Generation of the tumor-suppressive secretome from tumor cells.
Generation of the tumor-suppressive secretome from tumor cells.
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从肿瘤细胞中产生肿瘤抑制性分泌组。
DOI：
10.7150/thno.61006
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Yokota H
中科院分区：
文献类型：
--
作者：
Liu S;Sun X;Li K;Zha R;Feng Y;Sano T;Dong C;Liu Y;Aryal UK;Sudo A;Li BY;Yokota H
理由：癌细胞的进展取决于土壤，建立抑制性土壤可能是一种治疗选择。我们先前通过激活MSC中的Wnt信号转导来创建肿瘤抑制分泌体。在这里，我们研究了抗肿瘤分泌体是否可以从肿瘤细胞产生。方法：通过过表达β-catenin或给予Wnt激活剂BML 284来激活肿瘤细胞中的Wnt信号。将其条件培养基（CM）应用于癌细胞或组织，并评价CM的效果。还通过μCT成像和组织学评价了C57 BL/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在CM中富集的新型肿瘤抑制蛋白。结果如下：β-连环蛋白的过表达或BML 284的施用产生来自乳腺癌、前列腺癌和胰腺癌细胞的肿瘤抑制性分泌体。在小鼠模型中，β-连环蛋白过表达的CM减少了肿瘤生长和肿瘤驱动的骨破坏。用BML 284处理的CM也观察到这种抑制。除了p53和Trail，蛋白质组学分析显示CM富含烯醇化酶1（Eno 1）和泛素C（Ubc），表现出显着的肿瘤抑制作用。重要的是，Eno 1免疫沉淀CD 44，细胞表面粘附受体，其沉默抑制Eno 1驱动的肿瘤抑制。一项全癌生存分析显示，CM下调MMP 9、Runx 2和Snail对生存结果有显著影响（p < 0.00001）。与非肿瘤细胞相比，CM呈现对肿瘤细胞的选择性抑制，并且其下调免疫逃逸调节剂PD-L1。结论：肿瘤抑制性分泌物组可以从肿瘤细胞中产生，其中β-catenin具有两种相反的作用，即在肿瘤细胞中作为细胞内肿瘤促进剂和在CM中作为细胞外肿瘤抑制剂的产生者。Eno 1在CM中富集，并且其与CD 44的相互作用参与Eno 1的抗肿瘤作用。除了为治疗原发性癌症和转移提供了一种潜在的选择外，该结果还表明，侵袭性肿瘤可能通过肿瘤抑制分泌体抑制侵袭性较低的肿瘤的生长。
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. Methods: 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. Results: 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. Conclusions: 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.
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影响因子：
--
作者：
Frampton AE;Prado MM;López-Jiménez E;Fajardo-Puerta AB;Jawad ZAR;Lawton P;Giovannetti E;Habib NA;Castellano L;Stebbing J;Krell J;Jiao LR
通讯作者：
Jiao LR
DOI：
10.1073/pnas.1806643115
发表时间：
2018-10-16
影响因子：
11.1
作者：
Choi BK;Dayaram T;Parikh N;Wilkins AD;Nagarajan M;Novikov IB;Bachman BJ;Jung SY;Haas PJ;Labrie JL;Pickering CR;Adikesavan AK;Regenbogen S;Kato L;Lelescu A;Buchovecky CM;Zhang H;Bao SH;Boyer S;Weber G;Scott KL;Chen Y;Spangler S;Donehower LA;Lichtarge O
通讯作者：
Lichtarge O
DOI：
10.1158/1078-0432.ccr-13-0495
发表时间：
2013-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kang R;Zhang Q;Zeh HJ 3rd;Lotze MT;Tang D
通讯作者：
Tang D
DOI：
10.1007/978-1-4471-6458-6_8
发表时间：
2014-01-01
期刊：
ANTICANCER GENES
影响因子：
--
作者：
Fulda, Simone
通讯作者：
Fulda, Simone
影响因子：
12.7
作者：
Fan, Yao;Jalali, Aydin;Yokota, Hiroki
通讯作者：
Yokota, Hiroki