title: Dermal fibroblasts induce cell cycle arrest and block epithelial-mesenchymal transition to inhibit the early stage melanoma development.
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.
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45267.
authors.forename: Linli
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45267.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45267.
authors.forename: R
authors.initials: R
authors.lastname: Randall Wickett
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45267.
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D021381:Protein Transport; D015398:Signal Transduction; D059016:Tumor Microenvironment; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D051176:beta Catenin
keywords: Melanoma; Wnt signaling; stromal fibroblasts; tumor microenvironment; β-catenin