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

Overview

MeSH Major

  • Carcinoma, Renal Cell
  • Gene Expression Regulation, Neoplastic
  • Kidney Neoplasms
  • Myofibroblasts

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.

publication date

  • December 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3281492

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-10-2279

PubMed ID

  • 20952505

Additional Document Info

start page

  • 9682

end page

  • 92

volume

  • 70

number

  • 23