpha production of monocytes was found to be defective in patients with EBC. Finally, T-cell proliferation in response to tetanus toxoid (TT) was significantly decreased in patients with EBC compared with healthy control females (p < 0.0001). Furthermore, T-cell proliferation in response to TT-pulsed APC derived from healthy controls was significantly inhibited in the presence of anti-CD54 and/or anti-CD80 antibodies in a dose-dependent manner, thus corroborating the necessity of the presence of CD54 and CD80 as costimulatory molecules in the present setting. We conclude that monocytes derived from patients with EBC showed a simultaneous defect of expression of CD54 and its regulation via TNF-alpha, CD80 and CD86 as well as T-cell proliferation following exposure to TT-pulsed APC. Based upon these findings, it is speculated that defects in costimulatory molecule expression might contribute to tolerance of the immune system towards the presence of malignant cells in patients with EBC.

Detection of minimal residual disease in patients with cancer: A review of techniques, clinical implications, and emerging therapeutic consequences

Article

Feb 2000

The issue of minimal residual disease (MRD) manifesting itself by the presence of undetected disseminated isolated tumor cells in both tissues and hematopoietic autografts from patients with early-stage malignancies or from patients in clinical complete remission has been discussed widely during the last decade. Based on the current understanding of the pathogenesis of malignancy, disseminated tumor cells persisting after conventional oncologic treatment modalities or after reinfusion of contaminated autologous hematopoietic cells constitute the source of subsequent recurrence of disease. Accordingly, much emphasis is placed on the detection and characterization of disseminated isolated tumor cells in both basic and clinical research. This effort is aimed at a better understanding of the processes of metastasis and tumor dormancy and, ultimately, the estimation of prognosis, molecular monitoring, and the design of new therapeutic agents in oncology. In our review, we used computerized (MEDLINE, Embase) and manual searches to summarize laboratory and clinical data concerning MRD focusing on the issue of MRD in solid malignancies. We give a detailed overview of the methods used for the detection and molecular characterization of disseminated tumor cells and of the prevalence and prognostic significance of the detection of MRD in patients and hematopoietic autografts. Finally, we discuss the emerging therapeutic consequences of the detection of disseminated tumor cells, with special emphasis on the therapeutic potential of antibodies. We conclude that the detection of MRD represents a hallmark for the diagnosis, monitoring, and treatment of malignant conditions in future clinical trials.

T-cell-directed cancer vaccines: mechanisms of immune escape and immune tolerance

Article

Jun 2001

Recent clinical trials using vaccines directed toward tumour-associated antigens (TA) have shown the increasing capacity of vaccines to cause immunologic responses. In fact, strongly reactive TA-specific cytolytic T-lymphocytes and tumour-infiltrating lymphocytes (TIL) can be identified and expanded ex vivo from patients with metastatic melanoma vaccinated with melanoma-associated antigens. Paradoxically, this strong immunological response does not correlate with clinical tumour regression. Proposed mechanisms responsible for this glaring inconsistency are numerous and varied; systemic immunosuppressive as well as local mechanistic factors are implicated. In this review we will critically evaluate the possible mechanisms that allow tumours to escape immune destruction and be tolerated by the immune system. In addition, strategies that may allow further insight into the biology of tumour rejection are discussed, in the hope of deepening the understanding of this phenomenon and enhancing its therapeutic potential.

LIGHT stimulates IFNγ-mediated intercellular adhesion molecule-1 upregulation of cancer cells

Article

May 2003
HUM IMMUNOL

Intercellular adhesion molecule-1 (ICAM-1) works as one of the ligands for activating the killing activity of natural killer (NK) cells and cancer specific cytotoxic T lymphocytes (CTL). Expression of ICAM-1 enhances lymphocyte adhesion to the cancer cells in vivo. Cancer cell lines express significantly lower level of ICAM-1 than that of normal epithelium or benign cells. Overexpression of LIGHT (LIGHT: homologous to lymphotoxins, indicating inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator [HVEM/TR2]) in MDA-MB-231 human breast cancer cells was observed to suppress tumor growth in vivo. In order to elucidate the mechanisms how LIGHT overexpression could trigger tumor suppression, the expression level of a panel of cell surface makers CD54, CD56, CD95, and CD119 was investigated in a group of cancer cells. Flow cytometry analysis results demonstrate that LIGHT gene expression in cancer cells can greatly increase ICAM-1 expression level, IFNgamma alone can stimulate cancer cells to express ICAM-1, which can be highly augmented by LIGHT in a dose-dependent manner. This upregulation of ICAM-1 expression is not only at ICAM-1 protein trafficking level on cell surface as demonstrated by flow cytometry analysis, but also at ICAM-1 total protein level as confirmed by Western blot. There is no difference of expression level among these cancer cell lines for the other three cell surface markers: CD56, CD95 (Fas), and CD119. It was confirmed that LIGHT enhancement upregulation of ICAM-1 expression is at least STAT1 and JAK1 dependent by using STAT1-deficient U3A and JAK1-deficient E2A4 cells. These findings suggest that LIGHT-induced inhibition of tumor growth is highly correlated with its upregulation of ICAM-1 expression.

