High expression of EpCAM and the tetraspanin CO-029 has been associated with colorectal cancer progression. However, opposing results have been reported on CD44 variant isoform v6 (CD44v6) expression. We recently noted in rat gastrointestinal tumors that EpCAM, claudin-7, CO-029, and CD44v6 were frequently coexpressed and could form a complex. This finding suggested the possibly that the complex, rather than the individual molecules, could support tumor progression. The expression of EpCAM, claudin-7, CO-029, and CD44v6 expression was evaluated in colorectal cancer (n = 104), liver metastasis (n = 66), and tumor-free colon and liver tissue. Coexpression and complex formation of the molecules was correlated with clinical variables and apoptosis resistance. EpCAM, claudin-7, CO-029, and CD44v6 expression was up-regulated in colon cancer and liver metastasis. Expression of the four molecules did not correlate with tumor staging and grading. However, coexpression inversely correlated with disease-free survival. Coexpression was accompanied by complex formation and recruitment into tetraspanin-enriched membrane microdomains (TEM). Claudin-7 contributes to complex formation inasmuch as in the absence of claudin-7, EpCAM hardly associates with CO-029 and CD44v6 and is not recruited into TEMs. Notably, colorectal cancer lines that expressed the EpCAM/claudin-7/CO-029/CD44v6 complex displayed a higher degree of apoptosis resistance than lines devoid of any one of the four molecules. Expression of EpCAM, claudin-7, CO-029, and CD44v6 by themselves cannot be considered as prognostic markers in colorectal cancer. However, claudin-7 -associated EpCAM is recruited into TEM and forms a complex with CO-029 and CD44v6 that facilitates metastasis formation. (Mol Cancer Res 2007;5(6):553 -67)
Purpose: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor.We recently reported that after protein kinase C activation, colocalization of a6h4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors. Experimental Design: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility. Results: The majority of pancreatic and colorectal tumors expressed the a2, a3, a6, h1, and h4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of a6h4 and CO-029 was restricted to tumor cells, whereas a1, a2, a3, a6, h1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and h1expression was observed at comparably high levels in healthy pancreatic tissue. a3h1frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas a6h4 colocalized and coimmunoprecipitated mostly with CD151and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151and CO-029 with h4 and was accompanied by internalization of the integrintetraspanin complex, decreased laminin 5 adhesion, and increased cell migration. Conclusion: a6h4 is selectively up-regulated in pancreatic and colorectal cancer. The association of a6h4 with CD151and CO-029 correlates with increased tumor cell motility.Pancreatic adenocarcinoma is a leading cause of cancer-related death and the frequency is increasing steadily (1). Patients with pancreatic adenocarcinoma have a very poor prognosis, the 1-year survival rate being <20% and the 5-year survival rate being <1% in most clinical centers. This is partly due to the fact that >80% of patients have massive metastatic spread at the time of diagnosis (1, 2). The early spread is proposed to proceed after settling of tumor cells in the peritoneal cavity and the penetration into blood vessels via so-called peritoneal pores, with formation of metastases preferentially in the liver (3). The mechanisms underlying the extraordinarily high invasive capacity of pancreatic adenocarcinoma are not yet understood. It is suggested that altered expression of adhesion molecules, particularly of integrins, might be an important factor (4).Changes in expression of integrins, particularly, a3h1 and a6h4, are frequently related to the metastatic capacity of tumor cells (5, 6). Reports on the integrin expression profile in pancreatic adenocarcinoma revealed partly contradictory results. It has been described that a2, a3, a5, a6, av, h1, and h4 are overexpressed in pancreatic adenocarcinoma lines, that do not express the a1, a4, or h2 integrins (7). High a6 expression on tumor tissue and w...
Activated T cells rapidly assemble filamentous (F-)
Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4+CD25high lymph node cells from mice repeatedly treated with a contact sensitizer. This obviously is a consequence of a dominance of freshly activated cells as compared with regulatory CD4+CD25+ T cells. Instead, a population of Gr-1+CD11b+ cells was significantly increased in skin and spleen of AA mice repeatedly treated with a contact sensitizer. Gr-1+CD11b+ spleen cells mostly expressed CD31. Expression of several proinflammatory cytokines as well as of the IFN-γ receptor and the TNF receptor I were increased. Particularly in the skin, Gr-1+ cells expressed several chemokines and CCR8 at high levels. Gr-1+CD11b+ cells most potently suppressed AA effector cell proliferation in vitro and promoted partial hair regrowth in vivo. When cocultured with CD4+ or CD8+ cells from AA mice, the Gr-1+CD11b+ cells secreted high levels of NO. However, possibly due to high level Bcl-2 protein expression in AA T cells, apoptosis induction remained unaltered. Instead, ζ-chain expression was strongly down-regulated, which was accompanied by a decrease in ZAP70 and ERK1/2 phosphorylation. Thus, a chronic eczema supports the expansion and activation of myeloid suppressor cells that, via ζ-chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo.
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