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Histopathology 03/2008; 52(3):399-402. · 3.08 Impact Factor
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ABSTRACT: Loss of CD95 expression in tumour cells occurs frequently in colon carcinoma and may be associated with disease progression. On the other hand, neo-expression of CD95L in tumour cells may contribute to immune evasion.
We aimed at further exploring the functional role and prognostic significance of the CD95/CD95L death inducing system in colon carcinomas.
CD95 and CD95L expression was examined by immunohistochemistry in 128 R0 resected UICC (International Union against Cancer) stage II/III colon carcinomas and correlated with disease free survival.
CD95 expression in tumour cells was observed in only 30 carcinomas (23.4%) whereas the others had at least a minor subpopulation of CD95 negative cells. Loss of CD95 in tumour cells was related to adverse prognosis in uni- and multivariate analysis (p = 0.046 and p = 0.036, respectively). Tumour infiltrating lymphocytes (TIL) were the major source of CD95L in colon carcinomas. CD95L+TIL were present in 83% of cases whereas CD95L was found in tumour cells in only 12% of cases. Moreover, a high rate of CD95L+TIL correlated with prolonged disease free survival in patients with UICC stage II (p = 0.05) but not in those with stage III.
Loss of CD95 in tumour cells may be an independent prognostic factor in colon carcinomas. The CD95L counterattack is not a relevant feature in colon carcinoma but CD95L+TIL may contribute to tumour control in the early stages of the disease, exerting a concurrent selection pressure in the direction of CD95 abrogation/resistance.
Gut 06/2005; 54(5):661-5. · 10.11 Impact Factor
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ABSTRACT: CD95 is a member of the tumor necrosis factor receptor family. It is constitutively expressed on the basolateral membrane of intestinal epithelial cells (IEC) and induces apoptosis when cross-linked by its natural ligand, CD95L. The significance of providing such a death-inducing mechanism in IEC is not yet clear. In recent years a multitude of studies have been published addressing the question of where and under which conditions CD95L is produced in the gut in the normal and neoplastic situation. Although some of these studies have considerably influenced our view on the role of the CD95/CD95L system, it appears necessary to critically review published data which are in part confusing and contradictory. To date compelling evidence of CD95L expression in untransformed IEC is lacking, and involvement of the CD95/CD95L system in the physiological epithelial cell turnover appears unlikely. Whereas CD95L is overexpressed in T-cells under inflammatory conditions, its significance for mucosal damage in inflammatory bowel diseases is obscured by possible redundancies in cell death mechanisms. Finally, recent data indicate that the intriguing CD95L counterattack concept in gastrointestinal tract cancer needs to be revised.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2003; 442(3):218-25. · 2.49 Impact Factor
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American Journal of Clinical Pathology 11/2001; 116(4):616-8. · 2.60 Impact Factor
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ABSTRACT: Primary mediastinal B-cell lymphoma is a locally highly aggressive but poorly disseminating tumor composed of medium sized or large cells most probably of thymic medullary origin. It has a mature B-cell phenotype, typically lacks immunoglobulin expression and has variable defects in expression of HLA-molecules. We present here a cell line, MedB-1, derived from such a tumor. As is frequently found in mediastinal B-cell lymphomas in situ, MedB-1 is CD10(-), CD19(+), CD21(-), CD22(+), CD23(+), CD25(-), CD37(+), CD38(-), CD39(+), CD40(+), CD54(+), CD95(+). Like the parental tumor, MedB-1 lacks HLA-A,B,C alpha-chains and beta(2)microglobulin and expresses HLA-D molecules at decreased levels. Both parental tumor and MedB-1 cells are clonally related as shown by immunoglobulin heavy chain gene rearrangement analysis. Unlike the parental tumor tissue, the MedB-1 cell line cytoplasmically expresses IgG/kappa in a very small subset of cells under standard culture conditions. MedB-1 does not contain any Epstein-Barr virus DNA. In a tissue adhesion assay MedB-1 cells showed an extensive binding to the medullary region of normal thymus. Altogether, MedB-1 is a suitable tool for functional and molecular analysis of this distinct lymphoma entity.