ICAM-1 Mediated Tumor-Mesothelial Cell Adhesion is Modulated by IL-6 and TNF-α: A Potential Mechanism by Which Surgical Trauma Increases Peritoneal Metastases

Article

May 2003

Peritoneal metastases frequently occur in different gastrointestinal cancers and have a poor prognosis. It is known that surgical injury promotes tumor growth and local recurrence rates and also the degree of surgical trauma correlated with the amount of tumor implantation into the peritoneum. The mechanism that mediates tumor cell adhesion to the mesothelium is not fully understood. This study investigates the role of ICAM-1, an important mediator of trans-mesothelial leucocyte migration, in tumor-mesothelial interactions as the initial step in the development of peritoneal recurrence using an in vitro model incorporating mesothelial cell monolayer derived from omental samples. We also investigate how the cytokines interleukins 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) modulate this process. We demonstrate that ICAM-1 blockade reduces the ability of both pancreatic and colonic cancer cell lines to adhere to the mesothelium. Preincubation of the mesothelial cell monolayer with either IL-6 or TNF-alpha enhances tumor cell adhesion, and this is associated with an increased expression of ICAM-1. Mesothelial CD44 expression, which has previously been implicated in this process, was unaffected by these cytokines. The use of an inhibitory monoclonal antibody against ICAM-1 attenuated the enhanced adhesion mediated by IL-6 or TNF-alpha. This study suggests that mesothelial ICAM-1 plays a role in the adhesion of tumor cells to the peritoneum in the development of peritoneal metastases.

Mechanisms of resistance to natural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia

Article

Apr 2005
EXP HEMATOL

Natural killer (NK) cell-mediated cytotoxicity contributes to the innate immune response against numerous malignancies, including leukemias. Acute lymphoblastic leukemias (ALL) often display a high degree of resistance, the mechanisms of which have not been elucidated. We used the well-characterized NK cell line NK-92 as a model to investigate whether mechanisms commonly implicated in tumor escape from NK cell killing are relevant for ALL. We demonstrate selective resistance of B-precursor ALL to NK-92 cytotoxicity even in the absence of inhibitory killer cell immunoglobulin-like receptors (KIR), except for KIR2DL4. We also show that human leukocyte antigen-G, a ligand of KIR2DL4, expressed on a subset of ALL, does not mediate resistance of NK-cell mediated lysis. Similarly, intracellular adhesion molecule/lymphocyte function-associated antigen-1 interaction did not contribute significantly to resistance. In contrast the NK-sensitive T-ALL (MOLT-4) expressed moderate amounts of MHC class I chain-related gene AB (MICA/B) a ligand for the NK cell activating receptor NKG2D, while expression of MICA/B was absent in resistant B-ALL cell lines. The NK cell-resistance of B-lineage ALLs does not appear to involve inhibitory mechanisms, but suggests deficient NK cell activation. Thus, immunostrategies designed to enhance ALL sensitivity toward NK cell-mediated cytotoxicity should focus on mechanisms of NK cell activation.

