CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

Abstract

CCN3/nephroblastoma overexpressed belongs to the CCN family of genes that encode secreted proteins associated with the extracellular matrix (ECM) and exert regulatory effects at the cellular level. Overexpression of CCN3 was shown in metastatic melanoma cells compared with cells of the primary tumor from the same patient. Analysis of short-term cultures from 50 primary and metastatic melanomas revealed a heterogeneous expression pattern of both the 46-kDa fulllength cytoplasmic/secreted protein and the 32-kDa nucleartruncated form. The different protein expression patterns were not associated with gene alterations or polymorphisms. Like the metastatic cells expressing high levels of the 46-kDa CCN3, cells transfected to overexpress CCN3 showed increased adhesion to ECM proteins, whereas inhibition of CCN3 expression by small interfering RNA decreased adhesion to laminin and vitronectin. CCN3 overexpression induced increased expression of laminin and vitronectin integrin receptors A7B1 and AvB5 by increasing their mRNA production. Moreover, CCN3 secreted by melanoma cells acted as an adhesion matrix protein for melanoma cells themselves. Analysis of CCN3 protein expression with respect to melanoma progression detected the protein in all visceral metastases tested and in most nodal metastases from relapsing patients but in only a few nodal metastases from nonrelapsing patients and cutaneous metastases. Consistently, xenotransplantation in immunodeficient mice showed a higher metastatic potential of melanoma cells overexpressing CCN3. Together, these data indicate a role for CCN3 in melanoma cell interaction with the ECM by regulating integrin expression, resulting in altered cell adhesion and leading melanoma progression to aggressive disease. [Cancer Res 2008;68(3):715-23]

CCN3 Impairs Osteoblast and Stimulates Osteoclast Differentiation to Favor Breast Cancer Metastasis to Bone

“…Whereas some studies suggest that CCN3 exerts growth suppressive effects on glioma, melanoma, and breast cancer cells, [13][14][15] others support a prometastatic role for this protein in melanoma. 16 CCN3 can impair the proliferation of Ewing's sarcoma cells but promote their migration and invasion, 17 supporting the observed association between high CCN3 levels and metastatic disease in this cancer type. 18,19 Finally, high CCN3 levels correlate with poor outcome in patients with osteosarcoma or prostate cancer.…”

“…58,59 These observations are in agreement with a recent study demonstrating that CCN3 increases the metastatic potential of melanoma cells without affecting subcutaneous growth rates. 16 CCN3 can impair the proliferation of Ewing's sarcoma cells and diminish their tumorigenicity in vivo while enhancing the migratory and invasive phenotype of Ewing's sarcoma cells. 17 Moreover, high CCN3 levels are associated with increases in the incidence of metastatic disease in patients with Ewing's sarcoma.…”

CCN3: Doctor Jekyll and Mister Hyde

“…The role of CCN3 in the establishment of visceral metastases was supported by the observation that SCID mice injected with cells stably expressing CCN3 developed a much higher number of hepatic metastatic metastases than the mice injected with CCN3 negative tumor cells (Vallacchi et al 2008). …”

Microenvironment and tumor progression of melanoma: New therapeutic prospectives

“…Nevertheless, these data are partially in contrast with studies that showed CCN3 anti-proliferative activity in vitro (Benini et al, 2005;Fukunaga-Kalabis et al, 2008a). Moreover, it has been seen that, while CCN3 expression is decreased in cutaneous melanoma metastasis (Fukunaga-Kalabis et al, 2008a), its expression is copious in visceral metastases (Vallacchi et al, 2008), probably due to the capacity of this protein to specifically address melanoma tumor cells to metastasize visceral organs, such as SPARC acts towards lung metastases.…”

“…Concerning CCN3, whose expression is in reverse correlation to neoplastic progression of a melanoma, many experiments on both induction and silencing have been performed using cell and animal models, with subsequent alterations in the cell capacity to adhere to laminin and vitronectin (Vallacchi et al, 2008).…”