Zhang Bingyu, Dang Jianzhong, Ba Diandian, Wang Cencen, Han Juan, Zheng Fang
Department of Paediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Oncol Lett. 2018 Nov;16(5):6163-6170. doi: 10.3892/ol.2018.9354. Epub 2018 Aug 23.
Extensive clinical evidence supports that cytotoxic T lymphocyte antigen-4 (CTLA-4) is expressed in a variety of human malignant tumour cells in addition to T cells. In certain types of cancer, the overexpression of CTLA-4 is associated with poor patient prognosis. However, few studies have demonstrated the effects of tumour-intrinsic CTLA-4 in cancer stem cells, including melanoma stem cells (MSCs). In the present study, it was demonstrated that melanoma cell-intrinsic CTLA-4 induced tumour cell proliferation and suppressed tumour cell apoptosis. Furthermore, CTLA-4 was expressed in aldehyde dehydrogenase (ALDH)+ MSCs. CTLA-4 inhibited MSCs proliferation by blocking antibodies and significantly downregulated ALDH1A1, ALDH1A3 and ALDH2 mRNA expression (P<0.01). Functionally, blocking CTLA-4 in melanoma cell lines suppressed the properties of stem-like cells, including ALDH activity and significantly suppressed the ability of these cells to form spheres (P<0.05). In addition, the blocking of CTLA-4 in melanoma cells suppressed the properties of stem-like cells , including the capacity for tumourigenesis. The presence of residual ALDH+ MSCs within the tumour was observed, and the blocking CTLA-4 significantly decreased the number of residual ALDH+ MSCs (P<0.01). Altogether, these results indicate the identification of a novel mechanism underlying melanoma progression in the present study and that CTLA-4-targeted therapy may benefit candidate CTLA-4-targeted therapy by improving the long-term outcome for patients with advanced stages of melanoma.
大量临床证据支持，除了T细胞外，细胞毒性T淋巴细胞抗原4（CTLA-4）在多种人类恶性肿瘤细胞中也有表达。在某些类型的癌症中，CTLA-4的过表达与患者预后不良相关。然而，很少有研究证明肿瘤内在的CTLA-4对癌症干细胞的影响，包括黑色素瘤干细胞（MSC）。在本研究中，证明了黑色素瘤细胞内在的CTLA-4可诱导肿瘤细胞增殖并抑制肿瘤细胞凋亡。此外，CTLA-4在醛脱氢酶（ALDH）+ MSC中表达。CTLA-4通过阻断抗体抑制MSC增殖，并显著下调ALDH1A1、ALDH1A3和ALDH2 mRNA表达（P<0.01）。在功能上，阻断黑色素瘤细胞系中的CTLA-4可抑制干细胞样细胞的特性，包括ALDH活性，并显著抑制这些细胞形成球体的能力（P<0.05）。此外，阻断黑色素瘤细胞中的CTLA-4可抑制干细胞样细胞的特性，包括肿瘤发生能力。观察到肿瘤内存在残留的ALDH+ MSC，阻断CTLA-4可显著减少残留的ALDH+ MSC数量（P<0.01）。总之，这些结果表明在本研究中确定了黑色素瘤进展的一种新机制，并且CTLA-4靶向治疗可能通过改善晚期黑色素瘤患者的长期预后而使候选CTLA-4靶向治疗受益。
