Sano Tomohiko, Sun Xun, Feng Yan, Liu Shengzhi, Hase Misato, Fan Yao, Zha Rongrong, Wu Di, Aryal Uma K, Li Bai-Yan, Sudo Akihiro, Yokota Hiroki
Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Edobashi Tsu 2-174, Japan.
Cancers (Basel). 2021 Mar 3;13(5):1061. doi: 10.3390/cancers13051061.
The brain is a common site of metastasis from advanced breast cancer but few effective treatments are available. We examined a therapeutic option with a conditioned medium (CM), focusing on the role of Lrp5 and β-catenin in Wnt signaling, and IL1ra in osteocytes. Osteocytes presented the innate anti-tumor effect and the overexpression of the above genes strengthened their action. In a mouse model, the injection of their CM inhibited mammary tumors and tumor-driven osteolysis. Importantly, Lrp5- and/or IL1ra-overexpressing osteocytes or the local administration of β-catenin-overexpressing CM markedly inhibited brain tumors. In the transport analysis, tumor-suppressing factors in CM were shown to diffuse through the skull. Mechanistically, the CM with overexpression of the above genes downregulated oncogenic genes such as MMP9, Runx2, TGFβ, and Snail in breast cancer cells. Also, the CM with β-catenin overexpression downregulated CXCL1 and CXCL5 and upregulated tumor suppressors such as LIMA1, DSP, p53, and TRAIL in breast cancer cells. Notably, whole-genome proteomics revealed that histone H4 was enriched in CM and acted as an atypical tumor suppressor. Lrp5-overexpressing MSCs were also shown to act as anti-tumor agents. Collectively, this study demonstrated the therapeutic role of engineered CM in brain tumors and the tumor-suppressing action of extracellular histone H4. The result sheds light on the potential CM-based therapy for breast cancer-associated brain metastases in a minimally invasive manner.
脑是晚期乳腺癌常见的转移部位，但有效的治疗方法却很少。我们研究了一种使用条件培养基（CM）的治疗方案，重点关注低密度脂蛋白受体相关蛋白5（Lrp5）和β-连环蛋白在Wnt信号通路中的作用，以及白细胞介素1受体拮抗剂（IL1ra）在骨细胞中的作用。骨细胞具有天然的抗肿瘤作用，上述基因的过表达增强了它们的作用。在小鼠模型中，注射它们的条件培养基可抑制乳腺肿瘤和肿瘤驱动的骨溶解。重要的是，过表达Lrp5和/或IL1ra的骨细胞或局部给予过表达β-连环蛋白的条件培养基可显著抑制脑肿瘤。在转运分析中，条件培养基中的肿瘤抑制因子显示可通过颅骨扩散。从机制上讲，过表达上述基因的条件培养基可下调乳腺癌细胞中的致癌基因，如基质金属蛋白酶9（MMP9）、 runt相关转录因子2（Runx2）、转化生长因子β（TGFβ）和蜗牛蛋白（Snail）。此外，过表达β-连环蛋白的条件培养基可下调乳腺癌细胞中的趋化因子CXC趋化因子配体1（CXCL1）和CXC趋化因子配体5（CXCL5），并上调肿瘤抑制因子，如富含亮氨酸重复序列的整合素结合蛋白1（LIMA1）、桥粒斑蛋白（DSP）、p53和肿瘤坏死因子相关凋亡诱导配体（TRAIL）。值得注意的是，全基因组蛋白质组学显示组蛋白H4在条件培养基中富集，并作为一种非典型肿瘤抑制因子发挥作用。过表达Lrp5的间充质干细胞也显示出抗肿瘤作用。总的来说，这项研究证明了工程化条件培养基在脑肿瘤中的治疗作用以及细胞外组蛋白H4的肿瘤抑制作用。该结果为以微创方式基于条件培养基治疗乳腺癌相关脑转移瘤的潜力提供了线索。
