Details

Autor(en) / Beteiligte

• Dutta, Anindita
• Li, Jing
• Lu, Huimin
• Akech, Jacqueline
• Pratap, Jitesh
• Wang, Tao
• Zerlanko, Brad J.
• FitzGerald, Thomas J.
• Jiang, Zhong
• Birbe, Ruth
• Wixted, John
• Violette, Shelia M.
• Stein, Janet L.
• Stein, Gary S.
• Lian, Jane B.
• Languino, Lucia R.

Titel

The αvβ6 integrin promotes an osteolytic program through upregulation of MMP2

Ist Teil von

• Cancer research (Chicago, Ill.), 2014-01, Vol.74 (5), p.1598-1608

Erscheinungsjahr

2014

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.