Involvement of visinin-like protein-1 (VSNL-1) in regulating proliferative and invasive properties of neuroblastoma

Article

Full-text available

Nov 2007
CARCINOGENESIS

Tumor growth and metastasis require that tumor cells must have either the potential to shift genetically or epigenetically between proliferative and invasive phenotypes or both phenotypes simultaneously. In the present study, we demonstrated that neuroblastoma growth and invasion were distinct processes that were carried out by proliferative and invasive phenotypes of tumor cells, respectively. Two subpopulations from human neuroblastoma cell line were isolated: highly invasive (HI) cells and low-invasive (LI) cells. HI and LI cells had different proliferative rate and metastatic ability in vitro and in vivo. In addition, they had distinct activated signal pathways and sensitivities to chemotherapy drugs. Affymetrix microarray and quantitative reverse transcriptase-polymerase chain reaction revealed that visinin-like protein-1 (VSNL-1) mRNA in HI cells was significantly higher than that in LI cells. We also observed that VSNL-1 was over-expressed in tumor specimens from patients with distant organ metastases compared with those without metastases. Furthermore, the invasive and proliferative phenotypes of neuroblastoma cells could be exchanged by regulation of VSNL-1 expression in vitro and in vivo. Up-regulation of VSNL-1 potentiated the anoikis-resistant ability of neuroblastoma cell. The expression of anoikis inhibitor TrkB, intracellular adhesion molecule 1, major histocompatibility complex class I, CD44 and CD44v6 was associated with VSNL-1 level. These results suggested that distinct roles of proliferative and invasive phenotypes contributed to neuroblastoma progression and strongly demonstrated that VSNL-1 played a very important role in neuroblastoma metastasis.

Beyond angiogenesis: The role of endothelium in the bone marrow vascular niche

Article

Feb 2008
TRANSL RES

Specific tissue microenvironments, or niches, are critical for homing and maintenance of both stem cells and tumor cells in vivo. Little is known, however, about the molecular interactions between individual cells within these microenvironments. Recent studies that describe a newly identified hematopoietic stem and tumor cell vascular niche in the bone marrow (BM) suggest a critical role for vascular endothelial cell signaling and raise the possibility that bidirectional interactions of these cells with the vasculature regulate the niche dynamically. The mechanisms that govern hematopoietic stem cell (HSC)/tumor cell cross-talk with endothelial cells provide a promising new direction for future studies. Here we review recent advances that open new avenues of study in this field.

Investigation of the mechanisms of tissue factor-mediated evasion of tumour cells from cellular cytotoxicity

Article

Oct 2008

We previously reported that overexpression of tissue factor (TF) protected HT29 tumour cells from cellular cytotoxicity through a mechanism requiring the presence of the cytoplasmic domain of TF. In this investigation the mechanism of TF-mediated immune evasion has been examined. The influence of alanine-substitution at Ser253 and Ser258 of TF (TF(Ala253) and TF( Ala258)) on the induction of cytotoxic evasion, as well as expression of vascular cell adhesion molecule-1 and intra-cellular adhesion molecule-1 (VCAM-1 and ICAM-1) was investigated. Moreover, we examined the effect of transfection of four 20-mer peptides, corresponding to the C-terminal residues of TF, with different phosphorylation states, on promotion of evasion from cell cytotoxicity. Cells overexpressing TF(Ala258) and to a lesser extent overexpressing TF(Ala253,) exhibited a reduced ability to evade cellular cytotoxicity compared to cells overexpressing the wild-type TF. Furthermore, the increase in protection acquired was greatest on transfection of Ser258-phosphsorylated form of the cytoplasmic peptide, lower in double-phosphorylated and Ser253-phosphorylated peptides respectively, and lowest in the unphosphorylated form. Finally, the expression of VCAM-1 mRNA as well as surface antigen was reduced on overexpression of TF(wt) but was partially reverted in the cells transfected to overexpress TF(Ala253) or TF(Ala258). These data show that the phosphorylation of TF at Ser258 and to a lesser extent Ser253, plays an essential role in the protective influence of TF on immune evasion by tumour cells, and that the mechanism could involve the downregulation of key surface antigens, such as adhesion proteins, involved in cell:cell interaction.

Distribution of a putative cell surface receptor for fibronectin and laminin in the avian embryo

