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Hypoxia-Inducible Factor 1 in Clear Cell Renal Cell Carcinoma

Authors' Affiliations: Departments of ¹ Urology, ² Pathology and Laboratory Medicine, and ³ Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

Requests for reprints: Arie S. Belldegrun, Department of Urology, David Geffen School of Medicine at UCLA, 66-118 CHS Los Angeles, CA 90095-1738. Phone: 310-206-1434; Fax: 310-206-5343; E-mail: abelldegrun{at}mednet.ucla.edu.

Purpose: Hypoxia-inducible factor-1 (HIF-1) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1 in renal cell carcinoma (RCC).

Experimental Design: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.

Results: HIF-1 expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1 was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1 was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1 expression predicted outcome in metastatic patients: patients with high HIF-1 expression (>35%) had significantly worse survival than patients with low expression (35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1 and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.

Conclusions: HIF-1 is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1 and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.