Transforming Growth Factor-β/Smad Signaling Inhibits Melanoma Cancer Stem Cell Self-Renewal, Tumor Formation and Metastasis

Abstract

The secreted protein transforming growth factor-beta (TGFβ) plays essential roles, ranging from cell growth regulation and cell differentiation in both normal and cancer cells. In melanoma, TGFβ acts as a potent tumor suppressor in melanoma by blocking cell cycle progression and inducing apoptosis. In the present study, we found TGFβ to regulate cancer stemness in melanoma through the Smad signaling pathway. We discovered that TGFβ/Smad signaling inhibits melanosphere formation in multiple melanoma cell lines and reduces expression of the CD133+ cancer stem cell subpopulation in a Smad3-dependent manner. Using preclinical models of melanoma, we further showed that preventing Smad3/4 signaling, by means of CRISPR knockouts, promoted both tumorigenesis and lung metastasis in vivo. Collectively, our results define new functions for the TGFβ/Smad signaling axis in melanoma stem-cell maintenance and open avenues for new therapeutic approaches to this disease.

Multiple Endocrine Neoplasia Type 1 Regulates TGFβ-Mediated Suppression of Tumor Formation and Metastasis in Melanoma

“…MEN1 patients can develop malignancies other than classical endocrine tumors, including skin tumors [ 29 ]. Previous work from our laboratory and others showed that the TGFβ signaling pathway acts as a potent tumor suppressor in melanoma [ 12 , 13 , 14 , 15 ]. Thus, we investigated whether MEN1 could relay some of the TGFβ tumor-suppressive response in melanoma.…”

“…The TGFβ/Smad signaling pathway exerts potent tumor-suppressive effects on melanoma [ 15 ]. We thus investigated the role and contribution of MEN1 downstream of TGFβ-mediated growth inhibition.…”

“…TGFβ signals through a complex of two serine/threonine kinase receptors and intracellular Smad proteins (Smad2, 3, and 4). In melanoma, the TGFβ/Smad3 signaling pathway strongly suppresses tumorigenesis by blocking cell growth, immortalization, and cancer stem cell self-renewal activities, and by inducing cell death and autophagy [ 13 , 14 , 15 ].…”

Cancer Stem Cells from Definition to Detection and Targeted Drugs

“…They showed that TGF-β acts as a potent suppressor of tumour development, migration, and metastasis. Additionally, it has been shown that there is potential in the use of agents that stimulate or mimic TGF-β as new methods to fight melanoma [159].…”

“…Also, for an efficacious therapy, all CSCs should be precisely eradicated to minimise risk of recurrence. In the past few years, a global effort has been made to design innovative therapeutic strategies against CSCs [10,[150][151][152][153][154][155][156][157][158][159]. The results seem to be promising to improve long-term health outcomes; however, the biology of CSCs and their susceptibility to various types of therapy depend on the model on which the research was carried out.…”