Epithelial ovarian cancer (EOC) is a disease that causes 140,000 deaths every year. Nerve growth factor (NGF) and its high affinity receptor TRKA play important roles in follicular maturation, follicle-stimulating hormone (FSH) receptor acquisition and ovulation in normal ovary. Also, NGF has many roles in EOC cells: increasing survival, proliferation, cyclooxigenase-2 (COX-2), vascular endothelial growth factor (VEGF) and metalloproteinase ADAM17 expression. Besides, NGF inhibits calreticulin translocation from the endoplasmic reticulum to cell surface, possibly diminishing the efficacy of immunogenic therapies in EOC. Additionally, NGF acts as an angiogenic factor by a direct stimulation of migration, differentiation and proliferation of endothelial cells. Among the numerous factors actually described to be important in many types of cancer, including EOC, are the microRNAs (miRs). Indeed, it has been found that miR-143 is downregulate in EOC, which correlates with an increase of COX-2; concomitantly, NGF increases COX-2 as mentioned. Furthermore, NGF increases miR-222 and its target is the metalloproteinase inhibitor TIMP3, increasing the ADAM17 function. Also, NGF increases cMYC transcription factor in EOC, which decreases miR-23 levels regulating proteins involved in cell cycle and tumor growth. Therefore, NGF/TRKA signaling pathways alter the expression of many proteins and deregulate miRs in EOC, leading to the progression of this cancer.
Part of the book: Ovarian Cancer
In the last years, the antidiabetic drug metformin has received considerable attention in pursuing new drugs for anticancer treatments. Several reports have shown that metformin would have antitumor effects, not only attributable to its systemic effects but also due to direct effects on tumor cells. It has been proposed that metformin could be a suitable alternative for the treatment of gynecological cancers, such as ovarian cancer. This disease is characterized by high cell proliferation and angiogenesis potential, because ovarian cancer cells overexpress most oncogenic molecules including growth factors. The aim of the present chapter is to discuss the molecular mechanism by which metformin would affect tumor cells, with focus on epithelial ovarian cancer.
Part of the book: Metformin