International Journal of Cancer 06/2001; 92(3):348-53. · 5.44 Impact Factor
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ABSTRACT: In recent years, some studies on the expression of CD95(Fas/APO-1) ligand (CD95L) in tissues or cells raised concerns about the specificity of the antibodies used. We therefore tested 12 CD95L antibodies for their reliability in immunocyto/histochemistry by (i) staining CD95L-transfected and control CV-1/EBNA cells and (ii) comparing staining patterns in immunohistochemically labeled tissue sections with the localization of CD95L+ cells in in situ hybridization. While G247-4, NOK-1, NOK-2, 4H9, and MIKE-1 stained CD95L-transfected cells and did not significantly bind to controls, G247-4 was the only antibody giving satisfying signals in tissue sections perfectly matching the distribution of CD95L+ cells by in situ hybridization. MAb 33, C-20, and N-20 comparably stained both transfected and control cells and showed considerable background or falsely positive staining in sections. MIKE-2, 8B8, A11, and 4A5 did not or only very faintly bind to either cells and, thus, were not tested on sections. We conclude that G247-4 is the only tested antibody that is recommendable for immunohistochemistry.
Cell Death and Differentiation 04/2001; 8(3):273-8. · 8.85 Impact Factor
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ABSTRACT: Acinar regression in chronic pancreatitis may be due to immune attack in parenchymal areas neoexpressing HLA-DR molecules. CD4+Th1 cytotoxic T cells induce apoptosis of their targets via oligomerizing CD95 (APO-1/Fas) death receptors on target cells by their CD95 ligand (CD95L). We determined the expression of CD95 and CD95L in epithelia of normal and chronically inflamed pancreatic tissues. We applied RT-PCR and Western blotting for CD95L expression profiles, serial frozen section immunohistochemistry to detect CD95, CD95L, and HLA-DR molecules, CD3, CD4, CD11c, and S-100 protein (S100p). Normal pancreases and chronic pancreatitis contain CD95L message and protein. Immunohistochemistry revealed a mutually exclusive expression of CD95 and CD95L. Physiologically, acini were CD95-/CD95L+, ducts were CD95-/CD95L-, and islets were CD95-/CD95L+. In areas of lymphohistiocytic infiltration, mainly consisting of CD3+CD4+ T cells and CD11c+, CD4+/-, S100p+ interstitial dendritic cells, and in areas of initial fibrosis, acini and ducts were HLA-DR+, acini CD95+/CD95L-, and ducts CD95+/CD95L-. Islet cells were CD95-/CD95L+ in both conditions. IFNgamma levels in protein lysates, as measured by an immunoassay, were significantly higher in chronic pancreatitis than in normal pancreas (p < 0.0003). In vitro, IFNgamma down-modulated CD95L message and protein in ASPC1 and BxPc3 pancreatic carcinoma cells. In conclusion, pancreatic epithelia differentially express CD95 and CD95L in a mutually exclusive manner. In chronic pancreatitis the CD95-/CD95L+ status is conserved in islet cells even in the vicinity of lymphohistiocytic infiltrates, whereas it is lost in acini coexpressing HLA-DR. As a potential consequence, and possibly triggered by local release of IFNgamma, CD4-Th1 cells may cognately interact with and successfully attack exocrine cells by triggering CD95 on their target without being killed by epithelial, CD95L-mediated, counterattack.
Laboratory Investigation 03/2001; 81(3):317-26. · 3.64 Impact Factor
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ABSTRACT: We report an unusual case of rhinolith in the nasal septum in an 11-year-old girl. The rhinolith was detected on X-radiographs made for the planning of an orthodontic treatment. There were no symptoms like nasal obstruction, chronic infection or epistaxis in the young patient. The histopathologic examination after surgical removal showed hyaline cartilage, local fibrosis and pronounced hemosiderosis, indicating possible prior bleeding. Therefore, an endogenic etiology of the intraseptal rhinolith, e.g. a prior trauma of the nasal septum, is assumed. A review of the literature is included.