Article

Full-text available

Sep 1986

Danuta Krotoski

The cell substratum attachment (CSAT) antibody recognizes a 140-kD cell surface receptor complex involved in adhesion to fibronectin (FN) and laminin (LM) (Horwitz, A., K. Duggan, R. Greggs, C. Decker, and C. Buck, 1985, J. Cell Biol., 101:2134-2144). Here, we describe the distribution of the CSAT antigen along with FN and LM in the early avian embryo. At the light microscopic level, the staining patterns for the CSAT receptor and the extracellular matrix molecules to which it binds were largely codistributed. The CSAT antigen was observed on numerous tissues during gastrulation, neurulation, and neural crest migration: for example, the surface of neural crest cells and the basal surface of epithelial tissues such as the ectoderm, neural tube, notochord, and dermomyotome. FN and LM immunoreactivity was observed in the basement membranes surrounding many of these epithelial tissues, as well as around the otic and optic vesicles. In addition, the pathways followed by cranial neural crest cells were lined with FN and LM. In the trunk region, FN and LM were observed surrounding a subpopulation of neural crest cells. However, neither molecule exhibited the selective distribution pattern necessary for a guiding role in trunk neural crest migration. The levels of CSAT, FN, and LM are dynamic in the embryo, perhaps reflecting that the balance of surface-substratum adhesions contributes to initiation, migration, and localization of some neural crest cell populations.

Absolute Requirement of CDll /CD18 Adhesion Molecules, FcRII, and the Phosphatidylinositol-Linked FcRIII for Monoclonal Antibody-Mediated Neutrophil Antihuman Tumor Cytotoxicity

Article

Full-text available

Apr 1992

We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.

Distribution of a putative cell surface receptor for fibronectin and laminin in the avian embryo

Article

Full-text available

Oct 1986

The Lymphocyte Function-Associated LFA-1, CD2, and LFA-3 molecules: Cell adhesion receptors of the Immune System

Article

Full-text available

Feb 1987

Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity

Article

Mar 1992

We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM- CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.

BIOLOGY OF DISEASE - ROLE OF INTEGRINS AND OTHER CELL-ADHESION MOLECULES IN TUMOR PROGRESSION AND METASTASIS

Article

Jan 1993

SM ALBELDA

Integrins: Versatility, modulation, and signaling in cell adhesion

Article

Apr 1992
CELL

Richard O Hynes

The Lymphocyte Function-Associated Lfa-1, Cd2, And Lfa-3 Molecules: Cell Adhesion Receptors Of The Immune System

Article

Jan 1987

T. Springer

Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix

Article

Dec 1992

Cancer metastasis poses the greatest challenge to the eradication of malignancy. The majority of clinical and experimental evidence indicates that metastasis is a non-random, organ-specific process. Tumor cell interaction with endothelium and subendothelial matrix constitutes the most crucial factor in determining the organ preference of metastasis. A plethora of cell surface adhesion molecules, which encompass four major families (i.e., integrins, cadherins, immunoglobulins and selectins) and many other unclassified molecules, mediate tumor-host interactions. Adhesion molecules and adhesion processes are involved in most, if not all, of the intermediate steps of the metastatic cascade. Decreased E-cadherin expression and increased CD44 expression are clearly correlated with the acquisition of the invasive capacity of primary tumor cells. Similarly, altered expression pattern of many other adhesion molecules such as upregulated expression of the laminin receptors and depressed expression of fibronectin receptors (alpha 5 beta 1) appears to be involved in tumor cell invasion into the subendothelial matrix. Tumor cell-endothelium interactions involve several well-defined sequential steps that can be analyzed by the 'Docking and Locking' hypothesis at the molecular level. Tumor cell-matrix interactions are determined by the repertoire of adhesion receptors of tumor cells and the unique composition of organ-specific matrices. Our experimental data, together with others', suggest that the integrin alpha IIb beta 3 is one of the major players in these tumor-host interactions. Tumor-host interaction is a dynamic process which is constantly modulated by a host of factors including various cytokines, growth factors and arachidonate metabolites such as 12(S)-HETE. Delineation of the molecular mechanisms of tumor-host interactions may provide additional means to intervene in the metastatic process.

Haynes, R.O. Integrins: Versatility and signaling in cell adhesion. Cell 69, 11-25

Article

May 1992
CELL

Richard O Hynes

Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.

Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity

Article

Jan 1992
CELL

Eugene C Butcher

Adhesion Receptors of the Immune System

Article

Sep 1990

Timothy A. Springer

The adhesive interactions of cells with other cells and with the extracellular matrix are crucial to all developmental processes, but have a central role in the functions of the immune system throughout life. Three families of cell-surface molecules regulate the migration of lymphocytes and the interactions of activated cells during immune responses.

