In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type

Oncogene. 2005 Jun 23;24(27):4349-61. doi: 10.1038/sj.onc.1208620.


Altered expression of CCN3 has been observed in a variety of musculoskeletal tumours, including Ewing's sarcoma (ES). Despite its widespread distribution, very little is known about its biological functions and molecular mechanisms of action. We transfected CCN3 gene into a CCN3-negative ES cell line and analysed the in vitro and in vivo behaviours of stably transfected clones. Forced expression of CCN3 significantly reduced cell proliferation in vitro, growth in anchorage-independent conditions, and tumorigenicity in nude mice. Despite the antiproliferative effect, CCN3-transfected ES cells displayed increased migration and invasion of Matrigel. The decreased expression of alpha2beta1 integrin receptor and the increased amount of cell surface-associated matrix metalloproteinase (MMP)-9 following the expression of CCN3 may be the basis for the increased migratory abilities of transfected cells. Cells lacking alpha2beta1 are less facilitated to have stable anchorage since the predominant collagen extracted from ES tissue is indeed type I collagen, and proMMP-9 was recently found to provide a cellular switch between stationary and migratory ES cell phase. Our findings are in line with those recently obtained in glioblastoma. However, the underlying molecular mechanisms appear to be different, further highlighting the importance of the cellular context in the regulation of function of CCN proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Line
  • Cell Movement*
  • Cell Proliferation
  • Clone Cells / metabolism
  • Clone Cells / pathology
  • Connective Tissue Growth Factor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Nephroblastoma Overexpressed Protein
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Sarcoma, Ewing / genetics
  • Sarcoma, Ewing / metabolism*
  • Sarcoma, Ewing / pathology*
  • Transfection


  • CCN2 protein, mouse
  • Ccn3 protein, mouse
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Nephroblastoma Overexpressed Protein
  • Connective Tissue Growth Factor
  • Receptor, IGF Type 1
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptor, Platelet-Derived Growth Factor beta
  • Matrix Metalloproteinases