Genomic deregulation during metastasis of renal cell carcinoma implements a myofibroblast-like program of gene expression Journal Article

   

Authors:	López-Lago, M. A.; Thodima, V. J.; Guttapalli, A.; Chan, T.; Heguy, A.; Molina, A. M.; Reuter, V. E.; Motzer, R. J.; Chaganti, R. S. K.
Article Title:	Genomic deregulation during metastasis of renal cell carcinoma implements a myofibroblast-like program of gene expression
Abstract:	Clear cell renal cell carcinoma (RCC) is the most common and invasive adult kidney cancer. The genetic and biological mechanisms that drive metastatic spread of RCC remain largely unknown. We have investigated the molecular signatures and underlying genomic aberrations associated with RCC metastasis, using an approach that combines a human xenograft model; expression profiling of RNA, DNA, and microRNA (miRNA); functional verification; and clinical validation. We show that increased metastatic activity is associated with acquisition of a myofibroblast-like signature in both tumor cell lines and in metastatic tumor biopsies. Our results also show that the mesenchymal trait did not provide an invasive advantage to the metastatic tumor cells. We further show that some of the constituents of the mesenchymal signature, including the expression of the well-characterized myofibroblastic marker S100A4, are functionally relevant. Epigenetic silencing and miRNA-induced expression changes accounted for the change in expression of a significant number of genes, including S100A4, in the myofibroblastic signature; however, DNA copy number variation did not affect the same set of genes. These findings provide evidence that widespread genetic and epigenetic alterations can lead directly to global deregulation of gene expression and contribute to the development or progression of RCC metastasis culminating in a highly malignant myofibroblast-like cell. ©2010 AACR.
Keywords:	adult; gene mutation; human cell; cancer growth; nonhuman; outcome assessment; animal cell; mouse; animals; mice; animal tissue; mesenchyme cell; microrna; gene expression profiling; animal experiment; animal model; tumor biopsy; tumor xenograft; mice, scid; tumor cells, cultured; dna methylation; kidney carcinoma; kidney neoplasms; gene expression regulation, neoplastic; carcinoma, renal cell; oligonucleotide array sequence analysis; promoter regions, genetic; tumor cell; neoplasm metastasis; neoplasms, experimental; transplantation, heterologous; gene control; gene silencing; myofibroblast; micrornas; mice, inbred nod; mesoderm; kidney metastasis; epithelial-mesenchymal transition; copy number variation; calvasculin; myofibroblasts
Journal Title:	Cancer Research
Volume:	70
Issue:	23
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2010-12-01
Start Page:	9682
End Page:	9692
Language:	English
DOI:	10.1158/0008-5472.can-10-2279
PUBMED:	20952505
PROVIDER:	scopus
PMCID:	PMC3281492
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-78649918621&partnerID=40&md5=1c1a9832a89a74040663df649266bf03
Notes:	--- - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus"

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