Lytic effector cell function following kidney transplantation

Article

May 1987
TRANSPL P

The Leukocyte Integrins

Article

Feb 1989
ADV IMMUNOL

Cellular adhesion and recognition mechanisms are among the most basic requirements for the evolution of multicellular organisms. During the development of an embryo, cellular adhesion proteins can impart position-specific information that guide cell migration, localization, and the transfer of information between cells. As cells are triggered to differentiate to form tissues or organs, adhesion proteins help to maintain the organization and integrity of the body. The immune system is comprised of a network of cells in which cellular recognition mechanisms have been highly specialized. The function of the immune system is to distinguish self from nonself and to eliminate the latter. Two major protein families, the integrin family and the immunoglobulin superfamily, have evolved to guide cell-extracellular matrix (ECM) and cell-cell interactions for both developmental processes and immune function. The immunoglobulin superfamily, which includes the polymorphic antigen-specific receptors of lymphocytes, has recently been reviewed (1). This review will focus on the molecular biology of the leukocyte integrins, LFA-1, Mac-1, and p150,95 and their role in mediating inflammation.

Integrins: A Family of Cell Surface Receptors

Article

Mar 1987
CELL

Richard O Hynes

The Regulation of Lymphocyte Traffic

Article

Feb 1986
CURR TOP MICROBIOL

Eugene C Butcher

The distribution of lymphocytes among the tissues of the body is not random. Both the number and the representation of particular functional subsets of lymphocytes are carefully controlled, differing in each lymphoid organ or tissue in a manner that presumably reflects local immune requirements. The tissue distribution of lymphocytes is a function of lymphocyte class, of their previous history or stage of differentiation, and of their antigenic specificity. For example, those lymphocyte populations primarily responsible for humoral immunity (B cells) predominate in the spleen and in the gut-associated Peyer’s patches, whereas T cells, which are primarily regulatory and cytotoxic cells, are the major lymphocyte type in the peripheral lymph nodes and skin (Stevens et al. 1982; Streilein 1978). Functionally and antigenically defined T-cell subsets are also unequally distributed between mucosal and nonmucosal lymphoid tissues (Elson et al. 1979; Kraal et al. 1983). The distribution of certain effector and effector-precursor populations can be even more restricted: especially dramatic is the segregation of IgA- vs. IgG-expressing B cells. Surface IgA-bearing lymphocytes are highly represented in the mucosa-associated lymphoid organs, and the mucosal surfaces attract predominantly IgA-secreting plasma cells (Guy-Grand et al. 1974; reviewed by Lamm 1976). In nonmucosal sites, such as peripheral lymph nodes or the skin, IgA-bearing cells are rare, and most plasma cells secrete IgM or IgG. Lymphocytes can also segregate in vivo on the basis of antigen specificity: antigen-specific B and T cells are disproportionately represented in lymph nodes or spleen challenged with antigen (Kraal et al. 1982; Sprent 1980) and antigen-specific plasma cells accumulate in tissue sites of specific antigen deposition (Husband and Gowans 1978; Husband 1982).

Regulation of ICAM-1 (CD54) expression in human breast cancer cell lines by Interleukin 6 and fibroblast-derived factors

Article

Jul 1994

Four human breast cancer cell lines (T47D, ZR-75-1, MCF7D and HS578T) were examined for the effects of cytokines on expression of cell surface antigens. Interferon (IFN)gamma up-regulated the expression of ICAM-I (CD54) in all the cell lines and coordinately up-regulated both CD54 and CD40 expression in T47D. Tumour necrosis factor (TNF)alpha, interleukin (IL)1 alpha, IL1 beta and IL6 also up-regulated the expression of CD54 in all the cell lines but CD40 was unaffected. Levels of expression of CD11a, CD18, CD49b, CD58 and CD71 were unaltered by these cytokines. Conditioned medium (CM) generated from human fibroblasts, and in particular from foetal cells, was highly effective in up-regulating expression of ICAM-1 but not of CD40 in the breast cancer cell lines. ICAM-1 induction correlated with IL6 bioactivity in these CMs. Combinations of IL6 with other cytokines, such as IL1, resulted in further increases in ICAM-1 expression. Our observations suggest that IL6 is involved in intercellular signalling between mesenchyme and breast cancer epithelium.

