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 alphavbeta6 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-beta1; 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 alphavbeta6 integrin promotes this type of metastasis. We show for the first time that alphavbeta6 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 alphavbeta6 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 alphavbeta6-expressing cells. However, by using MMP2 short hairpin RNA, we demonstrate that the alphavbeta6 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 alphav-containing integrin, alphavbeta5, fails to show similar responses, underscoring the significance of alphavbeta6 activity. Overall, these mechanistic studies establish that expression of a single integrin, alphavbeta6, 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.

Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The alpha(v)beta(6) integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2]. Here, we investigate the expression of alpha(v)beta(6) in mouse models of prostatic inflammation and prostate cancer to establish a possible relationship between inflammation of the prostate, alpha(v)beta(6) expression and the progression of prostate cancer. Using immunohistochemical techniques, we show expression of alpha(v)beta(6) in two in vivo mouse models; the Pten(pc)-/- model containing a prostate- specific Pten tumor suppressor deletion that causes cancer, and the prostate ovalbumin-expressing transgenic (POET) inflammation mouse model. We show that the alpha(v)beta(6) integrin is induced in prostate cancer and inflammation in vivo in these two mouse models. alpha(v)beta(6) is expressed in all the mice with cancer in the Pten(pc-/-) model but not in age-matched wild-type mice. In the POET inflammation model, alpha(v)beta(6) is expressed in mice injected with activated T-cells, but in none of the control mice. In the POET model, we also used real time PCR to assess the expression of Transforming Growth Factor Beta 1 (TGFbeta1), a factor in inflammation that is activated by alpha(v)beta(6). In conclusion, through in vivo evidence, we conclude that alpha(v)beta(6) integrin may be a crucial link between prostatic inflammation and prostatic adenocarcinoma.