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

Authors' Affiliations: ¹ Department of Tumor Progression and Tumor Defense, German Cancer Research Center, ² Department of Surgery, Faculty of Medicine, University Heidelberg, Heidelberg, ³ Department of Applied Genetics, University of Karlsruhe, Karlsruhe, Germany; ⁴ Institute of Molecular Genetics, Academy of Science of the Czech Republic, Prague, Czech Republic; ⁵ Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan; ⁶ The Wistar Institute, Philadelphia, Pennsylvania; and ⁷ School of Biomedical Sciences, University of Newcastle, Callaghan, New South Wales, Australia

Requests for reprints: Margot Zöller, Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: 49-622-142-2454; Fax: 49-622-142-4760; E-mail: m.zoeller{at}dkfz.de.

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 6ß4 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 2, 3, 6, ß1, and ß4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of 6ß4 and CO-029 was restricted to tumor cells, whereas 1, 2, 3, 6, ß1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and ß1 expression was observed at comparably high levels in healthy pancreatic tissue. 3ß1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas 6ß4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with ß4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration.

Conclusion: 6ß4 is selectively up-regulated in pancreatic and colorectal cancer. The association of 6ß4 with CD151 and CO-029 correlates with increased tumor cell motility.

Key Words: human pancreatic adenocarcinoma • 6ß4 integrin • tetraspanin • motility

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