|M.Sc Student||Boris Shneyer|
|Subject||Mechanisms by which hSef Suppresses Prostate Cancer|
|Department||Department of Biology||Supervisor||Full Professor Ron Dina|
|Full Thesis text|
Cancer cells utilize different mechanisms to propagate in an uncontrolled manner. One such mechanism is the downregulation of tumor suppressor genes (TSGs) whose products can inhibit cancer cell proliferation and survival. Sef is a TSG and an inhibitor of both growth factor and pro-inflammatory cytokine signaling. Human Sef (hSef) expression is lost in a variety of carcinomas and its silencing accelerates cell proliferation, while ectopic hSef expression inhibits cell proliferation. Therefore, restoring Sef expression in human tumors in-vivo may have therapeutic potential as it is expected to suppress tumor growth. Here, we tested this hypothesis in a syngeneic mouse model of prostate cancer, which is the leading cause of death among men. Our approach was to inject Sef expression vectors into pre-formed prostate tumors and facilitate plasmid penetration into the cells using therapeutic ultrasound (TUS). Previous studies in our group with the cytosolic isoform hSef, (termed hSef-b) revealed that it suppresses tumor growth and preliminary evidence suggested that hSef-b might also suppress blood vessel formation, a previously unknown Sef function. The goal of the current study was to complete the analysis of the anti-angiogenic capability of hSef-b and to find out if the transmembrane isoform of hSef (termed hSef-a) has a similar function. hSef-b reduced blood vessel density of Tramp-c2 tumors by about 2.5 fold. hSef-a suppressed tumor growth and similarly to hSef-b exerted an anti-angiogenic effect. This effect was accompanied by reduction of mRNA levels of pro-angiogenic factors such as FGF2, KDR/VEGFR2 and an increase in the mRNA level of an anti-angiogenic factor Thrombospondin-1. Mechanistically, both isoforms inhibited the activation of ERK/MAPK and the NF-κB pathway in Tramp-c2 cells, pathways that normally promote cell growth and angiogenesis. It is noteworthy, that hSef-b was not known to inhibit NF-κB. Collectively, these results revealed a previously unknown Sef function and suggest that Sef can inhibit tumor progression via several mechanisms.