Understanding the autocrine VEGF signaling in malignant tumors

Abstract

Angiogenesis is a complex and highly regulated process that is critical for tumor progression and me-tastasis. This process is regulated by several growth factors including vascular endothelial growth factor-A (VEGF-A). VEGF-A is secreted by hypoxic tumor cells and surrounding tissues; it seems to be the major fac-tor under a variety of conditions associated with angiogenesis. Furthermore, receptors to VEGF-A are ex-pressed in not only endothelial cells but also various types of malignancies, in which they function in the autocrine and paracrine biological actions of tumor cells. To know real effect of autocrine and paracrine ac-tion of VEGF-A, it needs to consider functional correlation between expression patterns of VEGF receptors and effect of VEGF-A. In this project, I studied which condition and how autocrine and paracrine VEGF sig-naling affects to malignant tumor cells. After brief introduction of this thesis in chapter 1, I elucidated that tumor cells-dependent expression of VEGF-A and its receptors contributes different dependency or signaling of autocrine VEGF-A in malignant tumors in chapter 2 and 3. In this research, I suggest malignant tumors classified into two groups; autocrine VEGF sensitive and autocrine VEGF resistant. Experimental results showed that analysis using the public microarray database Gene Expression Omnibus indicates significantly higher mRNA expression of VEGF and VEGFRs in colorectal cancer and high grade astrocytoma but not in hepatocellular carcinoma compared to normal tissue. Human malignant astrocytoma cell lines, U251-MG and U373-MG, and HT-1080 fibrosarcoma cells expressed relatively higher levels of VEGF and VEGFRs compared to hepatocellular and colorectal cancer cell lines. Administration of exogenous VEGF-A induced cell growth in a dose dependent fashion in these cells but not in colorectal and hepatocellular cancer cells, and blockade of VEGF inhibited cell survival only in U251-MG, U373-MG, and HT-1080 cells. Further...