Canonical Wnt and TGF-β/BMP signaling enhance melanocyte regeneration and suppress invasiveness, migration, and proliferation of melanoma cells

Abstract

Tissue regeneration and cancer share remarkable features including activation of cell proliferation and migration. Yet, tumors considerably differ from the regenerating tissue with respect to abnormal proliferation, invasive growth, and metastasis. Thus, it is likely that cancer resembles early stages of regeneration with increased proliferation, but separates from the later stages with reduced proliferation and enhanced differentiation. Here, by exploiting the zebrafish melanocytes that can efficiently regenerate and be induced to undergo malignant melanoma, we unravel the transcriptome profiles of the regenerating melanocytes during early and late regeneration, and the melanocytic nevi and malignant melanoma. Our global comparison of the gene expression profiles of melanocyte regeneration and nevi/melanoma uncovers the differential regulation of a substantial number of genes related to Wnt signaling and TGF-{beta}/BMP signaling pathways between regeneration and cancer. Functional activation of canonical Wnt or TGF-{beta}/BMP pathways during melanocyte regeneration promoted melanocyte regeneration and potently suppressed the invasiveness, migration, and proliferation of human melanoma cells in vitro and in vivo. Therefore, differential regulation of signaling mechanisms between regeneration and cancer can be exploited to stop tumor growth and develop new anticancer therapies.