Abstract
Novel targeted and immunotherapeutic approaches have revolutionized the treatment of metastatic melanoma. A better understanding of the melanoma-microenvironment, in particular the interaction of cells with extracellular matrix molecules, may help to further improve these new therapeutic strategies.We observed that the extracellular matrix molecule biglycan (Bgn) was expressed in certain human melanoma cells and primary fibroblasts when evaluated by microarray-based gene expression analysis. Bgn expression in the melanoma tissues correlated with low overall-survival and low progression-free-survival in patients. To understand the functional role of Bgn we used gene-targeted mice lacking functional Bgn. Here we observed that melanoma growth, metastasis-formation and tumor-related death were reduced in Bgn−/− mice compared to Bgn+/+ mice. In vitro invasion of melanoma cells into organotypic-matrices derived from Bgn−/− fibroblasts was reduced compared to melanoma invasion into Bgn-proficient matrices. Tissue stiffness as determined by atomic-force-microscopy was reduced in Bgn−/− matrices. Isolation of melanoma cells and fibroblasts from the stiffer Bgn+/+ matrices revealed an increase in integrin-β1 expression compared to the Bgn−/− fibroblast matrices. Overexpression of integrin-β1 in B16-melanoma cells abolished the survival benefit seen in Bgn−/− mice. Consistent with the studies performed in mice, the abundance of Bgn-expression in human melanoma samples positively correlated with the expression of integrin-β1, which is in agreement with results from the organotypic invasion-assay and the in vivo mouse studies.This study describes a novel role for Bgn-related tissue stiffness in the melanoma-microenvironment via regulation of integrin-β1 expression by melanoma cells in both mice and humans.
Highlights
Non-cellular components of the tumor microenvironment, in particular extracellular matrix molecules (ECM), were shown to promote cancer progression via direct effects on tumor cells and indirect effects on fibroblasts, immune cells and angiogenesis [1, 2]
We observed that the genes DCN, LUM and BGN (Bgn), which are members of the small leucinerich proteoglycan (SLRP) family [17], were within the highest expressed ECM genes in both melanoma cells and fibroblasts (Figure 1A)
A high level of Bgn expression in the tumor cells of human melanoma tissue was associated with reduced overall survival (OS) and progression-free survival (PFS) (Figure 1D, 1E)
Summary
Non-cellular components of the tumor microenvironment, in particular extracellular matrix molecules (ECM), were shown to promote cancer progression via direct effects on tumor cells and indirect effects on fibroblasts, immune cells and angiogenesis [1, 2]. Rigidity of the matrix substrate increases traction forces within the cell and enhances cell migration due to lamellipodia and lamella expansion towards the rigid substrate [3]. Stroma within a tumor microenvironment is typically stiffer than normal stroma [4] This stiffer tumor stroma is characterized by alterations in collagen architecture, such as linearized and cross-linked collagen, which has been shown to promote tumor cell migration [5]. Enhanced tumor cell motility relies on increased integrin clustering on the cell surface, forming focal adhesions due to altered collagen configuration [2]
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