Abstract
Stromal fibroblasts are an integral part of the tumor stroma and constantly interact with cancer cells to promote their initiation and progression. However, the role and function of dermal fibroblasts during the early stage of melanoma development remain poorly understood. We, therefore, designed a novel genetic approach to deactivate stromal fibroblasts at the onset of melanoma formation by targeted ablation of β‐catenin. To our surprise, melanoma tumors formed from β‐catenin‐deficient group (B16F10 mixed with β‐catenin‐deficient fibroblasts) appeared earlier than tumors formed from control group (B16F10 mixed with normal dermal fibroblasts). At the end point when tumors were collected, mutant tumors were bigger and heavier than control tumors. Further analysis showed that there were fewer amounts of stromal fibroblasts and myofibroblasts inside mutant tumor stroma. Melanoma tumors from control group showed reduced proliferation, down‐regulated expression of cyclin D1 and increased expression of cyclin‐dependent kinase inhibitor p16, suggesting dermal fibroblasts blocked the onset of melanoma tumor formation by inducing a cell cycle arrest in B16F10 melanoma cells. Furthermore, we discovered that dermal fibroblasts prevented epithelial‐mesenchymal transition in melanoma cells. Overall, our findings demonstrated that dermal fibroblasts crosstalk with melanoma cells to regulate in vivo tumor development via multiple mechanisms, and the outcomes of their reciprocal interactions depend on activation states of stromal fibroblasts and stages of melanoma development.
Highlights
Cutaneous melanoma consists of melanoma cells and a heterogeneous mix of genetically stable non- cancer cells, including endothelial cells, immune cells, and fibroblasts, embedded in a tumor-s pecific extracellular matrix (ECM) [1]
We discovered that tumor cells had decreased E-cadherin expression (Fig. 6B) and increased N-cadherin and Vimentin expression (Fig. 6D and F) in melanoma tumors formed from B16F10; bcat/Fb mixture
It has been reported that melanocytes are restricted in the epidermis due to the E-cadherin-mediated interactions with keratinocytes [34]
Summary
Cutaneous melanoma consists of melanoma cells and a heterogeneous mix of genetically stable non- cancer cells, including endothelial cells, immune cells, and fibroblasts, embedded in a tumor-s pecific extracellular matrix (ECM) [1]. Infiltrated and surrounding stromal fibroblasts are stimulated into an activated state through continuous paracrine cell–cell communication with tumor cells and transdifferentiate into cancer-associated fibroblasts (CAFs) [3]. CAFs subsequently acquire properties of myofibroblasts and produce various growth factors, cytokines, and ECM proteins, which remodel the stromal architecture of the diseased tissue and create an optimal niche for tumor cells to grow, migrate, and evade death. One major source of CAFs in melanoma is resident normal skin fibroblasts (NFs), which are recruited and activated by chemical factors released from melanoma cells [5].
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