International Journal of Pediatric Otorhinolaryngology 08/2000; 53(3):225-8. · 1.17 Impact Factor
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ABSTRACT: The tumor necrosis factor receptor (TNFR) family is a still-growing group of homologous transmembrane proteins, some of which bear an intracellular "death domain" and are able to directly mediate apoptosis. Apoptosis is induced upon trimerization of the receptors by their natural ligands' constituting the complementary TNF family. The best-characterized apoptosis-mediating TNFR family member is CD95 (APO-1/Fas). CD95 is functionally expressed on the basolateral surface of colonic epithelial cells regardless of their position along the crypt axis. The biological significance of this CD95 expression in the gut, however, is still under discussion. Although it is unlikely that the CD95/CD95L system is involved in the physiologic regeneration of the intestinal epithelium, this system may play an important role in the pathogenesis of inflammatory bowel diseases. In contrast to the normal epithelium, colon carcinoma cell lines are mostly resistant to CD95-induced apoptosis. The detection of CD95L expression in colon carcinoma cell lines has led to the concept of carcinomas as "immunoprivileged sites," where invading immune cells are killed by CD95L-expressing tumor cells. A more recently described member of the TNF family is TRAIL, which is also able to induce apoptosis. As yet, four TRAIL receptors have been cloned, two of which (TRAIL-R1 and 2) bear a death domain and mediate apoptosis, whereas two others (TRAIL-R3 and 4) lack (functional) death domains and are supposed to act as decoy receptors. Because many tumor cell lines in vitro are sensitive to TRAIL-induced apoptosis while their normal counterparts are not, TRAIL is currently under discussion as a possible anticancer therapeutic agent.
Annals of the New York Academy of Sciences 02/2000; 915:162-70. · 3.15 Impact Factor
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M Paulli, J Sträter,
U Gianelli,
M T Rousset,
M Gambacorta,
E Orlandi,
C Klersy,
T Lavabre-Bertrand,
E Morra,
C Manegold,
M Lazzarino,
U Magrini,
P Möller
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ABSTRACT: Mediastinal B-cell lymphoma (MBL) is a distinct variant of aggressive non-Hodgkin's lymphoma with characteristic clinical and biological features but less well-defined histomorphology. We reevaluated 124 biopsy specimens from 109 MBL patients of an Italian/French/German retrospective clinical study. MBL was primarily diagnosed on clinical and histological grounds in conjunction with the detection of CD20 expression by immunohistology. Cytologically, MBL features limited intralesional but considerable interindividual cytological diversity, ranging from medium-sized to very large, atypical cells. Sclerosis and necrosis are restricted to extrathymic and extranodal sites of involvement, predominantly the lung, as is angioinvasion, which predominantly affects larger vessels. The medium-sized and the large cell variants resemble marginal zone lymphoma variants, whereas the very large cell variant of MBL has not so far been found to have any extramediastinal counterpart. We conclude that MBL displays a broad morphological spectrum covering more than is implied by the term "diffuse large cell lymphoma." Because statistical analysis of cytological and histological criteria failed to correlate with prognosis in this comprehensive group of patients, we think it inadvisable further to subclassify MBL.
Human Pathlogy 03/1999; 30(2):178-87. · 2.88 Impact Factor
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ABSTRACT: CD95(Fas/APO-1)-ligand (CD95L) mediates apoptosis by trimerization of the CD95 receptor on the surface of sensitive cells. In vitro studies have shown CD95L expression mainly by activated T cells and suggested a role for CD95L in the regulation of immune responses. Little is known, however, about the cellular distribution of CD95L in situ in the normal human immune system. We investigated CD95L expression in tissue sections of the thymus, lymph node, spleen, tonsil, and gastrointestinal tract using in situ hybridization and two monoclonal antibodies. In all these organs, cells expressing CD95L message and protein were scarce and comprised scattered lymphocytes, rare nonlymphoid cells, and a subset of epithelioid endothelial cells. Surprisingly, a subset of plasma cells turned out to be the most prominent producers of CD95L, matching the reports on CD95L in myeloma cells. CD95L+ plasma cells were most numerous in the mucosa-associated lymphoid tissue. This also applied to acquired mucosa-associated lymphoid tissue in chronic gastritis in which CD95L+ plasma cells were found scattered in the lamina propria. Our data suggest that plasma cells as yet may be neglected modulators of immune responses.
