Investigating tumor suppressor genes involved in renal cell carcinomas

Kidney cancer is a complex disease comprising several types of renal carcinomas, which are classified in different subtypes based on their histological characteristics. A small number of cases of renal cancers are due to hereditary predispositions and nearly all the knowledge on the molecular pathogenesis of kidney cancers was learned by the investigation of these hereditary forms of renal carcinomas. In this thesis, we studied two hereditary diseases predisposing to the development of kidney cancer, von Hippel Lindau (VHL) and Birt-Hogg-Dube (BHD) syndromes, and their causative genes, VHL and FLCN respectively. First, we investigated the role of the extracellular matrix (ECM) regulation by VHL during tumorigenesis and angiogenesis, and we demonstrated that inactivation of the VHL-ECM assembly pathway results in highly vascularized tumors with a disrupted ECM. We concluded that loss of the ECM assembly promotes and maintains tumor angiogenesis by providing a way for new blood vessels to invade the tumor tissue. In the second part of this thesis, we developed a novel VHL mouse model to investigate the possible cooperation between VHL and p53 during tumorigenesis. We observed that inactivation of both tumor suppressor genes accelerate the formation of liver hemangiomas and splenic hemangiosarcomas. Furthermore, concomitant deletion of VHL and p53 abolished the development of lymphoma usually associated with loss of p53. Our results indicate that the phenotypes arising following the inactivation of VHL and p53 is organ-dependent. Finally, to study the pathogenesis of the BHD syndrome, we developed a new mouse model using an established embryonic stem cell line. We described the murine Flcn expression pattern and noticed that homozygous disruption of Flcn was embryonically lethal early during development. Furthermore, we observed a continuum of kidney lesions from renal tubules hyperproliferation to rare adenoma. FLCN tumor suppressor role was also substantiated using a human kidney cancer cells system. Altogether, these studies have confirmed a role for the VHL-ECM pathway during tumor angiogenesis and have led to the development of two mouse models to study the molecular mechanisms linked to VHL and FLCN during the formation of various kidney tumors.