Integrin a6 Promotes an Osteolytic Program in Cancer Cells by Upregulating MMP2

The molecular circuitries controlling osseous prostate metastasis are known to depend on the activity of multiple pathways, including integrin signaling. Here, we demonstrate that the alpha v beta 6 integrin is upregulated in human prostate cancer bone metastasis. In prostate cancer cells, this integrin is a functionally active receptor for fibronectin and latency-associated peptide-TGF-beta 1; it mediates attachment and migration upon ligand binding and is localized in focal contacts. Given the propensity of prostate cancer cells to form bone metastatic lesions, we investigated whether the alpha v beta 6 integrin promotes this type of metastasis. We show for the first time that alpha v beta 6 selectively induces matrix metalloproteinase 2 (MMP2) in vitro in multiple prostate cancer cells and promotes osteolysis in vivo in an immunodeficient mouse model of bone metastasis through upregulation of MMP2, but not MMP9. The effect of alpha v beta 6 on MMP2 expression and activity is independent of androgen receptor in the analyzed prostate cancer cells. Increased levels of parathyroid hormone-related protein (PTHrP), known to induce osteoclastogenesis, were also observed in alpha v beta 6-expressing cells. However, by using MMP2 short hairpin RNA, we demonstrate that the alpha v beta 6 effect on bone loss is due to upregulation of soluble MMP2 by the cancer cells, not due to changes in tumor growth rate. Another related av-containing integrin, alpha v beta 5, fails to show similar responses, underscoring the significance of alpha v beta 6 activity. Overall, these mechanistic studies establish that expression of a single integrin, alpha v beta 6, contributes to the cancer cell-mediated program of osteolysis by inducing matrix degradation through MMP2. Our results open new prospects for molecular therapy for metastatic bone disease.