Expression, regulation, and function of the KIT tyrosine kinase receptor and its ligand, stem cell factor, in human epithelial ovarian cancer.

摘要

This Ph.D. project sought to determine the expression, regulation, and function of the KIT-SCF receptor-ligand system in human epithelia] ovarian cancer.; The expression of c-KIT and SCF in normal ovaries, in cultured ovarian surface epithelium (OSE), and in epithelia] ovarian tumors was analyzed. Normal OSE expressed SCF, but not c-KIT; however, epithelia] invaginations and inclusion cysts often expressed KIT protein. Of 15 benign ovarian tumors and tumors of low malignant potential, 87% expressed c-KIT, and 92% of these co-expressed SCF, suggesting the possibility of autocrine growth regulation. Of 35 malignant ovarian cancers, 71% expressed c-KIT (92% co-expressed SCF), with a trend for decreased c-KIT expression in advanced stage disease. Of 34 patients with malignant tumors for whom follow-up information was available (median follow-up time of 24 months), 9 had tumors that did not express c- KIT, 8 (89%) of whom have died and the remaining 1 has recurrent disease. Of the 25 patients with tumors expressing c-KIT, 56% are still alive, eight of whom have no evidence of disease. Importantly, statistical analysis indicated that patients whose tumors did not express c-KIT had a significantly shorter (p 0.05) disease-free survival time than patients who had KIT-expressing tumors.; Studies were carried out to identify intraovarian growth regulatory factors which may regulate c-KIT and SCF expression in ovarian cancer cells, and to determine whether activated KIT can affect the proliferation and survival of these cells. HEY cells, which co-expressed KIT and SCF, were treated with transforming growth factor (TGF)-α, TGF-β, and dibutyryl cyclic AMP (dbcAMP) and their cellular proliferation and expression of c- KIT and SCF were examined.; A series of transfection studies were carried out to determine if enforced c-kit expression inhuman ovarian carcinoma cells could regulate cellular proliferation. Transient transfection of c-kit into HEY cells resulted in decreased proliferation. Similarly, stable transfection of c-kit into A2780-cp cells, which do not express endogenous c-KIT, also resulted in a decreased proliferative rate. In contrast to the ovarian cancer cells, increased proliferation was documented for NIH 3T3 fibroblast cells transiently transfected with c-kit.; Together, these results suggest that the positive prognostic value of c-KIT expression in ovarian tumors is related to its negative growth regulatory function in ovarian cancer cells. (Abstract shortened by UMI.)