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 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 non-transgenic control mice. Further, 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.

Anthracycline Inhibits Recruitment of Hypoxia-inducible Transcription Factors and Suppresses Tumor Cell Migration and Cardiac Angiogenic Response in the Host

“…In addition, there is evidence that overexpression of HIF-1␣ in the renal proximal tubules is sufficient to induce tumors (17), collectively suggesting that the aggressive phenotype associated with HIF-2 may be acquired irrespective of the VHL status and that HIF-1 also serves a tumorigenic role depending on the cellular background. Therefore, we repeated experiments using A498 cells reconstituted with the mouse VHL homologue (A498/Vhlh) and the Caki-1 RCC cell line harboring normal VHL status and a dominant pattern of HIF-1␣ expression.…”

Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

“…In view of abundant evidence linking certain types of cysts to defects in primary cilia, it has been suggested that the microtubule stabilization function of VHL is key to its role in suppressing cysts (66). Several mouse models in which the VHL gene has been inactivated develop various cysts (although not SCAs) (67)(68)(69)(70), suggesting fertile avenues for future research on this topic.…”

Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α

“…Biallelic inactivation of VHL is an early event in most ccRCCs, but deletion of Vhl in renal epithelial cells in mice does not cause tumor formation (5 (25,(46)(47)(48). Vhl/Trp53 deletion leads to the formation of simple and atypical renal cysts, renal tumors as well as carcinomas in other organs of the genital tract (8).…”

“…These studies argue that whereas HIF2a activity is tumor promoting, there is a selection against HIF1a expression or activity during the progression of some cases of ccRCC. On the other hand, because HIF1a is strongly expressed in single and multicellular clusters of VHL-null cells and in cystic lesions in VHL patients (4), and because transgenic overexpression of HIF1a in mouse proximal tubular epithelial cells causes a clear cell appearance, increased proliferation, and a disorganized tubular morphology (25), and because many human ccRCCs express HIF1a and HIF1a target genes (26), it may also be argued that HIF1a plays an important role in promoting ccRCC development. These studies have largely focused on fully transformed, genetically complex ccRCC cell lines derived from advanced tumors, and it remains unclear if and how HIF1a and HIF2a contribute to the earliest stages of initiation of ccRCC.…”