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Targeting of ?(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer.

ABSTRACT: Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide ?(v)-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that ?(v)-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking ?(v)-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms.

SUBMITTER: van der Horst G

PROVIDER: S-EPMC3114245 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Targeting of α(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer.

van der Horst Geertje G van den Hoogen Christel C Buijs Jeroen T JT Cheung Henry H Bloys Henny H Pelger Rob C M RC Lorenzon Giocondo G Heckmann Bertrand B Feyen Jean J Pujuguet Philippe P Blanque Roland R Clément-Lacroix Philippe P van der Pluijm Gabri G

Neoplasia (New York, N.Y.) 20110601 6

Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide α(v)-integrin antagonist GLPG0187 dose-dependently inc ...[more]

PMID: 21677875

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Targeting of ?(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer.

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Targeting of α(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer.

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