Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
Theranostics. 2021 Jul 25;11(17):8517-8534. doi: 10.7150/thno.61006. eCollection 2021.
: The progression of cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option. We previously created tumor-suppressive secretomes by activating Wnt signaling in MSCs. Here, we examined whether the anti-tumor secretomes can be produced from tumor cells. Wnt signaling was activated in tumor cells by overexpressing β-catenin or administering BML284, a Wnt activator. Their conditioned medium (CM) was applied to cancer cells or tissues, and the effects of CM were evaluated. Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through μCT imaging and histology. Whole-genome proteomics analysis was conducted to determine and characterize novel tumor-suppressing proteins, which were enriched in CM. The overexpression of β-catenin or the administration of BML284 generated tumor-suppressive secretomes from breast, prostate and pancreatic cancer cells. In the mouse model, β-catenin-overexpressing CM reduced tumor growth and tumor-driven bone destruction. This inhibition was also observed with BML284-treated CM. Besides p53 and Trail, proteomics analysis revealed that CM was enriched with enolase 1 (Eno1) and ubiquitin C (Ubc) that presented notable tumor-suppressing actions. Importantly, Eno1 immunoprecipitated CD44, a cell-surface adhesion receptor, and its silencing suppressed Eno1-driven tumor inhibition. A pan-cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes ( < 0.00001). CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator. The tumor-suppressive secretome can be generated from tumor cells, in which β-catenin presented two opposing roles, as an intracellular tumor promoter in tumor cells and a generator of extracellular tumor suppressor in CM. Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-tumor action. Besides presenting a potential option for treating primary cancers and metastases, the result indicates that aggressive tumors may inhibit the growth of less aggressive tumors via tumor-suppressive secretomes.
癌细胞的进展取决于土壤，而构建抑制性土壤可能是一种治疗选择。我们之前通过激活 MSC 中的 Wnt 信号来创建肿瘤抑制性的分泌组。在这里，我们研究了来自肿瘤细胞的抗肿瘤分泌组是否可以产生。通过过表达 β-catenin 或给予 Wnt 激活剂 BML284 激活肿瘤细胞中的 Wnt 信号。将它们的条件培养基（CM）应用于癌细胞或组织，并评估 CM 的作用。还通过 μCT 成像和组织学评估 C57BL/6 雌性小鼠乳腺脂肪垫和胫骨中的肿瘤生长。通过全基因组蛋白质组学分析确定并表征了在 CM 中富集的新型肿瘤抑制蛋白。β-catenin 的过表达或 BML284 的给药从乳腺癌、前列腺癌和胰腺癌细胞中产生了肿瘤抑制性的分泌组。在小鼠模型中，β-catenin 过表达的 CM 减少了肿瘤生长和肿瘤驱动的骨破坏。用 BML284 处理的 CM 也观察到了这种抑制作用。除了 p53 和 Trail 之外，蛋白质组学分析还表明，CM 富含烯醇酶 1（Eno1）和泛素 C（Ubc），它们具有显著的肿瘤抑制作用。重要的是，Eno1 免疫沉淀了细胞表面黏附受体 CD44，其沉默抑制了 Eno1 驱动的肿瘤抑制作用。泛癌生存分析显示，CM 下调 MMP9、Runx2 和 Snail 对生存结果有显著影响（<0.00001）。CM 对肿瘤细胞表现出选择性抑制作用，而对非肿瘤细胞没有抑制作用，并下调了免疫逃逸调节剂 PD-L1。肿瘤抑制性分泌组可以从肿瘤细胞中产生，其中β-catenin 表现出两种相反的作用，即在肿瘤细胞中作为细胞内肿瘤促进剂，在 CM 中作为细胞外肿瘤抑制剂。Eno1 在 CM 中富集，其与 CD44 的相互作用参与了 Eno1 的抗肿瘤作用。除了为治疗原发性癌症和转移提供潜在选择外，该结果表明，侵袭性肿瘤可能通过肿瘤抑制性分泌组抑制侵袭性较弱的肿瘤的生长。
