Tumor Physiology and Biology of the Ovary

“REGULATION OF THE MECHANISMS INVOLVED IN OVARIAN FUNCTION AND ANGIOGENESIS”

The development and regression of the ovarian follicle is a continuous and cyclical process that depends on endocrine, paracrine, autocrine signals and essential cell to cell interactions that regulate female fertility. These processes involve the synthesis of local factors that produce the selection and maturation of the dominant follicles, triggering ovulation. Those follicles that do not reach this stage regress through a process called follicular atresia. After ovulation, the remaining cells of the ovarian follicle will form the corpus luteum (CL), whose main function is to secrete progesterone, which is essential for the implantation of the blastocyst and maintenance of pregnancy. However, if this does not occur or when it is no longer necessary for the maintenance of the placenta, the CL stops producing progesterone and regresses by luteolysis. Apoptosis plays a critical role in luteolysis and follicular atresia. The factors involved in these processes trigger different signal transduction pathways that promote cell survival or inhibit apoptosis. Furthermore, all of these processes (follicular growth and regression, LC development, and luteolysis) require dynamic changes in the ovarian vascular network, the regulation of which still raises unsolved questions. Angiogenesis is the process by which a new vasculature is formed from pre-existing vessels and involves the activation, proliferation and migration of endothelial cells, which will form new vascular sprouts that will connect neighboring vessels. In recent years, new cell signaling pathways involved in angiogenesis have begun to be described, including the Notch, Wnt/beta-catenin systems, and the hypoxia-inducible factor HIF1α. In addition to the role of the Notch, Wnt and HIF1α pathways in normal ovarian function, it has been reported that their alterations would be involved in the appearance of different gynecological diseases. Thus, the constitutive activation of HIF1α could lead to situations of cellular adaptation involved in alterations of the luteal phase. The short or insufficient luteal phase is a gynecological disorder closely linked to failures in luteal production of progesterone, in implantation and is associated with recurrent miscarriage. It is known that an increase in angiogenesis occurs at the beginning of the luteal phase, in part due to the hypoxic conditions present in the last follicular stage. In contrast, prior to luteal regression, blood flow decreases and luteal hypoxia increases. In both cases, this mechanism is associated with an increase in HIF1-α which, among others, activates the expression of genes related to cell death. Based on this background, the general objective of this line of research is focused on evaluating the participation of HIF1α and its interaction with the Notch system and the Wnt/beta-catenin signaling pathway in the regulation of folliculogenesis, luteinization and ovarian angiogenesis.

“MOLECULAR MECHANISMS INVOLVED IN THE PROGRESSION”

Ovarian cancer is, among gynecological diseases, the most difficult to detect and treat. This is due to the absence of specific symptoms in the early stages and its high recurrence. Despite being one of the solid tumors with the greatest response to treatment, this type of tumor usually recurs. Among gynecological diseases, it is the one with the highest mortality/incidence ratio and in the last two decades no new therapeutics have been developed that generate a significant change in the treatment of this disease. This determines the need to find new therapeutic strategies, for which it is essential to know the mechanisms that regulate the development of ovarian cancer. There are numerous different processes that contribute to tumor development and progression. In our laboratory we are interested in the mechanism of angiogenesis, essential process for tumor growth and spread, and in molecular mechanisms that govern the proliferation and change towards a migratory and invasive phenotype of tumor cells. Tumor angiogenesis has been the target of numerous antitumor therapies, which are based on the fact that tumors depend on the process of angiogenesis and the formation of the vasculature to maintain and develop. On the other hand, the epithelial-mesenchymal transition process (EMT) is the process by which epithelial cells undergo morphological changes characteristic of a transition from epithelial to fibroblastic phenotype, leading to an increase in the capacity for mobility and invasion of cells and, therefore, plays a fundamental role in tumor progression. In our laboratory, we study in experimental models of ovarian cancer processes responsible for tumor development and survival, such as angiogenesis and epithelial-to-mesenchymal transition. Our experiments involve both in vitro and in vivo techniques. Through understanding the interaction of tumor cells and their microenvironment, it will be possible for us to postulate new therapeutic strategies that are effective in terms of their antitumor power, and more innocuous for the patient suffering from this disease. Hypoxia is a condition given by low oxygen tension that is pathologically observed in most malignant tumors. In particular, in ovarian tumors, HIF1α is associated with a poor prognosis for the patient regardless of the stage of the disease. It has been described that in hypoxic tumors, a large number of mechanisms are activated for their survival, including angiogenesis, glycolysis, and the gene machinery necessary for their dissemination is expressed. The interaction between Notch and hypoxia has been demonstrated in different tumors, including breast cancer and glioblastoma. However, it has not been established whether the HIF1α factor interacts with the Notch system or with sexual steroids in ovarian tumors, which is why we began the study the action of HIF1α in aspects related to ovarian tumor growth and the interaction of the Notch system and endocrine effectors in this process.