Targeting of αv-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 α(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 α(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 α(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.

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

“…In the in vitro study it significantly prevented the ORX-induced bone loss and reduced the number of osteoclasts. These in vitro and in vivo results suggest it as a potent inhibitor of angiogenesis [15]. The exposure of the GIPG0187 to GL-261 and SMA-560 mouse glioma cells resulted in reduced viability and cell death at very low concentrations (1 nM).…”

“…These are the prime type of integrins that are present in the endothelial cells and helps in angiogenesis via the basic fibroblast growth factor (bFGF) and tumor necrosis factor-α and also contribute to the malignant spread of various tumor cells such as breast carcinoma, prostrate carcinoma and melanoma [12][13][14]. Up regulation of α v β 3 integrin is observed profoundly upon neo-vessel formation to vascularize the most of the human cancer cells during angiogenesis and invasion [6,15,16]. Hence the inhibition α v β 3 integrin by cyclic RHD peptides, peptidomimetics and monoclonal antibodies induce endothelial cell apoptosis there by resulting in angiogenesis inhibition and are considered as potential targets to attain antiangiogenic properties.…”

The malignant social network

“…92, 93 These results highlight loss of specific integrin expression is associated with CSCs and a metastasic phenotype. It suggests that integrins serve in many cases to act as anchors, possibly maintaining CSCs as fixed, quiescent entities within their microenvironment preventing replication, differentiation and tumor progression.…”

Stem Cells and Prostate Cancer

“…Targeting of integrins by an α v -integrin antagonist (GLPG0187) could inhibit the de novo formation and progression of bone metastases in PC by antitumor (including inhibition of epithelial-to-mesenchymal transition and the size of the PCSC population), antiresorptive, and antiangiogenic mechanisms [125].…”