Integrin αvβ6 Promotes an Osteolytic Program in Cancer Cells by Upregulating MMP2

Abstract

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 αvβ6 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-TGFβ1; 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 αvβ6 integrin promotes this type of metastasis. We show for the first time that αvβ6 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 αvβ6 on MMP2 expression and activity is independent of androgen receptor in the analyzed prostate cancer cells. Increased levels of PTHrP, known to induce osteoclastogenesis, were also observed in αvβ6 expressing cells. However, using MMP2 shRNA, we demonstrate that the αvβ6 effect on bone loss is due to upregulation of soluble MMP2 by the cancer cells, not to changes in tumor growth rate. Another related αv-containing integrin, αvβ5, fails to show similar responses, underscoring the significance of αvβ6 activity. Overall, these mechanistic studies establish that expression of a single integrin, αvβ6, contributes to the cancer cell mediated program of osteolysis by inducing matrix degradation through MMP2. Our results open new prospects for molecular therapy of metastatic bone disease.

The αvβ6 Integrin Is Transferred Intercellularly via Exosomes

“…We have previously shown that the ␣ v ␤ 6 integrin plays a dynamic role in regulating the osteolytic lesion forming process in metastatic PrCa (26). Thereby, these findings implicate ␣ v ␤ 6 integrin as a master regulator of the metastatic phenotype in PrCa.…”

“…We asked whether ␣ v ␤ 6 could be transferred in this manner from PrCa cells expressing this integrin to ␣ v ␤ 6 -negative cells. PC3 and RWPE cell lines were chosen as a model for this study as they have been well characterized for ␣ v ␤ 6 expression both in vitro and in vivo (26) (Fig. 1A).…”

“…Cell Lines-PC3, DU145, C4-2B, and RWPE-2 (designated here RWPE) cell lines, culture conditions, and generation of cell transfectants have been previously described (26,33).…”

“…The cytoplasmic domain of the ␤ 6 subunit has been implicated in mediating cell proliferation and migration (22)(23)(24)(25). Finally, our group has recently shown that the ␣ v ␤ 6 integrin promotes an autonomous osteolytic program in PrCa cells by up-regulation and activation of the matrix metalloproteinase-2 (MMP2) (26).…”

Targeting TGF-β Signaling for Therapeutic Gain

“…A more fruitful approach may be to target proteins with a more restricted tissue expression profile than that of the TGF-b receptors, which might affect the TGF-b activity only in specific cells of the TME such as in DCs, NK cells, MDSCs and/or T cells. Integrins that activate TGF-b have been considered as such drug targets (Van Aarsen et al 2008;Dutta et al 2014). Another example is GARP, which is required for activation of latent TGF-b on Tregs and platelets (Stockis et al 2009;Tran et al 2009).…”