title: CCN2 Expression by Tumor Stroma Is Required for Melanoma Metastasis.
abstract: Metastatic melanoma has an extremely poor prognosis with few durable remissions. The secreted matricellular protein connective tissue growth factor (CCN2) is overexpressed in cancers including melanoma and may represent a viable therapeutic target. However, the mechanism underlying the contribution of CCN2 to melanoma progression is unclear. Herein, we use the highly metastatic murine melanoma cell line B16(F10) and syngeneic mice, in which CCN2 expression is knocked out in fibroblasts, to demonstrate that loss of CCN2, either in melanoma cells or in the niche, impedes the ability of melanoma cells to invade. Specifically, loss of CCN2 in melanoma cells diminished their ability to invade through collagen in vitro, and loss of fibroblast-derived CCN2 decreased spontaneous metastases of melanoma cells from the skin to the lungs in vivo. Proliferation and tumor growth were not affected by loss of CCN2. CCN2-deficient B16(F10) cells showed reduced expression of the matricellular protein periostin; addition of recombinant periostin rescued the in vitro invasion defect of these cells. Immunohistochemical analysis of CCN2-deficient mice confirmed loss of periostin expression in the absence of CCN2. CCN2 and periostin mRNA levels are positively correlated with each other and with the stromal composition of human melanoma lesions but not BRAF mutations. Thus, CCN2 promotes invasion and metastasis via periostin and should be further evaluated as a possible therapeutic target for BRAF inhibitor-resistant melanoma.
authors.affiliation: Department of Physiology and Pharmacology and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Hutchenreuther
authors.affiliation: Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Krista M
authors.initials: KM
authors.lastname: Vincent
authors.affiliation: London Regional Genomics Centre, Robarts Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Carter
authors.affiliation: Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada; Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Lynne-Marie
authors.initials: LM
authors.lastname: Postovit
authors.affiliation: Department of Physiology and Pharmacology and Dentistry, University of Western Ontario, London, Ontario, Canada. Electronic address: Andrew.leask@schulich.uwo.ca.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor / Q000235:genetics*; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008546:Melanoma, Experimental / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D015854:Up-Regulation
chemical_list: C526318:CCN2 protein, mouse; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor