Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers
Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers
复制标题
DOI：
10.2147/ott.s238143
复制
发表时间：
2020-01-01
影响因子：
4
通讯作者：
Liu, Chin-San
中科院分区：
文献类型：
--
作者：
Chang, Jui-Chih;Chang, Huei-Shin;Liu, Chin-San
背景资料：已证明整个线粒体的转移对治疗乳腺癌是有益的，因为它诱导细胞凋亡和药物敏感性;然而，这种益处的体内证据仍然很少。本研究使用三阴性乳腺癌的小鼠模型比较了具有本能（Mito）和由Pep-1缀合（P-Mito）诱导的膜融合形态的线粒体的移植。晚期严重免疫缺陷小鼠接受MDA-MB-231人乳腺癌细胞原位移植，随后移植5-溴-2 '-脱氧尿苷（BrdU）标记的Mito或P-Mito结果：连续给药1个月后，Mito组和P-Mito组肿瘤中BrdU标记的线粒体分别有8.2%和14.2%保留。Pep-1和P-Mito治疗均降低肿瘤重量（21.7% +/- 2.43% vs 40.6% +/- 2.28%），并导致Ki 67染色和血管生成的显著抑制。然而，只有P-Mito组表现出明显的坏死和DNA片段化，并伴有肿瘤微环境的改变，包括氧化应激和癌症相关成纤维细胞群的大小减少以及免疫细胞浸润增强。透射电子显微镜图像进一步揭示了一个细长的网络核周线粒体融合的一些周边线粒体在nonnecrotic区域的P-Mito组，以及增加线粒体融合蛋白和parkin相比，线粒体fistula protein.Conclusion：在这项研究中，线粒体移植的结果强调，促进线粒体融合是一个重要的调节剂在乳腺癌治疗。
Background: The transfer of whole mitochondria has been demonstrated to be beneficial for treating breast cancer because it induces apoptosis and drug sensitivity; however, in vivo evidence of this benefit remains scant. The present study compared the transplantation of mitochondria with instinctive (Mito) and membrane-fused morphologies induced by Pep-1 conjugation (P-Mito) using a mouse model of triple-negative breast cancers.Materials and Methods: Mice with advanced severe immunodeficiency received orthotopic implantation of MDA-MB-231 human breast cancer cells followed by transplants of 5-bromo-2'-deoxyuridine (BrdU)-labeled Mito or P-Mito (200 mu g [10 mu g/mu L]) through intratumoral injection at multiple points once a week for 4 weeks.Results: After 1 month of consecutive treatment, 8.2% and 14.2% of the BrdU-labeled mitochondria were preserved in tumors of the Mito and P-Mito groups, respectively. Both Pep-1 and P-Mito treatments reduced tumor weight (21.7% +/- 2.43% vs 40.6% +/- 2.28%) and led to marked inhibition of Ki67 staining and angiogenesis. However, only the P-Mito group exhibited obvious necrosis and DNA fragmentation accompanied by an altered tumor microenvironment, which included reduced oxidative stress and size of cancer-associated fibroblast populations and enhanced immune cell infiltration. Transmission electron microscopy images further revealed an elongated network of perinuclear mitochondria fused with a few peripheral mitochondria in the nonnecrotic area in the P-Mito group as well as increases in mitochondrial fusion proteins and parkin compared with mitochondrial fission proteins.Conclusion: In this study, the results of mitochondrial transplantation emphasized that the facilitation of mitochondrial fusion is a critical regulator in breast cancer therapy.