Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: Potential role of ADAM9
Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: Potential role of ADAM9
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DOI：
10.1002/ijc.33947
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发表时间：
2022-02-09
影响因子：
6.4
通讯作者：
Ueno, Hideki
中科院分区：
文献类型：
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作者：
Ao, Tadakazu;Mochizuki, Satsuki;Ueno, Hideki
肿瘤微环境在肿瘤侵袭性中起着关键作用。促结缔组织增生性反应(DR)在形态上分为成熟型、中间型和未成熟型，在结直肠癌(CRC)中具有很高的预后价值，并且在很大程度上由肿瘤相关成纤维细胞(CAF)组成。我们研究的目的是描述DR的分子背景，并了解CAF在肿瘤侵袭性中的作用。在1497名患者中初步研究了DR的预后意义。然后，从不同DR类型的患者组织中分离出CAF，并检测它们在体外和体内对肿瘤生长的影响。DR被证明具有很高的预后，未成熟DR组的患者无复发生存率最差。与成熟型DR的条件培养液(CAF(成熟))相比，未成熟型DR的CAF条件培养液(CAF(未成熟))显著促进了结直肠癌细胞系的增殖和迁移，并促进了结直肠癌衍生器官的生长。与CAF(成熟)相比，将CRC细胞与CAF(未成熟)一起皮下或原位移植到小鼠体内显著促进了肿瘤的生长和扩散。对分离自结直肠癌组织的CAF中“去整合素和金属蛋白水解酶”(ADAMS)表达的系统检测表明，ADAM9的分泌型亚型(ADAM9s)在未成熟型CAF中显著高于成熟型CAF。在未成熟的CAF中敲除ADAM9可消除其对结直肠癌细胞增殖和迁移的促进作用。CAFS来源的ADAM9通过增加肿瘤细胞的增殖和扩散而导致未成熟型DR结直肠癌患者的生存恶化。
The tumor microenvironment plays a key role in cancer aggressiveness. Desmoplastic reaction (DR), morphologically classified as Mature, Intermediate and Immature types, has previously been shown to be highly prognostic in colorectal cancer (CRC) and it consists to a large extent of cancer-associated fibroblasts (CAFs). The aim of our study was to characterize the molecular background of DR and understand the effects of CAFs in tumor aggressiveness. The prognostic significance of DR was initially examined in 1497 patients. Then CAFs originating from patient tissues with different DR types were isolated and their impact on tumor growth was examined both in vitro and in vivo. DR was shown to be highly prognostic, with patients within the Immature DR group conferring the worst relapse-free survival. The conditioned media of CAFs from tumor with Immature-type DR (CAFs(Immature)) significantly increased proliferation and migration of CRC cell lines and growth of CRC-derived organoids compared to that of CAFs from Mature-type DR (CAFs(Mature)). Subcutaneous or orthotopic implantation of CRC cells together with CAFs(Immature) in mice significantly promoted tumor growth and dissemination compared to implantation with CAFs(Mature). Systematic examination of the expression of "a disintegrin and metalloproteinases" (ADAMs) in CAFs isolated from CRC tissues showed that the secreted isoform of ADAM9 (ADAM9s) was significantly higher in CAFs(Immature) than in CAFs(Mature). Knockdown of ADAM9s in CAFs(Immature) abrogated the promoting effects on CRC cell proliferation and migration. CAFs-derived ADAM9s is implicated in deteriorating survival in CRC patients with Immature-type DR by increasing tumor cell proliferation and dissemination.