Abstract
Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alterations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma-associated fibroblasts (MAFs) that are highly abundant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal microenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we discuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progression, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes.
Highlights
The development and progression of Cutaneous melanoma (CM) are characterized by three distinct steps: Radial Growth Phase (RPG) where cancer cells localize only to the epidermic layer, RGP-confined microinvasive, typical of CM containing some malignant cells in the superficial papillary dermis and Vertical Growth Phase (VGP) representing the tumorigenic and/or mitogenic phase of melanoma [1]
Fedorenko et al demonstrated that vemurafenib (MAPKi) can activate local fibroblasts through paradoxical induction of the MAPK signalling pathway, forcing them to differentiate into CAFs and enhance hepatocyte growth factor (HGF) expression
Fibroblast populations are able to shift from an inactivated phenotype of quiescent fibroblasts to an activated phenotype of myofibroblasts or a constitutively activated phenotype of melanoma-associated fibroblasts (MAFs), depending on environmental modifications and cellular interactions [2,80]
Summary
The cellular components of the TME are characterized by impressive phenotypic plasticity sustained by crosstalk with each other and with melanoma cells and involved in the regulation of cancer growth, targeted therapy resistance and immunosurveillance [1,3]. In this scenario, it is important to note that the transition from the normal dermal microenvironment, regulating skin homeostasis, to TME, is a crucial process affecting CM development and it is influenced mostly by stromal fibroblast populations [1,2,5,6,7]. The deep understanding of signalling pathways regulating the flexible phenotype and secretory profiles of fibroblast populations, their interaction with cancer and stromal cells could be useful to develop therapeutic strategies targeting the TME and its pro-tumorigenic capability
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