Tumor Microenvironment for Melanoma Cells
Melanoma represents an ideal experimental system to model the influence of the tumor microenvironment on neoplastic cells given that a rich collection of cell types is localized in the physiological environment. Melanoma cells actively interact with the t
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Lawrence W. Wu, Meenhard Herlyn, and Gao Zhang
14.1 Introduction Melanoma is the most deadly cancer in the skin with a 5-year survival rate of advanced, metastatic disease at 15 %. Fortunately, recent years have witnessed breakthroughs in melanoma therapies such as targeted therapy, vemurafenib, to block the MAPK signaling pathway by specifically targeting mutated oncogenic BRAF (Bollag et al. 2010; Flaherty et al. 2010). Additionally, combining a BRAF inhibitor (Dabrafenib) with an MEK inhibitor (Trametinib) increased efficacy of treatment by overcoming certain resistance mechanisms with BRAF inhibition alone (Johnson et al. 2014; Shi et al. 2014). This increased efficacy is also seen in the combination of vemurafenib and cobimetinib, another MEK inhibitor (Larkin et al. 2014). Immune checkpoint blockade therapies targeting immune inhibitory molecules have yielded tremendous clinical responses as well. Targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) using Ipilimumab (anti-CTLA-4) paved the way for other immune checkpoint blockade therapies, such as nivolumab and pembrolizumab (anti-PD1), which target programmed cell death protein 1 (PD-1) (Hodi et al. 2010). Nivolumab was found to have greater response and efficacy than Ipilimumab as a single agent therapy (Robert et al. 2015). Additionally, the combination of nivolumab and Ipilimumab is more effective than single agent ipilumumab (Postow et al. 2015). Lastly, talimogene laherparepvec (T-VEC),
L.W. Wu Medical Scientist Training Program, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA M. Herlyn (*) • G. Zhang Molecular and Cellular Oncogenesis Program, The Wistar Institute Melanoma Research Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA e-mail: [email protected] © Springer International Publishing AG 2017 A. Bosserhoff (ed.), Melanoma Development, DOI 10.1007/978-3-319-41319-8_14
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IGF1 VEGF bFGF IL-6 CCL21
PDGF bFGF EGF TGFb IL-6
Melanocyte
Melanoma cell
soluble growth factor
Fibroblast Keratinocyte
Endothelial cell
Nevus cell
Basement membrane
Fig. 14.1 Schematic representation of cross-talk between melanoma cells and tumor microenvironment. Normal melanocytes are localized at the basement membrane that separates epidermis from dermis and they are tightly regulated by surrounding keratinocytes through direct cell–cell contact. Upon transformation, the tight regulation mediated by E-cadherin is lost and replaced by N-cadherin between melanoma cells and adjacent cells. During melanoma development and progression, melanoma cells secrete soluble factors to recruit distant fibroblasts or immune cells in tumor microenvironment to its peritumoral zone. Stromal cells, including fibroblasts, endothelial cells, and immune cells, are activated and participate through paracrine signaling pathways to facilitate degradation of the basement membrane, invasion into the dermis, and metastatic dissemination. The dynamic communication between mel
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