Cutaneous melanoma dissemination is dependent on the malignant cell properties and factors of intercellular crosstalk in the cancer microenvironment (Review)

Abstract

The incidence of cutaneous malignant melanoma has been steadily increasing worldwide for several decades. This phenomenon seems to follow the trend observed in many types of malignancies caused by multiple significant factors, including ageing. Despite the progress in cutaneous malignant melanoma therapeutic options, the curability of advanced disease after metastasis represents a serious challenge for further research. In this review, we summarise data on the microenvironment of cutaneous malignant melanoma with emphasis on intercellular signalling during the disease progression. Malignant melanocytes with features of neural crest stem cells interact with non-malignant populations within this microenvironment. We focus on representative bioactive factors regulating this intercellular crosstalk. We describe the possible key factors and signalling cascades responsible for the high complexity of the melanoma microenvironment and its premetastatic niches. Furthermore, we present the concept of melanoma early becoming a systemic disease. This systemic effect is presented as a background for the new horizons in the therapy of cutaneous melanoma.

New Prognostic Biomarkers and Drug Targets for Skin Cutaneous Melanoma via Comprehensive Bioinformatic Analysis and Validation

“…In both CM and UM, PMEL encodes a melanosome structural protein (28). Serum MIA interacts with extracellular matrix proteins, and its overexpression is also observed in breast cancer and colorectal cancer (29). MIA is also a reliable tumor marker in the serum of patients with malignant melanoma (30).…”

Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition

“…IL-6 secretion by 2D and 3D HDFn remained low and was not modified during the treatment, whereas treated CAFs secreted up to 120 pg/10 5 cells of IL-6 (12 times more than HDFn), especially when cells were cultured in the 3D configuration ( Figure A5 ). IL-6 is a well-known pro-inflammatory factor frequently up-regulated in serum and associated with tumor progression [ 33 ]. IL-6 is frequently overproduced by CAFs in different types of cancer [ 34 ] stimulating cancer cell proliferation, survival, invasiveness, and drug resistance [ 14 , 35 ].…”

Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity

“…Regarding genetic factors, fair-skinned, red-haired individuals are more susceptible to damage from UV radiation than those who have dark skin pigmentation due to polymorphisms in the melanocortin 1 receptor (MC1R) gene, which lead to reduced melanin production [ 6 , 7 ]. Molecular abnormalities can drive melanoma growth by stimulating proliferation, clonal survival and synthesis of growth factors and other molecules that ultimately modify the normal, microenvironment of the skin and how cells in this microenvironment communicate with each other [ 8 , 9 ].…”

“…Such a model, however, fails to explain the molecular signaling heterogeneity that characterizes melanoma [ 16 ]. This can be largely the result of various signaling cues and crosstalk from the surrounding microenvironment that can lead to changes in growth rate and rapid increase in aggressiveness [ 9 , 17 ]. The identification of the sources of these specific cues within the tumor microenvironment and, most importantly, the timing of their expression during the different stages of melanoma progression remains unclear.…”