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Integrin 2 Mediates Selective Metastasis to the Liver

Departments of ¹ Surgery; ² Anesthesiology and Critical Care Medicine, Cell Biology, and Pediatrics; and ³ Oncology, Sidney Kimmel Comprehensive Cancer Center; and ⁴ Gastrointestinal/Liver Division, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and Departments of ⁵ Surgery II and ⁶ Bioregulatory Function, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan

Requests for reprints: Richard D. Schulick, Department of Surgery, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Blalock 685, Baltimore, MD 21287. Phone: 410-614-9879; Fax: 410-614-9882; E-mail: rschulick{at}jhmi.edu.

Key Words: integrin • hepatic metastasis • melanoma • colorectal cancer • VLA2

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin 2. The direct role of integrin 2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin 2–mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV–dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin 2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin 2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation. [Cancer Res 2009;69(18):7320–8]