Vergani Elisabetta, Di Guardo Lorenza, Dugo Matteo, Rigoletto Sara, Tragni Gabrina, Ruggeri Roberta, Perrone Federica, Tamborini Elena, Gloghini Annunziata, Arienti Flavio, Vergani Barbara, Deho Paola, De Cecco Loris, Vallacchi Viviana, Frati Paola, Shahaj Eriomina, Villa Antonello, Santinami Mario, De Braud Filippo, Rivoltini Licia, Rodolfo Monica
Immunotherapy Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Oncotarget. 2016 Jan 26;7(4):4428-41. doi: 10.18632/oncotarget.6599.
In melanoma, the adaptative cell response to BRAF inhibitors includes altered patterns of cytokine production contributing to tumor progression and drug resistance. Among the factors produced by PLX4032-resistant melanoma cell lines, CCL2 was higher compared to the sensitive parental cell lines and increased upon drug treatment. CCL2 acted as an autocrine growth factor for melanoma cells, stimulating the proliferation and resistance to apoptosis. In patients, CCL2 is detected in melanoma cells in tumors and in plasma at levels that correlate with tumor burden and lactate dehydrogenase. Vemurafenib treatment increased the CCL2 levels in plasma, whereas the long-term clinical response was associated with low CCL2 levels.Increased CCL2 production was associated with miRNA deregulation in the resistant cells. miR-34a, miR-100 and miR-125b showed high expression in both resistant cells and in tumor biopsies that were obtained from treated patients, and they were involved in the control of cell proliferation and apoptosis. Inhibition of CCL2 and of the selected miRNAs restored both the cell apoptosis and the drug efficacy in resistant melanoma cells. Therefore, CCL2 and miRNAs are potential prognostic factors and attractive targets for counteracting treatment resistance in metastatic melanoma.
在黑色素瘤中，细胞对BRAF抑制剂的适应性反应包括细胞因子产生模式的改变，这有助于肿瘤进展和耐药性。在PLX4032耐药的黑色素瘤细胞系产生的因子中，与敏感的亲本细胞系相比，CCL2水平更高，且在药物处理后升高。CCL2作为黑色素瘤细胞的自分泌生长因子，刺激细胞增殖并抵抗凋亡。在患者中，肿瘤中的黑色素瘤细胞和血浆中均可检测到CCL2，其水平与肿瘤负荷和乳酸脱氢酶相关。维莫非尼治疗可增加血浆中CCL2水平，而长期临床反应与低CCL2水平相关。CCL2产生增加与耐药细胞中的miRNA失调有关。miR-34a、miR-100和miR-125b在耐药细胞和接受治疗患者的肿瘤活检组织中均高表达，且它们参与细胞增殖和凋亡的调控。抑制CCL2和所选miRNA可恢复耐药黑色素瘤细胞的细胞凋亡和药物疗效。因此，CCL2和miRNA是转移性黑色素瘤潜在的预后因素和克服治疗耐药性的有吸引力的靶点。
