Mi Zhiyong, Kuo Marissa C, Kuo Paul C
Department of Surgery, University of South Florida, Tampa, FL 33620, USA.
Department of Surgery, Vanderbilt University, Nashville, TN 37232, USA.
Cancers (Basel). 2023 Jun 20;15(12):3254. doi: 10.3390/cancers15123254.
Cancer progression depends on an accumulation of metastasis-supporting physiological changes, which are regulated by cell-signaling molecules. In this regard, a disintegrin and metalloproteinase 8 (Adam8) is a transmembrane glycoprotein that is selectively expressed and induced by a variety of inflammatory stimuli. In this study, we identified Adam8 as a sox2-dependent protein expressed in MDA-MB-231 breast cancer cells when cocultured with mesenchymal-stem-cell-derived myofibroblast-like cancer-associated fibroblasts (myCAF). We have previously found that myCAF-induced cancer stemness is required for the maintenance of the myCAF phenotype, suggesting that the initiation and maintenance of the myCAF phenotype require distinct cell-signaling crosstalk pathways between cancer cells and myCAF. Adam8 was identified as a candidate secreted protein induced by myCAF-mediated cancer stemness. Adam8 has a known sheddase function against which we developed an RNA aptamer, namely, Adam8-Apt1-26nt. The Adam8-Apt1-26nt-mediated blockade of the extracellular soluble Adam8 metalloproteinase domain abolishes the previously initiated myCAF phenotype, or, termed differently, blocks the maintenance of the myCAF phenotype. Consequently, cancer stemness is significantly decreased. Xenograft models show that Adam8-Apt-1-26nt administration is associated with decreased tumor growth and metastasis, while flow cytometric analyses demonstrate a significantly decreased fraction of myCAF after Adam8-Apt-1-26nt treatment. The role of soluble Adam8 in the maintenance of the myCAF phenotype has not been previously characterized. Our study suggests that the signal pathways for the induction or initiation of the myCAF phenotype may be distinct from those involved with the maintenance of the myCAF phenotype.
癌症进展取决于支持转移的生理变化的积累，这些变化由细胞信号分子调节。在这方面，解整合素和金属蛋白酶8（Adam8）是一种跨膜糖蛋白，由多种炎症刺激选择性表达和诱导。在本研究中，我们确定Adam8是一种与间充质干细胞衍生的肌成纤维细胞样癌症相关成纤维细胞（myCAF）共培养时在MDA-MB-231乳腺癌细胞中表达的sox2依赖性蛋白。我们之前发现，myCAF诱导的癌症干性是维持myCAF表型所必需的，这表明myCAF表型的启动和维持需要癌细胞与myCAF之间不同的细胞信号串扰途径。Adam8被确定为一种由myCAF介导的癌症干性诱导的候选分泌蛋白。Adam8具有已知的裂解酶功能，我们针对此开发了一种RNA适体，即Adam8-Apt1-26nt。Adam8-Apt1-26nt介导的细胞外可溶性Adam8金属蛋白酶结构域的阻断消除了先前启动的myCAF表型，或者换一种说法，阻断了myCAF表型的维持。因此，癌症干性显著降低。异种移植模型表明，给予Adam8-Apt-1-26nt与肿瘤生长和转移减少相关，而流式细胞术分析表明，Adam8-Apt-1-26nt处理后myCAF的比例显著降低。可溶性Adam8在维持myCAF表型中的作用此前尚未得到表征。我们的研究表明，myCAF表型诱导或启动的信号通路可能与维持myCAF表型的信号通路不同。
