Tumor-derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts

Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, the University of Texas Southwestern Medical School, Dallas, TX, USA.
Experimental Biology and Medicine (Impact Factor: 2.17). 02/2010; 235(2):263-70. DOI: 10.1258/ebm.2009.009215
Source: PubMed


Tumor infiltration of immune cells (polymorphonuclear cells [PMNs] and macrophages) was initially thought to be an attempt by the host organism to combat malignancy. It appears, however, that certain subsets of chronically activated immune cells likely promote tumor growth, facilitate tumor cell survival and aid in metastasis. The association between tumor cells and tumor-associated PMNs has been demonstrated in several types of cancer, but the presence of tumor-associated PMNs in pancreatic cancer has not been well studied in vivo. Intercellular adhesion molecule-1 (ICAM-1) functions in cell-cell and cell-extracellular matrix adhesion and has a physiological role in PMN tight adhesion of leukocytes via interaction with the ligands LFA-1 and Mac-1. Increased ICAM-1 expression correlates with poor prognosis in pancreatic cancer. Therefore, the aim of this study was to investigate the function of ICAM-1 and tumor-associated PMNs in pancreatic cancer progression using ICAM-1-null (ICAM-1(-/-)) mice. We hypothesize that ICAM-1 null mice have decreased pancreatic cancer progression. Surprisingly, there is no significant difference in pancreatic cancer progression in wild-type versus ICAM-1 null mice. Interestingly, we found that tumor-derived ICAM-1 co-localizes with host PMNs at the leading edge of the tumor in ICAM-1 null mice. These results suggest that tumor-derived ICAM-1 is a sufficient ligand for tumor-associated PMNs and may play a role in subsequent tumor growth and metastasis.

