Regulatory role of CCN3 in melanoma cell interaction with the extracellular matrix

Vallacchi, Viviana; Rodolfo, Monica

doi:10.4161/cam.3.1.6836

Cited by 12 publications

(10 citation statements)

References 30 publications

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“…The microenvironment consists of structural components of the extracellular matrix (ECM) and ECM-associated but structurally unrelated proteins, called matricellular proteins (1-3). Matricellular proteins modulate signaling pathways and facilitate epithelial-stromal cross-talk (2, 3). CCN proteins (named after C yr61, C TGF, and N OV) are conserved ECM-associated proteins with developmental functions (3-5).…”

Section: Introductionmentioning

confidence: 99%

CCN6 Modulates BMP Signaling via the Smad-Independent TAK1/p38 Pathway, Acting to Suppress Metastasis of Breast Cancer

Pal

Huang

et al. 2012

Cancer Research

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CCN6 is an extracellular matrix protein that exerts tumor suppressive functions in breast cancer, where its decreased expression is a feature of advanced disease. However, neither its role nor mechanism of action in breast cancer metastasis has been established. Bone morphogenetic proteins (BMPs), which constitute ligands of the TGF-β superfamily, are multifunctional cytokines that induce epithelial-mesenchymal transition (EMT), cell invasion and metastasis. In this study, we identify a CCN6-BMP4-TAK1 kinase signaling pathway that controls the ability of the p38 MAP kinase to regulate acinar morphogenesis and invasion of breast cells. ShRNA-mediated attenuation of CCN6 in human mammary epithelial (HME) cells led to BMP4 upregulation as a major response to exposure to the TGF-β superfamily. CCN6 attenuation also induced BMP4-mediated activation of the Smad-independent TAK1 and p38 kinases. Conversely, ectopic expression of CCN6 in breast cancer cells antagonized BMP4-mediated TAK1/p38 activation and invasive capacity, both by binding BMP4 protein as well as decreasing BMP4 protein levels. Effects on BMP4 and p38 were confirmed in vivo where they correlated with decreased metastasis. In clinical specimens, we found that CCN6 expression was inversely associated with BMP4 and phospho-p38 levels in 69% of invasive breast carcinomas examined, consistent with the functional results. Together our findings identify a novel modifier pathway through which CCN6 acts to limit breast cancer invasion and metastasis.

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Section: Introductionmentioning

confidence: 99%

CCN6 Modulates BMP Signaling via the Smad-Independent TAK1/p38 Pathway, Acting to Suppress Metastasis of Breast Cancer

Pal

Huang

et al. 2012

Cancer Research

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“…Recent studies have shown that the CCN protein family members also play important roles in tumorigenesis, including cancer cell proliferation, survival, adhesion, and invasion (4–9). CCN proteins are mostly secreted and extracellular-matrix associated, and have been proposed to connect signaling pathways and facilitate cross-talks between epithelium and stroma (1, 10). …”

Section: Introductionmentioning

confidence: 99%

Blockade of CCN6 (WISP3) Activates Growth Factor–Independent Survival and Resistance to Anoikis in Human Mammary Epithelial Cells

et al. 2010

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CCN6 is a secreted cysteine-rich matricellular protein (36.9 kDa) that exerts growth-inhibitory functions in breast cancer. Reduction or loss of CCN6 protein has been reported in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. However, the mechanism by which CCN6 loss promotes breast cancer growth remains to be defined. In the present study, we developed lentiviral-mediated short hairpin RNA CCN6 knockdown (KD) in nontumorigenic mammary epithelial cells MCF10A and HME. We discovered that CCN6 KD protects mammary epithelial cells from apoptosis and activates growth factorindependent survival. In the absence of exogenous growth factors, CCN6 KD was able to promote growth under anchorage-independent conditions and triggered resistance to detachment-induced cell death (anoikis). On serum starvation, CCN6 KD was sufficient for activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Growth factor-independent cell survival was stunted in CCN6 KD cells when treated with either human recombinant CCN6 protein or the PI3K inhibitor LY294002. Targeted inhibition of Akt isoforms revealed that the survival advantage rendered by CCN6 KD requires specific activation of Akt-1. The relevance of our studies to human breast cancer is highlighted by the finding that low CCN6 protein levels are associated with upregulated expression of phospho-Akt-1 (Ser 473 ) in 21% of invasive breast carcinomas. These results enable us to pinpoint one mechanism by which CCN6 controls survival of breast cells mediated by the PI3K/Akt-1 pathway. Cancer Res; 70(8); 3340-50. ©2010 AACR.

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“…Among the intrinsic properties of melanoma that might favor ulceration, proliferation and dissemination, the most convincing evidence is for the loss of E-cadherin expression, 10 the dual role of the matrix protein osteopontin, [46][47][48][49][50] and/or the lack of the matricellular CCN3 which inhibits melanocyte proliferation and stimulates adhesion to collagen type IV. [51][52][53] In addition, ulceration may have a direct influence on the local microenvironment that subsequently may favor dissemination. The presence of increased density of activated tumor-associated neutrophils in the superficial part of the lesion 10 and gene signatures associated with the wound healing pathway and pro-inflammatory cytokines (such as IL-1b, IL6 and IL8) 8 in ulcerated melanomas, compared with non ulcerated ones reenforce this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas

et al. 2019

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Before the era of immune checkpoint blockade, a meta-analysis encompassing fifteen trials reported that adjuvant IFN-α significantly reduces the risk of relapse and improves survival of ulcerated melanoma (UM) with no benefit for higher doses compared to lower doses. IFNa2b affects many cell intrinsic features of tumor cells and modulates the host innate and cognate immune responses. To better understand the biological traits associated with ulceration that could explain the efficacy of prophylactic type 1 IFN, we performed immunohistochemical analysis of various molecules (major histocompatibility complex class I and class II, MX Dynamin Like GTPase 1 (MX1), inducible Nitric-Oxide Synthase (iNOS) or CD47) in two retrospective cohorts of melanoma patients, one diagnosed with a primary cutaneous melanoma (1995-2013, N = 172, among whom 49% were ulcerated melanoma (UM)) and a second one diagnosed with metastatic melanoma amenable to lymph node resection (EORTC 18952 and 18991 trials, N = 98, among whom 44% were UM). We found that primary and metastatic UM exhibit higher basal expression of MHC class I molecules, independently of Breslow thickness, histology and lymphocytic infiltration compared with NUM and that primary UM harbored higher constitutive levels of the antiviral protein Mx1 at the border of tumor beds than NUM. These findings suggest that UM expand in a tumor microenvironment where chronic exposure to type 1 IFN could favor a response to exogenous IFNs.

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Regulatory role of CCN3 in melanoma cell interaction with the extracellular matrix

Cited by 12 publications

References 30 publications

CCN6 Modulates BMP Signaling via the Smad-Independent TAK1/p38 Pathway, Acting to Suppress Metastasis of Breast Cancer

CCN6 Modulates BMP Signaling via the Smad-Independent TAK1/p38 Pathway, Acting to Suppress Metastasis of Breast Cancer

Blockade of CCN6 (WISP3) Activates Growth Factor–Independent Survival and Resistance to Anoikis in Human Mammary Epithelial Cells

Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas

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