Recurrence and subsequent metastatic transformation of cancer develops from a subset of malignant cells, which show the ability to resist stress and to adapt to changing microenvironments. These tumor cells have distinctly different growth factor pathways and anti-apoptotic responses compared to the vast majority of cancer cells. Long-term therapeutic success can only be achieved by identifying and targeting the factors and signaling cascades that help these cells to survive during stress. Both microarray and immunohistochemical analysis on human prostate cancer tissue samples previously indicated an increased expression of Vascular Endothelial Growth Factor C (VEGF-C) in metastatic prostate cancer. We have discovered that VEGF-C acts directly on prostate cancer cells to protect them against oxidative stress. VEGF-C increased the survival of prostate cancer cells during hydrogen peroxide stress by activation of AKT1/PKBalpha. This activation was mediated by mTOR complex 2 (mTORC2). Finally, the transmembrane protein Neuropilin 2 was found to be an essential non-tyrosine kinase receptor for the activation of mTORC2 and AKT1 in this pathway. Indeed, our findings suggest a novel function of VEGF-C in protecting cancer cells from stress-induced cell death. This is distinctly different from the known paracrine function of VEGF-C in inducing lymphangiogenesis. Furthermore, we identified Neuopilin-2 as an upstream receptor for the activation of mTORC2. In conclusion, our data demonstrate that a novel VEGF-C/Neuropilin-2/mTORC2 axis is important for stress resistance and might have an essential role in recurrence and progression of prostate cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2371.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO