Heterogeneity of Melanoma with Stem Cell Properties
Metastatic melanoma continues to present a significant challenge—with a cure rate of less than 10% and a median survival of 6–9 months. Despite noteworthy advances in the field, the heterogeneity of melanoma tumors, comprised of cell subpopulations expres
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Heterogeneity of Melanoma with Stem Cell Properties Elisabeth A. Seftor, Naira V. Margaryan, Richard E. B. Seftor, and Mary J. C. Hendrix
Abstract Metastatic melanoma continues to present a significant challenge—with a cure rate of less than 10% and a median survival of 6–9 months. Despite noteworthy advances in the field, the heterogeneity of melanoma tumors, comprised of cell subpopulations expressing a cancer stem cell (CSC) phenotype concomitant with drug resistance markers presents a formidable challenge in the design of current therapies. Particularly vexing is the ability of distinct subpopulations of melanoma cells to resist standard-of-care treatments, resulting in relapse and progression to metastasis. Recent studies have provided new information and insights into the expression and function of CSC markers associated with the aggressive melanoma phenotype, such as the embryonic morphogen Nodal and CD133, together with a drug resistance marker ABCA1. This chapter highlights major findings that demonstrate the promise of targeting Nodal as a viable option to pursue in combination with standard-of-care therapy. In recognizing that aggressive melanoma tumors utilize multiple mechanisms to survive, we must consider a more strategic approach to effectively target heterogeneity, tumor cell plasticity, and functional adaptation and resistance to current therapies—to eliminate relapse, disease progression, and metastasis. Keywords Melanoma · Tumor plasticity · Heterogeneity · Cancer stem cell · Nodal · Drug resistance · ABCA1 · Vasculogenic mimicry · Recurrent disease · CD133 · Metastatic disease · Prognostic biomarker
E. A. Seftor · N. V. Margaryan · R. E. B. Seftor Department of Biochemistry and Cancer Institute, West Virginia University Health Sciences Center, One Medical Center Drive, Morgantown, WV, USA M. J. C. Hendrix (*) Department of Biology, Shepherd University, Shepherdstown, WV, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 A. Birbrair (ed.), Stem Cells Heterogeneity in Cancer, Advances in Experimental Medicine and Biology 1139, https://doi.org/10.1007/978-3-030-14366-4_6
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Abbreviations ABCA1 ATP-Binding Cassette gene/protein, member A1 BRAF V-RAF murine sarcoma viral oncogene homolog B1 BRAFi BRAF inhibitor CSCs Cancer Stem Cells DTIC Dacarbazine hESCs Human embryonic stem cells L-R Left-Right mAb Monoclonal antibody PD-1 Programmed death 1 TGFβ Transforming growth factor β VM Vasculogenic Mimicry
6.1 Introduction It is important to recognize that metastatic melanoma continues to be a significantly deadly cancer with a cure rate of less than 10% and a median survival of 6–9 months (Song et al. 2015). One of the greatest challenges in effectively eradicating aggressive melanoma is developing therapeutic strategies that can successfully target tumor heterogeneity—comprised of subpopulations of melanoma cells (expressing various markers) that have the potential to functionally adapt to their changing microenvironment and resist various stan
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