Tiazofurin Induces a Down-Modulation of ICAM-1 Expression on K562 Target Cells Impairing NK Adhesion and Killing

Article

Sep 1995

Tiazofurin treatment of K562 leukemia cells in vitro depletes the metabolites of the guanylate biosynthetic pathway, inducing erythroid differentiation, that, in turn, alters the phenotypic profile. As a consequence, K562 cells possibly modify their interaction with immune cells. Here we describe the binding and killing activity of peripheral blood NK cells against differentiating K562 cells and the correlation between their altered binding capacity and ICAM-1 expression levels in differentiating K562 cells. We found that decreased percentages of NK (and T) cells were bound to differentiating K562 cells generating a decreased cytotoxic activity. This corresponded to decreased expression of ICAM-1, as detected by FACS analysis and Western blot. Erythroid differentiation, binding and killing reduction, and ICAM-1 down-modulation were completely abrogated by guanosine treatment. Tiazofurin causes a decrease in lymphocyte recognition and binding to K562 target cells. This can be ascribed to the down-modulation of ICAM-1 expression on target cells, which, therefore, can escape killing, acquiring a selective survival advantage.

Interferon-γ-induced Intercellular Adhesion Molecule-1: Expression on Human Tumor Cells Enhances Bifunctional Antibody-mediated Lysis through a Lymphocyte Function-associated Antigen-1 Dependent Mechanism

Article

Nov 1993

Antitumor x anti-CD3 bifunctional antibodies (BFAs) affect tumor cell lysis by activating and physically linking T-cells and tumor cells. Since tumor target antigen expression does not correlate with susceptibility to BFA-mediated tumor cytotoxicity, we investigated the role of cell adhesion molecules as accessory molecules. In 3 human colon tumor cell lines (LS174T, WIDR, and COLO205), recombinant interferon-gamma (rIFN-gamma) consistently increased BFA-mediated tumor cell lysis by cultured peripheral blood lymphocytes and consistently increased tumor cell expression of intercellular adhesion molecule-1 (ICAM-1). Using cell conjugation assays, we demonstrated that ICAM-1 and lymphocyte function-associated antigen-1 (LFA-1) interactions were important for effector-to-target cell conjugate formation and demonstrated that tumor cell pretreatment with rIFN-gamma enhanced cell conjugate formation. Whereas anti-LFA-1 blocked all BFA-mediated tumor lysis and conjugate formation, anti-ICAM-1 blocked only the enhancing effects of rIFN-gamma for both cytolysis and conjugate formation. Although BFAs were shown to provide effector-to-target cell bridging, LFA-1 was found to be a common critical element required for BFA-mediated cell conjugation and lysis. ICAM-1, which was augmented by rIFN-gamma, appears to be only one of several ligands interacting with LFA-1. These results provide one explanation as to why high expression of tumor-associated antigen alone does not predict the susceptibility to BFA-mediated lysis and provides further support for the concept of combined modality immune therapies.

Role of integrins and other cell adhesion molecules in tumor progression and metastasis

Article

Feb 1993

S.M. Albelda

Despite rapid advances in our understanding of the biology of cell adhesion, the data available in the literature make it is difficult to propose one simple scheme in which cell adhesion molecules can be related to tumor growth and metastasis. This difficulty can be related to a number of factors. Some of the apparently conflicting experimental results that demonstrate both enhanced or diminished tumor cell adhesion during tumor progression may be attributed to the experimental systems used. Those studies that have injected tumor cells intravenously have, in general, shown that enhanced tumor cell adhesiveness correlates with metastatic ability. It should be recognized that this experimental approach bypasses many of the early stages of the metastatic cascade and is biased towards tumor cells with an enhanced ability to form aggregates with cells in the circulation and to adhere to distant vascular sites. On the other hand, studies that have implanted tumors into animals and allowed them to grow and metastasize (spontaneous metastasis) have generally demonstrated an inverse relationship between adhesive ability and the ability to metastasize. Another major obstacle in understanding the role of CAMs in metastasis is the well known problem of tumor heterogeneity and the phenotypic instability of metastatic cells over relatively short periods of time (141). The cells that make up a metastatic focus may thus be quite different from the tumor cells that originally formed the lesion. It is quite possible that the selective pressures that initially enable a cancer cell to form a metastatic lesion may be quite different than those that later favor rapid tissue growth. The major obstacle in making any sweeping generalizations about cell adhesion molecules and tumor progression, however, is that the process of successful metastasis is inherently complex, requiring tumor cells to possess decreased adhesive interactions with surrounding cells and extracellular matrix at some points in the cascade and increased adhesive interactions at other times. Based on the information available, the following scenario can be proposed. Using the schema shown in Figure 1, successful metastasis initially requires that normal cell-cell and cell-substratum adhesion be disrupted, causing release of neoplastic cells from the primary tumor (step 1). For epithelial tumors, down-regulation of cadherins and perhaps, integrins, appear to be involved. This loss of cell adhesion must be followed by migration of tumor cells into the vascular system (step 2), a step requiring efficient cell-substratum interactions. In melanomas, this step seems to require expression of the vitronectin receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