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    • "Previous murine studies have shown that the introduction of the ICAM-1 gene into tumor cells using retroviral vectors led to enhanced antitumor responses [5]. Furthermore, numerous studies have documented a link between the immune infiltrate and response to therapy [26,27]. Vesalainen et al. found that low numbers of tumor-infiltrating lymphocytes were a sign of high risk of tumor progression and fatal disease in an analysis with 325 cases with long-term follow-up [28]. "
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    ABSTRACT: E2F1 is the gatekeeper of the cell cycle controlling an analogous balance between proliferation and cell death. E2F1 expression is elevated in advanced prostate cancer. However, it is still unclear that the roles and mechanisms of E2F1 on prostate cancers. Targeted knockdown by interferon RNA was applied on two prostate cancer and Hela cell lines to examine the inverse correlation expression of E2F1 and ICAM-1. ICAM-1 promoter reporter and ChIP assays were used for analysis of the molecular basis of transcriptional regulation of E2F1 on ICAM-1. Co-IP assays were employed for testing the protein interaction between E2F1 and NF-kappaB. Tumor xenograft mice model with E2F1 and ICAM-1-knockdown prostate cancer cells were used to investigate the effects of E2F1 and ICAM-1 on antitumor immunity. E2F1 knockdown by a specific short hairpin RNA increased gene transcription and protein expression of ICAM-1. By using wild type and a series of mutant ICAM-1 promoter luciferase constructs, the NF-kappaB binding sites were found to be important for E2F1 regulation of ICAM-1 promoter. Targeted knockdown of E2F1 did not affect expression and phosphorylation of NF-kappaB and IkappaBalpha, but facilitated NF-kappaB binding to the ICAM-1 promoter, subsequently induced ICAM-1 transcription and production in prostate carcinoma cells. Furthermore, knockdown of E2F1 inhibited tumor growth of prostate cancer in vivo through increasing the susceptibility of tumor cells to ICAM-1-mediated anti-tumor immunity including enhancement of monocyte adhesion, leucocytes infiltration, as well as cytotoxicity against tumor cells. E2F1 knockdown inhibited prostate tumor growth in vitro and in vivo through sensitizing tumor cells to ICAM-1 mediated anti-immunity by NF-kappaB modulation, highlighting the potential of E2F1 as a therapeutic target.
    Full-text · Article · Apr 2014 · Molecular Cancer
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    • "ICAM1 has a role in cell–cell and cell–extracellular matrix adhesion. ICAM1 has previously been reported to be overexpressed in pancreatic cancer, and serves as an important docking point for polymorphonuclear cells that functionally promote tumor cell metastasis [95,96]. BCAM is a laminin receptor and a member of the immunoglobulin superfamily. "
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    ABSTRACT: In the post-genomic era, it has become evident that genetic changes alone are not sufficient to understand most disease processes including pancreatic cancer. Genome sequencing has revealed a complex set of genetic alterations in pancreatic cancer such as point mutations, chromosomal losses, gene amplifications and telomere shortening that drive cancerous growth through specific signaling pathways. Proteome-based approaches are important complements to genomic data and provide crucial information of the target driver molecules and their post-translational modifications. By applying quantitative mass spectrometry, this is an alternative way to identify biomarkers for early diagnosis and personalized medicine. We review the current quantitative mass spectrometric technologies and analyses that have been developed and applied in the last decade in the context of pancreatic cancer. Examples of candidate biomarkers that have been identified from these pancreas studies include among others, asporin, CD9, CXC chemokine ligand 7, fibronectin 1, galectin-1, gelsolin, intercellular adhesion molecule 1, insulin-like growth factor binding protein 2, metalloproteinase inhibitor 1, stromal cell derived factor 4, and transforming growth factor beta-induced protein. Many of these proteins are involved in various steps in pancreatic tumor progression including cell proliferation, adhesion, migration, invasion, metastasis, immune response and angiogenesis. These new protein candidates may provide essential information for the development of protein diagnostics and targeted therapies. We further argue that new strategies must be advanced and established for the integration of proteomic, transcriptomic and genomic data, in order to enhance biomarker translation. Large scale studies with meta data processing will pave the way for novel and unexpected correlations within pancreatic cancer, that will benefit the patient, with targeted treatment.
    Full-text · Article · Apr 2014 · Journal of Translational Medicine
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    • "Ligands of LFA-1 include intercellular adhesion molecules (ICAMs; ICAM-1, -2, -3, -4, and -5) [5] and junctional adhesion molecule (JAM)-1 [6], both of which are the members of the immunoglobulin superfamily (IgSF) receptors. As one of the most biologically important ligands for LFA-1, ICAM-1 is expressed at a low constitutive level in diverse types of cells and tissues, while its expression is greatly upregulated in response to inflammation [7] and in some tumors and their stroma [8], [9], [10], [11], [12], [13], [14]. The interaction of LFA-1 and ICAM-1 is contained within the single domains called the α I domain in LFA-1 and the first N-terminal domain (D1) of ICAM-1. "
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    ABSTRACT: Intermolecular contacts between integrin LFA-1 (α(L)β(2)) and ICAM-1 derive solely from the integrin α(L) I domain and the first domain (D1) of ICAM-1. This study presents a crystal structure of the engineered complex of the α(L) I domain and ICAM-1 D1. Previously, we engineered the I domain for high affinity by point mutations that were identified by a directed evolution approach. In order to examine α(L) I domain allostery between the C-terminal α7-helix (allosteric site) and the metal-ion dependent adhesion site (active site), we have chosen a high affinity variant without mutations directly influencing either the position of the α7-helix or the active sites. In our crystal, the α(L) I domain was found to have a high affinity conformation to D1 with its α7-helix displaced downward away from the binding interface, recapitulating a current understanding of the allostery in the I domain and its linkage to neighboring domains of integrins in signaling. To enable soluble D1 of ICAM-1 to fold on its own, we also engineered D1 to be functional by mutations, which were found to be those that would convert hydrogen bond networks in the solvent-excluded core into vdW contacts. The backbone structure of the β-sandwich fold and the epitope for I domain binding of the engineered D1 were essentially identical to those of wild-type D1. Most deviations in engineered D1 were found in the loops at the N-terminal region that interacts with human rhinovirus (HRV). Structural deviation found in engineered D1 was overall in agreement with the function of engineered D1 observed previously, i.e., full capacity binding to α(L) I domain but reduced interaction with HRV.
    Full-text · Article · Aug 2012 · PLoS ONE
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