title: Generation of a mouse model of Von Hippel-Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1α.
abstract: Renal cancers are highly aggressive and clinically challenging, but a transgenic mouse model to promote pathologic studies and therapeutic advances has yet to be established. Here, we report the generation of a transgenic mouse model of von Hippel-Lindau (VHL) renal cancer termed the TRACK model (transgenic model of cancer of the kidney). TRACK mice specifically express a mutated, constitutively active HIF1α in kidney proximal tubule (PT) cells. Kidney histologies displayed by TRACK mice are highly similar to histologies seen in patients with VHL disease, including areas of distorted tubular structure, cells with clear cytoplasm and increased glycogen and lipid deposition, multiple renal cysts, and early onset of clear cell renal cell carcinoma (ccRCC). Distorted tubules in TRACK mice exhibit higher levels of CA-IX, Glut1, and VEGF than tubules in nontransgenic control mice. Furthermore, these tubules exhibit increased numbers of endothelial cells, increased cell proliferation, and increased expression of the human ccRCC marker CD70(TNFSF7). Moreover, PT cells in kidney tubules from TRACK mice exhibit increased genomic instability, as monitored by elevated levels of γH2AX. Our findings establish that activated HIF1α in murine kidney PT cells is sufficient to promote cell proliferation, angiogenesis, genomic instability, and other phenotypic alterations characteristic of human VHL kidney disease, establishing the TRACK mouse as a valid preclinical model of human renal cell carcinoma.
authors: Department of Pharmacology, Weill Cornell Cancer Center, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York, USA.
authors: Leiping
authors: L
authors: Fu
authors: Gang
authors: G
authors: Wang
authors: Maria M
authors: MM
authors: Shevchuk
authors: David M
authors: DM
authors: Nanus
authors: Lorraine J
authors: LJ
authors: Gudas
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011993:Recombinant Fusion Proteins; D005723:gamma-Glutamyltransferase