American Journal Of Pathology 02/1999; 154(1):193-201. · 4.89 Impact Factor
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ABSTRACT: Apoptosis is a basic mechanism involved both in maintaining tissue homeostasis by elimination of senescent or potentially harmful cells and in the regulation of immune responses. If not properly regulated, however, it may lead to serious tissue damage. CD95(Fas/APO-1) is a surface receptor that mediates apoptosis upon oligomerization by its ligand, CD95L. The CD95/CD95L-system is one of the major effectors of cytotoxicity in inflammation with implications for both the prevention and the pathogenesis of autoimmune diseases. In primary biliary cirrhosis (PBC), an autoimmune disease, apoptosis has been repeatedly suspected to be the mechanism leading to progressive destruction of bile ducts. The role of apoptosis and its possible molecular inducers in PBC are discussed.
European Journal of Gastroenterology & Hepatology 08/1998; 10(7):539-41. · 1.76 Impact Factor
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ABSTRACT: The expression of alternatively spliced CD44 adhesion molecules has been implicated in the pathogenesis and metastasis of colorectal cancer. Using a new set of primers for exon-specific reverse transcription-polymerase chain reaction (RT-PCR) we delineated the exact exon composition of CD44 mRNAs in normal colorectal mucosa, including isolated colonic crypts, in colorectal carcinomas and in their hepatic metastases. In addition, the surface expression of CD44 isoforms was analysed by immunohistochemistry. We identified by RT-PCR eight variant transcripts expressed in colorectal carcinomas and their metastases, but also constitutively in normal colorectal epithelia. In the normal colorectal epithelium, the surface expression of CD44 standard and variant molecules was restricted to proliferating cells at the bottom of the crypts. Despite expression of these transcripts in colorectal cancers and their metastases, monoclonal antibodies specific for standard or variant epitopes encoded by exons v5 and v6 stained only a few neoplastic lesions. These data point to a differentiation-specific CD44 expression and splicing pattern in proliferating colorectal epithelia. However, they do not support a cancer- or metastasis-specific CD44 splicing pattern. Instead, cell surface availability of CD44 epitopes was reduced rather than increased in primary tumours and particularly in liver metastases.
European Journal of Cancer 07/1998; 34(7):1099-1104. · 5.54 Impact Factor
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ABSTRACT: CD95(APO-1/Fas) is a cell surface receptor that, when oligomerized by natural ligand, CD95L, or antibody, confers an apoptotic signal to apoptosis-sensitive cells. Whereas CD95 is expressed in every colonocyte of normal colon mucosa, CD95 is down-regulated or lost in the majority of colon carcinomas. To investigate the sensitivity to CD95-mediated apoptosis of normal and neoplastic colonocytes, we applied cross-linking CD95(anti-APO-1) monoclonal antibody to freshly isolated colon crypts and colon carcinoma cell lines and monitored apoptosis by DNA fragmentation and morphology. Normal colonocytes were constitutively sensitive to CD95-mediated apoptosis. All carcinoma lines were constitutively resistant but were sensitized upon pretreatment with IFN-gamma. Transcription blocking, protein synthesis, and export in carcinoma cells indicated that even low surface levels of CD95 were sufficient to efficiently transmit the signal. Despite low CD95 surface levels of non-IFNgamma-treated cells, actinomycin D, cycloheximide, and brefeldin A each sensitized all cell lines, but at different rates and kinetics. In this context, it was observed that a greatly delayed apoptotic response of SW620 cells was associated with the absence of antibody-induced CD95 capping. Phorbol 12-myristate 13-acetate inhibited CD95-mediated apoptosis by counteracting the IFNgamma-, actinomycin D-, and cycloheximide-mediated but not the brefeldin A-mediated sensitization. This phorbol 12-myristate 13-acetate-induced protection against apoptosis was completely abolished by staurosporine and by a selective protein kinase C inhibitor, Goe 6983. We conclude that, during malignant transformation, colonocytes acquire different mechanisms to escape CD95-mediated apoptosis. These include abrogation of CD95, inhibition of CD95 capping, and activation of antiapoptotic programs, both governed by and independent of protein kinase C.
