Perspective of Targeting Cancer-Associated Fibroblasts in Melanoma

Abstract

Melanoma is known as an exceptionally aggressive and treatment-resistant human cancer. Although a great deal of progress has been made in the past decade, including the development of immunotherapy using immune checkpoint inhibitors and targeted therapy using BRAF, MEK or KIT inhibitors, treatment for unresectable stage III, stage IV, and recurrent melanoma is still challenging with limited response rate, severe side effects and poor prognosis, highlighting an urgent need for discovering and designing more effective approaches to conquer melanoma. Melanoma is not only driven by malignant melanocytes, but also by the altered communication between neoplastic cells and non-malignant cell populations, including fibroblasts, endothelial and inflammatory cells, in the tumor stroma. Infiltrated and surrounding fibroblasts, also known as cancer-associated fibroblasts (CAFs), exhibit both phenotypical and physiological differences compared to normal dermal fibroblasts. They acquire properties of myofibroblasts, remodel the extracellular matrix (ECM) and architecture of the diseased tissue and secrete chemical factors, which all together promote the transformation process by encouraging tumor growth, angiogenesis, inflammation and metastasis and contribute to drug resistance. A number of in vitro and in vivo experiments have shown that stromal fibroblasts promote melanoma cell proliferation and they have been targeted to suppress tumor growth effectively. Evidently, a combination therapy co-targeting tumor cells and stromal fibroblasts may provide promising strategies to improve therapeutic outcomes and overcome treatment resistance. A significant benefit of targeting CAFs is that the approach aims to create a tumor-resistant environment that inhibits growth of melanomas carrying different genetic mutations. However, the origin of CAFs and precise mechanisms by which CAFs contribute to melanoma progression and drug resistance remain poorly understood. In this review, we discuss the origin, activation and heterogeneity of CAFs in the melanoma tumor microenvironment and examine the contributions of stromal fibroblasts at different stages of melanoma development. We also highlight the recent progression in dissecting and characterizing how local fibroblasts become reprogrammed and build a dynamic yet optimal microenvironment for tumors to develop and metastasize. In addition, we review key developments in ongoing preclinical studies and clinical applications targeting CAFs and tumor-stroma interactions for melanoma treatment.

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…The realization of these biological links justifies the design of clinical studies based on the targeting of CAF (and, more generally, reversal of the attributes of a protumorigenic microenvironment) in addition to targeting cancer cells in order to create a tumor-resistant environment that inhibits malignant phenotypes in diseased epithelial cells (Takebe et al 2013;Togo et al 2013;Zhou et al 2015). Such clinical studies can now be envisioned based on the findings from experimental studies with agents directed against fibroblast-specific proteins (FAP, COL11A1, and MFAP5) or signaling pathways exemplified in CAFs (TGF-β, hedgehog, Notch, FGF, PDGF, or C-X-C motif ligand 2 [CXCL2]/CXCR4 signaling).…”

Tipping Tumor Microenvironment against Drug Resistance

“…Functioning as the paracrine niche meanwhile, CAFs secret an important array of growth factors, including hepatic growth factor (HGF) and PDGF which bind to their specific receptors (c-MET and PDGFR respectively) on cancer cells, to activate downstream signaling kinase cascades and to consequently augment proliferation and survival of malignant cells [42,43]. CAFs can also produce CXCL12 and activate CXCR4 pathway, thereby enhancing tumor cell migration and cancer metastasis [44]. Besides, it has been found that, upon anti-cancer chemical compound treatment, CAFs strikingly up-regulate interleukine-17A (IL-17A) secretion, which is associated with promoting CSC renewal.…”

Reaping Wnt after calming Hippo: Wnt and Hippo signaling cross paths in lung cancer

“…However, exploiting this knowledge and restoring the functionality of these pathways is a daunting task. The immense progress in tumor immunology and immune therapy has shown the power of targeting nontumor cells rather than tumor cells (22).…”