A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue

Abstract

The development of a modified stromal microenvironment in response to neoplastic onset is a common feature of many tumors including cutaneous melanoma. At all stages, melanoma cells are embedded in a complex tissue composed by extracellular matrix components and several different cell populations. Thus, melanomagenesis is not only driven by malignant melanocytes, but also by the altered communication between melanocytes and non-malignant cell populations, including fibroblasts, endothelial and immune cells. In particular, cancer-associated fibroblasts (CAFs), also referred as melanoma-associated fibroblasts (MAFs) in the case of melanoma, are the most abundant stromal cells and play a significant contextual role in melanoma initiation, progression and metastasis. As a result of dynamic intercellular molecular dialogue between tumor and the stroma, non-neoplastic cells gain specific phenotypes and functions that are pro-tumorigenic. Targeting MAFs is thus considered a promising avenue to improve melanoma therapy. Growing evidence demonstrates that aberrant regulation of oncogenic signaling is not restricted to transformed cells but also occurs in MAFs. However, in some cases, signaling pathways present opposite regulation in melanoma and surrounding area, suggesting that therapeutic strategies need to carefully consider the tumor-stroma equilibrium. In this novel review, we analyze four major signaling pathways implicated in melanomagenesis, TGF-β, MAPK, Wnt/β-catenin and Hyppo signaling, from the complementary point of view of tumor cells and the microenvironment.

Keywords: cancer associated fibroblast; melanoma; melanomagenesis; tumor microenvironment.

Figure 1

Schematic representation of tumor–stroma cross-talk. In melanoma, tumor cells share their microenvironment with MAFs, immune cells and blood vessels. Resident fibroblasts might oppose an early anti-tumor activity or facilitate tumor development, whereas, during disease progression, activated MAFs gradually acquire a marked pro-tumorigenic phenotype. An intense bi-directional exchange of soluble factors between melanoma and surrounding cells significantly modifies in MAFs several intracellular signaling pathways including oncogenic pathways. Extracellular matrix supports tumor architecture and influences various signal transduction pathways in both tumor and associated cells.

Figure 2

Tumor promoting function of oncogenic pathways deregulated in CAFs. Scheme recapitulates data presented concerning Wnt, Hippo, TGFβ and MAPK pathways deregulation in MAFs and melanoma cells. Mostly, activation of these pathways in MAFs exerts a pro-tumorigenic effect with the exception of Hippo signaling that trigger a competition between tumor and stroma characterized by a tumor-suppressive function.