Tumor Suppressors APC and VHL: Gatekeepers of the Intestine and Kidney

Abstract

The isolation of the APC (Adenomatous Polyposis Coli) gene in 1991 and its establishment as the main regulator of the development of colorectal cancer (CRC) marked a milestone for the entire field of cancer molecular genetics. It was the first time that mutations in a single gene were found to result in most tumors arising in a particular anatomical venue. Germline mutations of the APC gene are responsible for the familial adenomatous polyposis (FAP), an inherited autosomal dominant condition leading not only to the development of multiple adenomas of the colorectum, but also of extra-colonic lesions of ectodermal, mesodermal, and endodermal origin. Of great interest is the fact that the APC gene is also mutated in the vast majority of sporadic colorectal tumors regardless of their degree of malignancy. Alterations of APC inappropriately activate the Wnt/β-catenin signal transduction pathway, in addition to affecting cellular events that could lead to tumorigenesis. Due to the extraordinary prevalence of APC mutations in CRC, APC has been dubbed the »gatekeeper« of proliferation of the colorectum. Following in APC’s footsteps, another »gatekeeper« gene was identified that regulates epithelial growth in the kidney: the von Hippel-Lindau (VHL) tumor suppressor. Like APC, heterozygous mutation of VHL results in an infrequent cancer syndrome, often associated with clear cell renal carcinoma (RCC). The majority of sporadic clear cell RCC samples also manifest biallelic VHL mutations, suggesting that this tumor suppressor holds the key to tumorigenesis in the majority of kidney cancers. Alterations of VHL inappropriately activate the Hypoxia Inducible factor (HIF) pathway, in addition to deregulating cytoskeletal processes that could influence tumorigenesis. In this chapter we review the events leading from initial APC mutations to the development of CRC and attempt to draw parallels to the lesser-charac-