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Type I Collagen Receptor (₂ß₁) Signaling Promotes the Growth of Human Prostate Cancer Cells within the Bone

Departments of ¹ Urology and ² Internal Medicine, The University of Michigan; ³ Velcura Therapeutics, Inc., Ann Arbor, Michigan

Requests for reprints: Christopher L. Hall, Department of Urology, University of Michigan, Room 5111 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0940. Phone: 734-647-9747; Fax: 734-936-9220; E-mail: clhall{at}umich.edu.

The most frequent site of prostate cancer metastasis is the bone. Adhesion to bone-specific factors may facilitate the selective metastasis of prostate cancer to the skeleton. Therefore, we tested whether prostate cancer bone metastasis is mediated by binding to type I collagen, the most abundant bone protein. We observed that only bone metastatic prostate cancer cells bound collagen I, whereas cells that form only visceral metastases failed to bind collagen. To confirm the relationship between collagen adhesion and bone metastatic potential, a collagen-binding variant of human LNCaP prostate cancer cells was derived through serial passage on type I collagen (LNCaP_col). Fluorescence-activated cell sorting analysis showed that LNCaP_col cells express increased levels of the integrin collagen I receptor ₂ß₁ compared with LNCaP cells. Antibodies to the ₂ß₁ complex inhibited LNCaP_col binding to collagen, confirming that integrins mediated the attachment. Correspondingly, LNCaP_col cells displayed enhanced chemotactic migration toward collagen I compared with LNCaP cells, an activity that could be blocked with ₂ß₁ antibodies. To directly test the role of ₂ß₁-dependent collagen binding in bone metastasis, LNCaP and LNCaP_col cells were injected into the tibia of nude mice. After 9 weeks, 7 of 13 (53%) mice injected with LNCaP_col developed bone tumors, whereas 0 of 8 mice injected with LNCaP cells had evidence of boney lesions. LNCaP_col cells were found to express increased levels of the metastasis-promoting RhoC GTPase compared with parental LNCaP. We conclude that collagen I attachment mediated by ₂ß₁ initiates motility programs through RhoC and suggest a mechanism for prostate cancer metastasis to the bone. (Cancer Res 2006; 66(17): 8648-54)

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