The roleof adhesion molecules in cancer invasion and metastasis

Article

Feb 1993

Jürgen Behrens

Invasion and metastasis of tumor cells is the primary cause for the fatal outcome of cancer diseases. A striking feature of metastatic cells is the considerable flexibility in their adhesive interactions with other cells or components of the extracellular matrix. This review will describe the involvement of specific cell adhesion receptors, extracellular matrix molecules, and cell dissociating cytokines in the metastatic cascade. We will particularly focus on disturbance of intercellular adhesion as a prerequisite for the release of invasive cells from carcinomas. We suggest that cell dissociation in these tumors is accomplished by loss of function or expression of the epithelial cell adhesion molecule E-cadherin, and through the activity of cell motility factors, like scatter factor.

Cell adhesion in the immune system

Article

Apr 1993
Immunol Today

Cell adhesion molecules have an important role to play in many facets of the immune system. At a recent meeting their role in leukocyte migration, inflammation, cancer metastasis and lymphocyte development was discussed.

Role of LFA-3, ICAM-1, and MHC class I on the sensitivity of human tumor cells to LAK cells

Article

Feb 1996

Cellular adhesion molecules have been shown to be involved in tumor cell killing by cytotoxic cells such as natural killer (NK), lymphokine-activated killer (LAK), and T cells, but the precise mechanisms involved have not been clearly determined and a single target molecule has not been identified. We have examined the relative sensitivities of a panel of human tumor cell lines to LAK cell-mediated killing, in order to correlate their sensitivities with LAK cell-tumor cell binding determined by flow cytometry, and also with expression of molecules putatively involved in both the adhesion and recognition process. Two cell adhesion molecules in the immunoglobulin supergene family lymphocyte function-associated antigen (LFA-3) and intercellular adhesion molecule (ICAM-1) expression by tumor cells were examined in detail with respect to the degree of LAK cell-tumor cell conjugation and cytotoxicity. LAK sensitivity of the tumor cell lines was not clearly related to the degree of binding and correlated most strongly with the level of LFA-3 expressed on these cell lines. Major histocompatability complex (MHC) Class I antigen (Ag) expression by tumors was also examined and correlated with an inhibitory effect on LAK cell-mediated killing. Interferon-gamma(IFN) treatment of two of these tumor lines decreased their sensitivity to LAK, and treated cells exhibited a higher level of MHC Class I Ag and ICAM-1 and an increased degree of conjugation with LAK cells. These findings demonstrate roles for LFA-3, ICAM-1, and MHC Class I expression in the LAK cell-tumor cell recognition and triggering of the lytic process.

Adhesion molecules - Part 1

Article

Jul 1996

Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells

Article

May 1996

Endothelial cells (EC) recruit circulating leukocytes to sites of inflammation, partly by expression of endothelial-leukocyte adhesion molecules. Whereas the regulation of some adhesion molecules is well characterized in cultured HUVEC, similar data for microvascular human test systems are limited. We studied the cytokine-regulated expression of vascular cell adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in cultured human intestinal microvascular endothelial cells (HIMEC). E-selectin and VCAM-1 were induced, and ICAM-1 was enhanced, in a dose-dependent fashion after stimulation with IL-1beta, TNF-alpha, and LPS. Each adhesion molecule displayed characteristic time-related responses comparable to those obtained with HUVEC, and each molecule supported adhesion of leukocytes. Notable disparities between the two endothelial test systems were that 1) expression of total cellular E-selectin (but not surface membrane expression) was sustained after 72 h of IL-1beta stimulation in HIMEC, contrasting a rapid biphasic response in HUVEC; 2) LPS did not maintain prolonged expression of ICAM-1 and VCAM-1 in HIMEC; and 3) VCAM-1 protein was dose-dependently up-regulated by IL-4 in HUVEC, peaking after 8 h, while IL-4 had only a negligible effect on the expression of this protein in HIMEC. In conclusion, the regulation of these adhesion molecules appears to be somewhat different in HIMEC compared with HUVEC, and the differences from available data on skin-derived microvascular endothelial cell cultures are to some extent substantial. Our findings document the importance of using relevant endothelial cell culture systems for studies of leukocyte-endothelial cell interactions.