Cancer Research 03/1998; 58(3):526-34. · 7.86 Impact Factor
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ABSTRACT: Ligation of CD95 (APO-1/Fas) by antibody or CD95 ligand (CD95L) induces apoptosis and, in some cell lines, growth. Normal colonic epithelial cells constitutively express CD95. The function of CD95 on colonocytes is unknown. The aim of this study was to elucidate the role of epithelial CD95 in the normal colon and in ulcerative colitis.
Intact colonic crypts were isolated, and the effects of CD95 ligation in vitro were studied. CD95L-expressing cells and apoptotic cells were detected in situ by RNA hybridization, immunohistochemistry, and DNA nick end labeling.
On CD95 ligation, isolated colonic crypt cells underwent apoptosis within 4 hours. No growth-promoting effect was observed. In normal colon, CD95L expression was restricted to few mononuclear cells randomly scattered within the lamina propria. Therefore, the CD95-CD95L system is very unlikely to operate in the regeneration of the colonic epithelium. However, in ulcerative colitis, the number of interstitial CD95L+ cells and the frequency of apoptosis in both lamina propria and epithelium were increased considerably. Further, a focal association of subepithelial CD95L+ mononuclear cells and epithelial apoptosis was observed.
In ulcerative colitis, soluble CD95L-mediated epithelial apoptosis may lead to a breakdown of the epithelial barrier function facilitating the invasion of pathogenic microorganisms.
Gastroenterology 08/1997; 113(1):160-7. · 11.68 Impact Factor
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M Lazzarino,
E Orlandi,
M Paulli, J Sträter,
C Klersy,
U Gianelli,
L Gargantini,
M T Rousset,
M Gambacorta,
E Marra,
T Lavabre-Bertrand,
U Magrini,
C Manegold,
C Bernasconi,
P Möller
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ABSTRACT: To define clinicopathologic features, response to treatment, and prognostic factors of primary mediastinal B-cell lymphoma (MBL), a CD20+ tumor recognized as a distinct entity among non-Hodgkin's lymphomas (NHL).
One hundred six patients presented with disease confined to thorax (86%), bulky mediastinum (73%), superior vena cava syndrome (47%), and contiguous infiltration (57%). Ninety-nine received doxorubicin-containing chemotherapy (CHT).
Thirty-five of 99 patients were primarily CHT-resistant, and 64 responded: 23 achieved complete response (CR) and 41 achieved response with residual mediastinal abnormality. Seventy-seven percent of responders received mediastinal radiotherapy (RT). Of 64 responders, 18 (28%) relapsed: none of 23 CR patients and 18 of 41 (44%) with residual mediastinal abnormality. Relapse-free survival rate of responders was 71% at 3 years. Actuarial 3-year survival rate was 52% for all patients and 82% for responders. Predictive factors of poor outcome were identified by logistic regression; Cox survival analysis was performed on death and relapse. Pericardial effusion (P < .001) and Eastern Cooperative Oncology Group (ECOG) performance status > or = 2 (P = .009) predicted nonresponse (NR) and affected survival. Less than partial midway response to CHT predicted NR to subsequent therapies. Bulky disease was related to persistent mediastinal abnormality and risk of relapse (P = .025).
MBL is an aggressive NHL with unique clinicopathologic aspects, often refractory to current CHT designed for high-grade NHL. Poor performance status and pericardial effusion predict NR and poor survival. Inadequate response after the first courses of front-line CHT predicts failure of subsequent treatment. Responders with bulky mediastinum or residual mediastinal abnormality after CHT are at risk of relapse. These factors should help to select high-risk patients for intensive treatments.
Journal of Clinical Oncology 04/1997; 15(4):1646-53. · 18.37 Impact Factor
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ABSTRACT: We established a new method to allow simultaneous in situ detection of mRNA expression and apoptotic DNA fragmentation in paraffin-embedded tissue sections. We used human thymic tissue to perform in situ hybridization with a digoxigenin-labeled CD95 (APO-1/Fas) ligand (CD95L)-specific probe followed by TdT-mediated biotin dUTP nick end-labeling (TUNEL) of apoptotic DNA fragments. Bound probes were visualized by an immunogold-silver enhancement technique and fragmented DNA was detected with a streptavidin-peroxidase system. This double labeling technique produced a distinct, dark cytoplasmic staining of CD95L mRNA-expressing cells and an intense red nuclear precipitate in apoptotic cells or bodies. This technique will be a useful tool for microtopographical analysis of apoptosis-related gene expression.
