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

Abstract

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 a2b1 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 a 2 b 1 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.

CCN family of proteins: critical modulators of the tumor cell microenvironment

“…In effect, here CCN5 along with CCN3 as another example, functions as the brakes for the CCN family where the other CCN proteins may act as drivers. In fact, a similar relationship had been gleaned from previous studies on other CCN proteins, like CCN3 (note CCN6 later on), which showed growth inhibitory properties ex vivo and anti tumor effects in vivo in glioblastoma (Gupta et al 2001), choriocarcinomas (Gellhaus et al 2004) and Ewing's sarcoma (Benini et al 2005), with interaction by other CCN members. The scenario is very much like other signaling intermediates, e.g.…”

“…The CCN3 link with prognosis in osteosarcoma and Ewing's tumors in patients has been previously reported Manara et al 2002). In Ewing's sarcoma, CCN3 plays a dual role, inhibiting proliferation while promoting migration and invasion of the same cells (Benini et al 2005). In comparison, melanomas overexpressing CCN3 show a higher metastatic potential studied as xenografts (Vallacchi et al 2008), while overexpression of CCN3 in human prostate cell lines (Maillard et al 2001) and high expression in high grade renal cell carcinomas (Glukhova et al 2001) favor an active role in tumorigenesis and progression.…”

CCN3/NOV small interfering RNA enhances fibrogenic gene expression in primary hepatic stellate cells and cirrhotic fat storing cell line CFSC

“…6a and b). It has been well established that overexpression of CCN3 promotes cell migration in different cancer cells (Benini et al 2005) and that CCN3/ NOV increases the activity of the small GTPase Rac1, revealing a pathway directly linking Cx43 to actin reorganization (Sin et al 2009). CCN3/NOV siRNA is able to attenuate gap closing in monolayer cell scratchinduced migration indicating that NOV/CCN3 promotes cell migration.…”

Domain-specific CCN3 antibodies as unique tools for structural and functional studies

“…CCN3 also modulates cell adhesion and migration (Benini et al 2005), and CCN3 expression in primary Ewing's tumors was associated with higher risk of developing metastasis (Manara et al 2002). These results suggest a critical role for CCN3 in cancer progression.…”