Colocalization of the Tetraspanins, CO-029 and CD151, with Integrins in Human Pancreatic Adenocarcinoma: Impact on Cell Motility

Abstract

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...

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Reduced body weight in male Tspan8-deficient mice

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