Molecular and Cellular Pathobiology Autophagy Control by the VEGF-C/NRP-2 Axis in Cancer and Its Implication for Treatment Resistance

A major contributor to cancer mortality is recurrence and subsequent metastatic transformation following therapeutic intervention. Therefore, in order to develop new treatment modalities and improve the efficacy of current ones, it is important to understand themolecularmechanisms that promote resistance to therapy in cancer cells. One pathway contributing to therapy resistance is autophagy, a self-digestive process that can eliminate unnecessaryordamagedorganelles toprotect cancercells fromdeath.Wehave found that theVEGF-C/NRP-2 axis is involved in the activation of autophagy, which helps cancer cell survival following treatment. Inhibition of mTOR complex 1 activity by this axis is the underlying mechanism for the activation of autophagy. Furthermore, we identified two VEGF-C/NRP-2-regulated genes, LAMP-2 and WDFY-1, that have previously been suggested to participate in autophagy and vesicular trafficking. Upregulation of WDFY-1 following VEGF-C or NRP-2 depletion contributes to cytotoxic drug-mediated cell death. Together, these data suggest a link between the VEGF-C/NRP-2 axis andcancer cell survival despite thepresenceof chemotherapy-inducedstress. Effective targetingof thispathway may lead to the development of new cancer therapies. Cancer Res; 73(1); 160–71. 2012 AACR.