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Cell and Tumor Biology |
and CXCR4 Expression in Hemangioblastoma and Clear Cell-Renal Cell Carcinoma: von Hippel-Lindau Loss-of-Function Induces Expression of a Ligand and Its Receptor
1 Microvascular and Molecular Neuro-oncology Laboratory, 2 Department of Pathology, 3 Division of Neuropathology, 4 Department of Neurosurgery, and 5 New York University Cancer Institute of New York University School of Medicine, New York, New York and 6 Vascular Program, Institute for Cell Engineering; Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology; and Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Requests for reprints: David Zagzag, Department of Pathology, Division of Neuropathology, New York University Medical Center, 550 First Avenue, New York, NY 10016. Phone: 212-263-6449; Fax: 212-263-8994; E-mail: dz4{at}nyu.edu.
The genetic hallmark of hemangioblastomas and clear cell-renal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxia-inducible factor-1
(HIF-1). In hemangioblastomas and CC-RCCs, HIF-1 is constitutively overexpressed leading to increased transcription of HIF-1–regulated genes, including vascular endothelial growth factor (VEGF). Because loss of VHL function is associated with increased expression of the chemokine receptor CXCR4 in CC-RCCs, we investigated the expression of HIF-1, CXCR4, and its ligand stromal cell–derived factor-1 (SDF-1) in hemangioblastomas and CC-RCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1 within tumor cells and endothelial cells of hemangioblastomas and CC-RCCs. HIF-1 was detected in tumor cell nuclei of both hemangioblastomas and CC-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1 protein at levels that were significantly higher than those found in normal tissue. Analysis of the VHL-null RCC line 786-0 revealed that SDF-1 mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1 mRNA was significantly decreased in HIF-1-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1 and CXCR4 protein expression confirmed the RNA findings in RCC lines and MEFs. These results suggest that loss-of-function of a single tumor suppressor gene can up-regulate the expression of both a ligand and its receptor, which may establish an autocrine signaling pathway with important roles in the pathogenesis of hemangioblastoma and CC-RCC.
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