Sun Xun, Li Kexin, Aryal Uma K, Li Bai-Yan, Yokota Hiroki
Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China.
Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Mol Ther Oncolytics. 2022 Aug 5;26:360-371. doi: 10.1016/j.omto.2022.08.003. eCollection 2022 Sep 15.
Despite the advance in medications in the past decade, aggressive breast cancer such as triple-negative breast cancer is difficult to treat. Here, we examined a counter-intuitive approach to converting human bone marrow-derived mesenchymal stem cells (MSCs) into induced tumor-suppressing cells by administering YS49, a PI3K/Akt activator. Notably, PI3K-activated MSCs generated tumor-suppressive proteomes, while PI3K-inactivated MSCs tumor-promotive proteomes. In a mouse model, the daily administration of YS49-treated MSC-derived CM decreased the progression of primary mammary tumors as well as the colonization of tumor cells in the lung. In the assay, the size of freshly isolated human breast cancer tissues, including estrogen receptor positive and negative as well as human epidermal growth factor receptor 2 (HER2) positive and negative, was decreased by YS49-treated MSC-derived CM. Hsp90ab1 was enriched in CM as an atypical tumor-suppressing protein and immunoprecipitated a non-muscle myosin, Myh9. Extracellular Hsp90ab1 and Myh9 exerted the anti-tumor action and inhibited the maturation of bone-resorbing osteoclasts. Collectively, this study demonstrated that the activation of PI3K generated tumor-suppressive proteomes in MSCs and supported the possibility of using patient-derived MSCs for the treatment of breast cancer and bone metastasis.
尽管在过去十年中药物治疗取得了进展，但三阴性乳腺癌等侵袭性乳腺癌仍难以治疗。在此，我们研究了一种违反直觉的方法，即通过给予PI3K/Akt激活剂YS49，将人骨髓间充质干细胞（MSC）转化为诱导性肿瘤抑制细胞。值得注意的是，PI3K激活的MSC产生肿瘤抑制蛋白质组，而PI3K失活的MSC产生肿瘤促进蛋白质组。在小鼠模型中，每天给予经YS49处理的MSC来源的条件培养基（CM）可降低原发性乳腺肿瘤的进展以及肿瘤细胞在肺部的定植。在该实验中，经YS49处理的MSC来源的CM可减小新鲜分离的人乳腺癌组织的大小，包括雌激素受体阳性和阴性以及人表皮生长因子受体2（HER2）阳性和阴性的组织。热休克蛋白90α（Hsp90ab1）作为一种非典型肿瘤抑制蛋白在CM中富集，并免疫沉淀了一种非肌肉肌球蛋白Myh9。细胞外Hsp90ab1和Myh9发挥抗肿瘤作用并抑制骨吸收破骨细胞的成熟。总体而言，本研究表明PI3K的激活在MSC中产生肿瘤抑制蛋白质组，并支持使用患者来源的MSC治疗乳腺癌和骨转移的可能性。
