The Transforming Growth Factor-alpha/Epidermal Growth Factor Receptor growth stimulatory axis in atypical proliferation of renal epithelial cells

N. de Paulsen, M.Sc. and S Lee, PhD

Department of Cellular and Molecular Medicine and Kidney Research Center, Faculty of Medicine, University of Ottawa, Ottawa, Ontario Canada

Inactivating mutations of the von Hippel-Lindau (VHL) tumor suppressor gene cause sporadic clear cell renal carcinoma (RCC), the most common form of malignancy of the human kidney. VHL functions as part of an active E3-ubiquitin ligase complex that targets the Hypoxia-Inducible Factor (HIF) transcription factor for oxygen-dependent degradation. Loss of VHL function results in the constitutive stabilization of HIF and subsequent activation of HIF-regulated genes including ones that code for angiogenic factor such as vascular endothelial growth factor. Overproduction of angiogenic factors might explain the highly vascularized nature of RCC but whether this is sufficient to explain oncogenesis still remains unknown. Here, we identify transforming growth factor-alpha (TGF-a) as a HIF-regulated genes overproduced by VHL-negative RCC. In contrast to other HIF-regulated angiogenic factors, TGF-a can also act as a potent growth factor for renal epithelial cells by stimulating proliferation through the EGF-R. We present evidence that RCC cells engage in a TGF-a/EGF-R intracrine loop enabling these cells to abnormally proliferate in culture. However, blocking the TGF-a/EGF-R intracrine loop in RCC cells was sufficient to restore basically all of the normal growth characteristics observed in normal renal epithelial cells. We will present evidence that renal cystic cells are also subjected to the same growth stimulatory event than RCC cells but in a VHL-competent background, which impedes their ability to progress into carcinoma. We will propose a model by which the HIF/TGF-a/EGF-R pathway is the sole event causing loss of growth control of renal epithelial cells into cysts or tumors.

KEY WORDS: Hypoxia-Inducible Factor, Ubiquitin Ligase, Oxygen Homeostasis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Familial and Hereditary Cancer.