Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Department of Public Health, University of Naples Federico II, Naples, Italy.
Semin Cancer Biol. 2019 Dec;59:187-207. doi: 10.1016/j.semcancer.2019.07.016. Epub 2019 Jul 27.
Cutaneous melanoma (CM) represents one of the most metastasizing and drug resistant solid tumors. CM is characterized by a remarkable metabolic plasticity and an important connection between oncogenic activation and energetic metabolism. In fact, melanoma cells can use both cytosolic and mitochondrial compartments to produce adenosine triphosphate (ATP) during cancer progression. However, the CM energetic demand mainly depends on glycolysis, whose upregulation is strictly linked to constitutive activation of BRAF/MAPK pathway affected by BRAF kinase mutant. Furthermore, the impressive metabolic plasticity of melanoma allows the development of resistance mechanisms to BRAF/MEK inhibitors (BRAFi/MEKi) and the adaptation to microenvironmental changes. The metabolic interaction between melanoma cells and tumor microenvironment affects the immune response and CM growth. In this review article, we describe the regulation of melanoma metabolic alterations and the metabolic interactions between cancer cells and microenvironment that influence melanoma progression and immune response. Finally, we summarize the hallmarks of melanoma therapies and we report BRAF/MEK pathway targeted therapy and mechanisms of metabolic resistance.
皮肤黑色素瘤（CM）是最具转移性和耐药性的实体肿瘤之一。CM 的特征是具有显著的代谢可塑性，以及致癌激活与能量代谢之间的重要联系。事实上，黑色素瘤细胞在癌症进展过程中可以利用细胞质和线粒体区室来产生三磷酸腺苷（ATP）。然而，CM 的能量需求主要依赖于糖酵解，其上调与受 BRAF 激酶突变影响的 BRAF/MAPK 通路的组成性激活严格相关。此外，黑色素瘤令人印象深刻的代谢可塑性允许对 BRAF/MEK 抑制剂（BRAFi/MEKi）产生耐药机制，并适应微环境变化。黑色素瘤细胞与肿瘤微环境之间的代谢相互作用会影响免疫反应和 CM 的生长。在这篇综述文章中，我们描述了黑色素瘤代谢改变的调控以及癌细胞与微环境之间的代谢相互作用，这些相互作用影响黑色素瘤的进展和免疫反应。最后，我们总结了黑色素瘤治疗的特征，并报告了 BRAF/MEK 通路靶向治疗和代谢耐药的机制。