Intercellular Adhesion Molecule-1

Article

Feb 1996

The intercellular adhesion molecule (ICAM) 1 is an Ig-like cell adhesion molecule expressed by several cell types, including leukocytes and endothelial cells. It can be induced in a cell-specific manner by several cytokines, for example, tumor necrosis factor-alpha, interleukin-1, and interferon-gamma, and inhibited by glucocorticoids. Its ligands are the membrane-bound integrin receptors LFA-1 and Mac-1 on leukocytes, CD43, the soluble molecule fibrinogen, the matrix factor hyaluronan, rhinoviruses, and Plasmodium falciparum malaria-infected erythrocytes. ICAM-1 expression is predominantly transcriptionally regulated. The ICAM-1 promoter contains several enhancer elements, among them a novel kappa B element which mediates effects of 12-O-tetradecanoylphorbol-13-acetate, interleukin-1, lipopolysaccharide, tumor necrosis factor-alpha, and glucocorticoids. Expression regulation is cell specific and depends on the availability of cytokine/hormone receptors, signal transduction pathways, transcription factors, and posttranscriptional modification. ICAM-1 plays a role in inflammatory processes and in the T-cell mediated host defense system. It functions as a costimulatory molecule on antigen-presenting cells to activate MHC class II restricted T-cells, and on other cell types in association with MHC class I to activate cytotoxic T-cells. ICAM-1 on endothelium plays an important role in migration of (activated) leukocytes to sites of inflammation. ICAM-1 is shed by the cell and detected in plasma as sICAM-1. Regulation and significance of sICAM-1 are as yet unclear, but sICAM-1 is increased in many pathological conditions. ICAM-1 may play a pathogenetic role in rhinovirus infections. Derangement of ICAM-1 expression probably contributes to the clinical manifestations of a variety of diseases, predominantly by interfering with normal immune function. Among these are malignancies (e.g., melanoma and lymphomas), many inflammatory disorders (e.g., asthma and autoimmune disorders), atherosclerosis, ischemia, certain neurological disorders, and allogeneic organ transplantation. Interference with ICAM-1 leukocyte interaction using mAbs, soluble ICAM-1, antisense ICAM-1 RNA, and in the case of melanoma mAb-coupled immunotoxin, may offer therapeutic possibilities in the future. Integration of knowledge concerning membrane-bound and soluble ICAM-1 into a single functional system is likely to contribute to elucidating the immunoregulatory function of ICAM-1 and its pathophysiological significance in various disease entities.

Adhesion molecules-Part I. New Engl

Jan 1996
1526-1529

P S Frenette
D D Wagner

FRENETTE, P.S. and WAGNER, D.D., Adhesion molecules-Part I. New Engl. J. Med., 334, 1526-1529 (1996).

Versatility, modulation and signaling in cell adhesion

Jan 1992
11-25

HYNES, R.O., Versatility, modulation and signaling in cell adhesion. Cell, 69, 11–25 (1992).

ng TNF-a 1 ng TNF-a 10 ng TNF-a ZR-75-1 15

Table Iii
Induction

TABLE III – INDUCTION OF ICAM-1 EXPRESSION BY TNF-a Cell line 0 TNF-a 0.1 ng TNF-a 1 ng TNF-a 10 ng TNF-a ZR-75-1 15.9 6 8.0 1 23.3 6 14.0 35.2 6 5.4** 42.8 6 13.9** MCF-7 43.6 6 20.5 38.6 6 1.5 56.5 6 2.1 54.7 6 11.3

05 vs. all other cell lines; **p , 0.01 vs. 0 TNF-a Biology of disease: role of integrins and other celladhesion molecules in tumor progression and metastasis

Jan 1993
4-17

*p, 0.05 vs. all other cell lines; **p, 0.01 vs. 0 TNF-a. REFERENCES ALBELDA, S.M., Biology of disease: role of integrins and other celladhesion molecules in tumor progression and metastasis. Lab. Invest. 68, 4–17 (1993).

Decreased expression of ICAM‐1 and its induction by tumor necrosis factor on breast‐cancer cells in vitro

Abstract

No full-text available

Recommended publications

85 P - Modulation of decreased adhesion molecule expression on breast cancer cell lines in vitro