Zhao Jing-Yi, Ma Xue-Lei, Li Zhi-Mian, Deng Rui, Wang Shi-Min, Shen Guo-Bo, Zhang Jing, Wang Feng-Tian, Zhang Bing-Lan, Wei Yu-Quan
The Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Guo Xue Xiang, No.37, Chengdu, 610041, Sichuan, People's Republic of China.
Clin Exp Med. 2015 May;15(2):127-35. doi: 10.1007/s10238-014-0277-6. Epub 2014 Mar 12.
The pathogenic mechanism of malignant melanoma involves the dynamic interplay of transformed cell and normal host cell, but cancer treatments always target each partition separately. In the tumor microenvironment, milk fat globule epidermal growth factor-8 (MFG-E8) is a secreted glycoprotein highly expressed in the vertical growth phase of melanoma, leading to tumor progression through coordinated αvβ3 and αvβ5 integrin signaling in tumor cells and host cells. Doxorubicin (Dox) is one of the most widely used antitumor drugs against a lot of solid tumors, including melanoma. In this work, Dox was used to combine with down-regulation of MFG-E8 by RNA interference (RNAi) in order to determine the synergistic effect of the antitumor activity in vivo. And the possible mechanisms were investigated. Results showed that combination group (MFG-E8 RNAi plus Dox) could inhibit the growth of melanoma more effectively than monotherapy or control groups. We found that the combination treatment induced more tumor cell apoptosis and inhibited more neovascularization than other groups. Moreover, this combination treatment attenuated CD4(+) CD25(+) Foxp3(+) Treg cells in tumor-infiltrating lymphocytes compared with other groups. Our findings suggested that MFG-E8 down-regulation enhanced the antitumor function of chemotherapy through coordinated cell apoptosis and immune-mediated mechanisms, which might be a feasible way for cancer therapy.
恶性黑色素瘤的致病机制涉及转化细胞与正常宿主细胞之间的动态相互作用，但癌症治疗总是分别针对每个部分。在肿瘤微环境中，乳脂肪球表皮生长因子8（MFG-E8）是一种分泌型糖蛋白，在黑色素瘤的垂直生长期高度表达，通过肿瘤细胞和宿主细胞中αvβ3和αvβ5整合素信号的协同作用导致肿瘤进展。阿霉素（Dox）是治疗包括黑色素瘤在内的多种实体瘤最广泛使用的抗肿瘤药物之一。在这项研究中，将Dox与通过RNA干扰（RNAi）下调MFG-E8相结合，以确定体内抗肿瘤活性的协同作用。并对可能的机制进行了研究。结果表明，联合治疗组（MFG-E8 RNAi加Dox）比单药治疗组或对照组更有效地抑制黑色素瘤的生长。我们发现，联合治疗比其他组诱导更多的肿瘤细胞凋亡并抑制更多的新生血管形成。此外，与其他组相比，这种联合治疗使肿瘤浸润淋巴细胞中的CD4(+) CD25(+) Foxp3(+)调节性T细胞减少。我们的研究结果表明，下调MFG-E8通过协调细胞凋亡和免疫介导机制增强了化疗的抗肿瘤功能，这可能是一种可行的癌症治疗方法。
