Rationale: 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./nMethods: 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./nResults: 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 (p < 0.00001). CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator./nConclusions: 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.

中文翻译：

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从肿瘤细胞产生抑癌分泌组

基本原理：癌细胞的进展取决于土壤，建造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 信号传导来创建肿瘤抑制分泌组。在这里，我们检查了抗肿瘤分泌蛋白组是否可以从肿瘤细胞中产生。/n方法：通过过表达 β-连环蛋白或施用 BML284（一种 Wnt 激活剂）在肿瘤细胞中激活 Wnt 信号传导。将他们的条件培养基 (CM) 应用于癌细胞或组织，并评估 CM 的效果。还通过 μCT 成像和组织学评估了 C57BL/6 雌性小鼠乳腺脂肪垫和胫骨中的肿瘤生长。进行全基因组蛋白质组学分析以确定和表征富含 CM 的新型肿瘤抑制蛋白。/n结果： β-连环蛋白的过表达或 BML284 的施用从乳腺癌、前列腺癌细胞和胰腺癌细胞中产生了肿瘤抑制分泌物。在小鼠模型中，过表达 β-连环蛋白的 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，蛋白质组学分析显示 CM 富含烯醇化酶 1 (Eno1) 和泛素 C (Ubc)，具有显着的肿瘤抑制作用。重要的是，Eno1 免疫沉淀 CD44，一种细胞表面粘附受体，其沉默抑制了 Eno1 驱动的肿瘤抑制。一项泛癌生存分析显示，CM 下调 MMP9、Runx2 和 Snail 对生存结果有显着影响（p< 0.00001)。与非肿瘤细胞相比，CM 对肿瘤细胞具有选择性抑制作用，并下调免疫逃逸调节剂 PD- L1。相反的作用，作为肿瘤细胞中的细胞内肿瘤启动子和 CM 中细胞外肿瘤抑制因子的产生者。Eno1 富含 CM，其与 CD44 的相互作用参与了 Eno1 的抗肿瘤作用。除了提供治疗原发性癌症和转移的潜在选择外，该结果表明侵袭性肿瘤可能通过肿瘤抑制分泌组抑制侵袭性较低的肿瘤的生长。