Pathway signature and cellular differentiation in clear cell renal cell carcinoma.
BACKGROUND
Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The purpose of this study is to define a biological pathway signature and a cellular differentiation program in ccRCC.


METHODS
We performed gene expression profiling of early-stage ccRCC and patient-matched normal renal tissue using Affymetrix HG-U133a and HG-U133b GeneChips combined with a comprehensive bioinformatic analyses, including pathway analysis. The results were validated by real time PCR and IHC on two independent sample sets. Cellular differentiation experiments were performed on ccRCC cell lines and their matched normal renal epithelial cells, in differentiation media, to determine their mesenchymal differentiation potential.


RESULTS
We identified a unique pathway signature with three major biological alterations-loss of normal renal function, down-regulated metabolism, and immune activation-which revealed an adipogenic gene expression signature linked to the hallmark lipid-laden clear cell morphology of ccRCC. Culturing normal renal and ccRCC cells in differentiation media showed that only ccRCC cells were induced to undergo adipogenic and, surprisingly, osteogenic differentiation. A gene expression signature consistent with epithelial mesenchymal transition (EMT) was identified for ccRCC. We revealed significant down-regulation of four developmental transcription factors (GATA3, TFCP2L1, TFAP2B, DMRT2) that are important for normal renal development.


CONCLUSIONS
ccRCC is characterized by a lack of epithelial differentiation, mesenchymal/adipogenic transdifferentiation, and pluripotent mesenchymal stem cell-like differentiation capacity in vitro. We suggest that down-regulation of developmental transcription factors may mediate the aberrant differentiation in ccRCC. We propose a model in which normal renal epithelial cells undergo dedifferentiation, EMT, and adipogenic transdifferentiation, resulting in ccRCC. Because ccRCC cells grown in adipogenic media regain the characteristic ccRCC phenotype, we have identified a new in vitro ccRCC cell model more resembling ccRCC tumor morphology.
Tun
Han W
HW
Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida, United States of America.
Marlow
Laura A
LA
von Roemeling
Christina A
CA
Cooper
Simon J
SJ
Kreinest
Pamela
P
Wu
Kevin
K
Luxon
Bruce A
BA
Sinha
Mala
M
Anastasiadis
Panos Z
PZ
Copland
John A
JA
D050156:Adipogenesis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D054338:Cell Transdifferentiation / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D010012:Osteogenesis / Q000235:genetics; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
D014408:Biomarkers, Tumor; D014157:Transcription Factors