Cilia, Cysts and Kidney Cancer:

Cilia and the Development of  Renal Cell Carcinoma

Renal cell carcinoma is the most common tumor of the urogenital tract and accounts for approximately 2% of all malignancies. The tumor suppressor gene VHL (Von-Hippel-Lindau disease gene) is mutated in almost all inherited and most sporadic renal cell carcinomas. In the rare genetic Von-Hippel-Lindau disease, patients develop a variety of tumors including both hemangioblastomas of the central nervous system and the retina and renal cell carcinoma, the latter of which is preceded by the development of pre-malignant renal cysts.

Our group has shown that the pVHL protein localizes to the cilium of renal tubular cells, where it plays an important role in the regulation of ciliogenesis. Recent studies have identified a ciliary maintenance pathway and shown that carcinogenesis in a number of tissues is associated with the mutation of cilia-related genes.

Members of our group are addressing the role of ciliary signaling in cancer progression and the importance of loss of cilia on the communication of cancer cells with their tumor microenvironment, thereby focusing on the
pathogenesis of the renal cell carcinoma. We could show that many cellular receptors that are involved in the control of migration, proliferation, differentiation and apoptosis localize to primary cilia. Redistribution of these receptors to other domains of the cellular plasma membrane appears to affect proliferative signaling and confer resistance to stimuli supposed to induce apoptosis and growth arrest.

Furthermore, the basal body which anchors the cilium at the apical plasma membrane is identical with the mother centriole and part of the centrosome of the mitotic spindle in cell division. Recent spectacular work identified a ciliary checkpoint in cell cycle and suggested that cilia have to undergo shortening and resorption before the cell is able to divide. We are currently addressing the cellular mechanisms that control cilia resorption, cilia control of cell cycle and cilia-dependent signaling in cancer progression.