Class 3 Semaphorins (Sema3s), are implicated in the regulation of both physiological and tumor angiogenesis. We have recently shown that Sema3A is an endogenous inhibitor that is lost during tumor progression and its reintroduction into a mouse model of pancreatic islet b-cell carcinogenesis (RIP-Tag2), resulted in reduced vascular density, blood vessel normalization, restoration of tumor normoxia, and inhibition of tumor growth (1). Here, we show that the treatment of tumor-bearing RIP-Tag2 mice with Sema3A by somatic gene transfer using adeno-associated virus (AAV)-8, induced a dramatic reduction of tumor invasiveness, the reappearance of E-cadherin and a down-modulation of vimentin, two known targets of cancer hypoxia regulated during epithelial-mesenchymal transition (EMT). Then, we sought to investigate whether the administration of Sema3A in tumors was able to overcome the evasive resistance observed in RIP-Tag2 upon treatment with Sunitinib, an anti-angiogenic tyrosine kinase receptors inhibitor (2). Notably, we observed a dramatic reduction of cancer invasiveness, liver and peri-pancreatic lymph node metastases in RIP-Tag2 mice simultaneously treated with Sema3A and Sunitinib for 4 weeks, compared to Sunitinib-treated controls. Moreover, while Sunitinib-treated tumors were highly hypoxic and displayed few pericyte-covered vessels, the combinatorial regimen of Sema3A with Sunitinib normalized the vasculature and restored tumor normoxia. Finally, Real-Time RT-PCR and confocal microscopy, revealed a strong increase of E-cadherin expression and a strong inhibition of Snail1, vimentin and other hypoxia-induced molecules such as HIF-1alpha and phosphorylated Met in tumors treated with Sema3A and Sunitinib compared to Sunitinib-treated cancers. Therefore, treatment of tumors with Sema3A may safely harness the therapeutic potential of anti-angiogenic drugs, by normalizing the vasculature, inhibiting tumor hypoxia, and modulating the expression of EMT markers and other hypoxic-induced genes activated by anti-angiogenic treatments.
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