Abstract
BackgroundProstate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested.MethodsWe isolated and characterized three lines of endothelial cells from prostate cancer and we tested the effect of Sunitinib and Sorafenib, and the combined treatment with the anti-androgen Casodex, on their angiogenic functions.ResultsEndothelial cells isolated from prostate tumors showed angiogenic properties and expression of androgen and vascular endothelial cell growth factor receptors. Sunitinib affected their proliferation, survival and motility while Sorafenib only showed a minor effect. At variance, Sunitinib and Sorafenib showed similar cytotoxic and anti-angiogenic effects on normal endothelial cells. Sorafenib and Sunitinib inhibited vascular endothelial cell growth factor receptor2 phosphorylation of prostate cancer endothelial cells, while they differentially modulated Akt phosphorylation as no inhibitory effect of Sorafenib was observed on Akt activation. The combined treatment of Casodex reverted the observed resistance to Sorafenib both on cell viability and on Akt activation, whereas it did not modify the response to Sunitinib.ConclusionsOur study demonstrates a resistant behavior of endothelial cells isolated from prostate cancer to Sorafenib, but not Sunitinib. Moreover, it shows the benefit of a multi-target therapy combining anti-angiogenic and anti-hormonal drugs to overcome resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-939) contains supplementary material, which is available to authorized users.
Highlights
Prostate cancer is the second leading cause of male cancer death in developed countries
CD146 was expressed at low levels (Figure 1), as previous reported on murine prostate cancer human samples (PTEC) isolated from spontaneous prostate tumors [17]
In order to investigate whether the different sensitivity to Sorafenib observed for PTEC was due to a reduced inhibition of the main target, we evaluated VEGFR2 activity by Western blot analyses in the presence of the two antiangiogenic drugs
Summary
Prostate cancer is the second leading cause of male cancer death in developed countries. The role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested. A bulk of evidence indicates that tumor blood vessels differ significantly from normal vessels for the structural organization and for the properties of endothelium [7,8,9,10,11,12]. TEC present functional alterations linked to increased survival, proliferation and angiogenic properties [13], as well as resistance to chemotherapeutics [16] All these molecular and functional alterations in TEC may result in altered sensitivity to the anti-angiogenic therapy. Information on the phenotype of TEC derived from prostate tumor and on their sensitivity to anti-angiogenic drugs is limited [17]
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