Stromal Cells Present in the Melanoma Niche Affect Tumor Invasiveness and Its Resistance to Therapy

Abstract

Malignant melanoma is a highly metastatic type of cancer, which arises frequently from transformed pigment cells and melanocytes as a result of long-term UV radiation exposure. In recent years, the incidence of newly diagnosed melanoma patients reached 5% of all cancer cases. Despite the development of novel targeted therapies directed against melanoma-specific markers, patients' response to treatment is often weak or short-term due to a rapid acquisition of drug resistance. Among the factors affecting therapy effectiveness, elements of the tumor microenvironment play a major role. Melanoma niche encompasses adjacent cells, such as keratinocytes, cancer-associated fibroblasts (CAFs), adipocytes, and immune cells, as well as components of the extracellular matrix and tumor-specific physicochemical properties. In this review, we summarize the current knowledge concerning the influence of cancer-associated cells (keratinocytes, CAFs, adipocytes) on the process of melanomagenesis, tumor progression, invasiveness, and the emergence of drug resistance in melanoma. We also address how melanoma can alter the differentiation and activation status of cells present in the tumor microenvironment. Understanding these complex interactions between malignant and cancer-associated cells could improve the development of effective antitumor therapeutic strategies.

Keywords: adipocytes; cancer-associated fibroblasts; drug resistance; invasion; keratynocytes; melanoma; tumor microenvironment.

Figure 1

Components of the melanoma microenvironment. Abbreviations: CAF, cancer-associated fibroblast; ECM, extracellular matrix.

Figure 2

The influence of keratinocytes on melanoma development. A detailed description of the processes regulated by keratinocytes can be found in the main text. Abbreviations: UV, ultraviolet; N-cad, N-cadherin; E-cad, E-cadherin; End-1, endothelin-1; CXCL1, C-X-C-motif chemokine 1; CXCL8, C-X-C-motif chemokine 8; TRIM16, Tripartite motif-containing protein 16.

Figure 3

The influence of fibroblasts on melanoma cell proliferation, invasion, ECM remodeling, angiogenesis, and drug resistance. A description of the presented phenomena can be found in the text. Abbreviations: IL6, interleukin 6; TNFα, tumor necrosis factor α; TGFβ, transforming growth factor β; miR155, microRNA 155; miR211, microRNA 211; CTGF, connective tissue growth factor; CXCL12, C-X-C-motif chemokine 12; MMP1, matrix metalloproteinase 1; MMP2, matrix metalloproteinase 2; MMP13, matrix metalloproteinase 13; MMP14, matrix metalloproteinase 14; FAPα, fibroblasts activating protein α; sFRP2, freezled-related protein 2; TRAF6, TNF receptor-associated factor 6; NRG1, neuregulin1; HGF, hepatocyte growth factor; CXCL5, C-X-C-motif chemokine; ECM, extracellular matrix; CAFs, cancer-associated fibroblasts.

Figure 4

The influence of adipocytes on melanoma proliferation, epithelial–mesenchymal transition, cell invasion, metastasis, angiogenesis, and drug resistance. A detailed description of the shown processes is present in the text. Abbreviations: FABP4, fatty acid binding protein 4; PPARy, peroxisome proliferator-activated receptor γ; miR-214-3p, microRNA 214-3p; FASN, fatty acid synthase; P-g, P-glycoprotein; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; IL-6, interleukin 6; MMP9, matrix metalloproteinases 9; FAO, fatty acid oxidation; MMPs, matrix metalloproteinases.