Journal of Histochemistry and Cytochemistry 01/1997; 44(12):1497-9. · 2.72 Impact Factor
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ABSTRACT: Ligation of CD95 (APO-1/Fas) cell surface receptors induces death in apoptosis-sensitive cells. Induction of apoptosis in adherent gamma interferon-stimulated HT-29 and COLO 205 colon carcinoma cells by cross-linking CD95 with anti-APO-1 monoclonal antibody resulted in detachment of the cells from hyaluronate starting about 1 h after antibody exposure. Loss of adhesion was paralleled by a substantial reduction of the multifunctional cell surface adhesion molecule CD44. As evidenced by cycloheximide treatment, this effect was not caused by impaired protein synthesis. Depletion of surface CD44 was also not due to membrane blebbing, since cytochalasin B failed to inhibit ascension from hyaluronate. Instead, ELISA and time kinetics showed increasing amounts of soluble CD44 in the supernatant of CD95-triggered cells. SDS-PAGE revealed that soluble CD44 had an apparent molecular mass of about 20 kD less than CD44 immunoprecipitated from intact cells. Thus, CD95-triggering induced shedding of CD44. Shedding is a novel mechanism operative in early steps of CD95-mediated apoptosis. Shedding surface molecules like CD44 might contribute to the active disintegration of dying epithelial cells in vivo.
The Journal of Cell Biology 09/1996; 134(4):1089-96. · 10.26 Impact Factor
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ABSTRACT: CD95 (APO-1/Fas), a cell surface receptor and member of the tumor necrosis factor receptor superfamily, induces apoptosis upon oligomerization. CD95 is broadly expressed in normal tissues. The CD95 ligand (CD95L) is a member of the tumor necrosis factor family of cytokines and exists in a membrane-bound and in a soluble form. In vitro, CD95L is expressed and released by activated T lymphocytes. The range of cell types capable of expressing CD95L in vivo is unknown so far. Using a specific probe for human CD95L and sensitive in situ hybridization, we examined CD95L mRNA expression along the gastrointestinal tract. The scarce lymphohistiocytic infiltrate within the lamina propria contained small subsets of medium-sized labeled cells, some of which bad short cytoplasmic protrusions and others of which were lymphoid in morphology. Autochthonous cells of the gastrointestinal tract did not contain any detectable transcripts except for Paneth cells that expressed CD95L mRNA at high levels. In ulcerative colitis, CD95L mRNA-positive inflammatory cells were increased in number, and metaplastic Paneth cells were the only epithelial cells expressing CD95L. Paneth cells are CD95 negative. Therefore, these cells may not commit CD95-mediated autocrine suicide. By secreting soluble CD95L, however, the Paneth cells might contribute to mucosal integrity.
American Journal Of Pathology 08/1996; 149(1):9-13. · 4.89 Impact Factor
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ABSTRACT: Apoptosis by loss of adherence is a recently described phenomenon termed "anoikis." beta 1, integrins are heterodimeric surface molecules mediating adhesion to the extracellular matrix. The aim of this study was to address whether anoikis accounts for the elimination of senescent enterocytes and, if so, whether beta 1 integrins are involved.
Whole crypts were isolated from normal human colonic mucosa and examined in vitro.
The vast majority of cells in resuspended crypts rapidly underwent apoptosis within 4 hours. Apoptosis was partially inhibited when cells had contact with collagen I-coated membranes or when whole crypts were embedded in a collagen gel. Preincubation of crypts with an inhibiting anti-beta 1 antibody before readhesion caused a much higher apoptotic rate. Confocal microscopy of embedded crypts revealed two critical zones of high sensitivity to temporary loss of adherence: the base of the crypts where stem cells are supposed to reside and the crypt mouth including the surface epithelium.
Survival of colonic epithelia crucially depends on matrix adhesion and is likely to be guaranteed by beta 1-integrin/ matrix interaction. The data strongly suggest that anoikis is the way senescent colon cells die.
Gastroenterology 06/1996; 110(6):1776-84. · 11.68 Impact Factor
