A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis

Abstract

Hallmarks of malignant melanoma are its propensity to metastasize and its resistance to treatment, giving patients with advanced disease a poor prognosis. The transition of melanoma from non-invasive radial growth phase (RGP) to invasive and metastatically competent vertical growth phase (VGP) is a major step in tumor progression, yet the mechanisms governing this transformation are unknown. Matrix Metalloproteinase-1 (MMP-1) is highly expressed by VGP melanomas, and is thought to contribute to melanoma progression by degrading type I collagen within the skin to facilitate melanoma invasion. Protease activated receptor-1 (PAR-1) is activated by MMP-1, and is also expressed by VGP melanomas. However, the effects MMP-1 signaling through PAR-1 have not been examined in melanoma. Here, we demonstrate that an MMP-1/PAR-1 signaling axis exists in VGP melanoma, and is necessary for melanoma invasion. Introduction of MMP-1 into RGP melanoma cells induced gene expression associated with tumor progression and promoted invasion in vitro, and enhanced tumor growth and conferred metastatic capability in vivo. This study demonstrates that both the type I collagenase and PAR-1 activating functions of MMP-1 are required for melanoma progression, and suggests that MMP-1 may be a major contributor to the transformation of melanoma from non-invasive to malignant disease.

MMP16 Mediates a Proteolytic Switch to Promote Cell–Cell Adhesion, Collagen Alignment, and Lymphatic Invasion in Melanoma

“…These soluble MMPs, although inefficient for invasion of tumor cells across cross-linked ECM barriers (9), degrade interstitial collagen and other ECM components. They have been linked to, for example, lung metastasis signature of breast carcinomas as well as signaling, adhesion, and motility toward metastasis in melanoma (34)(35)(36). Therefore, these proteases provide the MMP16-expressing melanomas with an alternative mechanism for ECM remodeling within the tumor nests to support growth perpendicularly toward the outlining collagen bundles.…”

Matrix Metalloproteinase-1-mediated Up-regulation of Vascular Endothelial Growth Factor-2 in Endothelial Cells

“…Similarly to thrombin, MMP-1 is also able to proteolytically activate PAR-1, subsequently promoting processes such as endothelial cell activation, permeability, and angiogenesis (30 -34). However, whereas MMP-1 and thrombin are both able to induce the expression of pro-angiogenic genes in microvascular endothelial cells, MMP-1, but not thrombin, is able to stimulate the production of VEGF-A (34). This evidence underscores the importance of MMP-1-mediated up-regulation of VEGFR2 and suggests a positive feedback mechanism by which MMP-1 augments VEGFR2 levels as well as VEGF-A production and release, thereby amplifying endothelial responses.…”

“…In some cancers MMP-1 is highly expressed (often times in levels equal to or greater than the concentration we used in these studies (41)) and can influence vascularization of tissue in the tumor microenvironment, thus facilitating angiogenesis and disease progression (42). Among others, a PAR-1/MMP-1 signaling axis has been shown to facilitate the formation of metastatically competent melanoma (34). In other pathologies, VEGFR2, PAR-1, and MMPs collectively have been shown to contribute to endothelial barrier regulation, facilitating transmigration of leukocytes into the surrounding milieu (4 -6).…”

Microenvironment and tumor progression of melanoma: New therapeutic prospectives

“…Several MMP have been described to be involved in the neoplastic evolution of melanoma. MMP-1 appears to be correlated to metastatic progression of melanoma (Blackburn et al, 2009). In particular, its activity seems to be correlated to the degradation of collagen Types I and IV, causing cell invasion through Matrigel (Blackburn et al, 2007).…”