Cabaço Luís C, Tomás Ana, Pojo Marta, Barral Duarte C
Chronic Diseases Research Center (CEDOC), NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisbon, Portugal.
Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisbon, Portugal.
Front Oncol. 2022 May 10;12:887366. doi: 10.3389/fonc.2022.887366. eCollection 2022.
Skin cancers are among the most common cancers worldwide and are increasingly prevalent. Cutaneous melanoma (CM) is characterized by the malignant transformation of melanocytes in the epidermis. Although CM shows lower incidence than other skin cancers, it is the most aggressive and responsible for the vast majority of skin cancer-related deaths. Indeed, 75% of patients present with invasive or metastatic tumors, even after surgical excision. In CM, the photoprotective pigment melanin, which is produced by melanocytes, plays a central role in the pathology of the disease. Melanin absorbs ultraviolet radiation and scavenges reactive oxygen/nitrogen species (ROS/RNS) resulting from the radiation exposure. However, the scavenged ROS/RNS modify melanin and lead to the induction of signature DNA damage in CM cells, namely cyclobutane pyrimidine dimers, which are known to promote CM immortalization and carcinogenesis. Despite triggering the malignant transformation of melanocytes and promoting initial tumor growth, the presence of melanin inside CM cells is described to negatively regulate their invasiveness by increasing cell stiffness and reducing elasticity. Emerging evidence also indicates that melanin secreted from CM cells is required for the immunomodulation of tumor microenvironment. Indeed, melanin transforms dermal fibroblasts in cancer-associated fibroblasts, suppresses the immune system and promotes tumor angiogenesis, thus sustaining CM progression and metastasis. Here, we review the current knowledge on the role of melanin secretion in CM aggressiveness and the molecular machinery involved, as well as the impact in tumor microenvironment and immune responses. A better understanding of this role and the molecular players involved could enable the modulation of melanin secretion to become a therapeutic strategy to impair CM invasion and metastasis and, hence, reduce the burden of CM-associated deaths.
皮肤癌是全球最常见的癌症之一，且发病率日益上升。皮肤黑色素瘤（CM）的特征是表皮中的黑素细胞发生恶性转化。尽管CM的发病率低于其他皮肤癌，但它是最具侵袭性的，并且导致了绝大多数与皮肤癌相关的死亡。事实上，即使在手术切除后，75%的患者仍会出现侵袭性或转移性肿瘤。在CM中，由黑素细胞产生的光保护色素黑色素在该疾病的病理过程中起核心作用。黑色素吸收紫外线辐射并清除辐射暴露产生的活性氧/氮物种（ROS/RNS）。然而，被清除的ROS/RNS会修饰黑色素，并导致CM细胞中特征性DNA损伤的诱导，即环丁烷嘧啶二聚体，已知其会促进CM的永生化和致癌作用。尽管黑色素引发了黑素细胞的恶性转化并促进了肿瘤的初始生长，但CM细胞内黑色素的存在被描述为通过增加细胞硬度和降低弹性来负向调节其侵袭性。新出现的证据还表明，CM细胞分泌的黑色素是肿瘤微环境免疫调节所必需的。事实上，黑色素将真皮成纤维细胞转化为癌症相关成纤维细胞，抑制免疫系统并促进肿瘤血管生成，从而维持CM的进展和转移。在这里，我们综述了关于黑色素分泌在CM侵袭性中的作用、所涉及的分子机制，以及对肿瘤微环境和免疫反应的影响的现有知识。更好地理解这一作用和所涉及的分子参与者可能使黑色素分泌的调节成为一种治疗策略，以损害CM的侵袭和转移，从而减轻与CM相关的死亡负担。
