Document Detail


Generation of a mouse model of Von Hippel-Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1α.
MedLine Citation:
PMID:  21908555     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Leiping Fu; Gang Wang; Maria M Shevchuk; David M Nanus; Lorraine J Gudas
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-09
Journal Detail:
Title:  Cancer research     Volume:  71     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-01     Completed Date:  2012-01-09     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6848-56     Citation Subset:  IM    
Copyright Information:
©2011 AACR.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution
Animals
Carcinoma, Renal Cell / genetics*,  pathology
Cell Division
Cell Hypoxia
Disease Models, Animal*
Genomic Instability / genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / chemistry,  genetics,  physiology*
Kidney Diseases, Cystic / genetics,  pathology
Kidney Neoplasms / genetics*,  pathology
Kidney Tubules, Proximal / metabolism,  pathology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutagenesis, Site-Directed
Neovascularization, Pathologic / genetics,  pathology
Promoter Regions, Genetic
Recombinant Fusion Proteins / physiology
Structure-Activity Relationship
Tumor Markers, Biological / biosynthesis
Up-Regulation / genetics
gamma-Glutamyltransferase / genetics
von Hippel-Lindau Disease / genetics*,  pathology
Grant Support
ID/Acronym/Agency:
R25 CA105012/CA/NCI NIH HHS; R25 CA105012-04/CA/NCI NIH HHS; R25105012//PHS HHS
Chemical
Reg. No./Substance:
0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Recombinant Fusion Proteins; 0/Tumor Markers, Biological; EC 2.3.2.2/gamma-Glutamyltransferase
Comments/Corrections
Comment In:
J Urol. 2012 Jun;187(6):2275-6   [PMID:  22579209 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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