Extracellular Matrix Degradation Products Downregulate Neoplastic Esophageal Cell Phenotype.
Extracellular Matrix Degradation Products Downregulate Neoplastic Esophageal Cell Phenotype.
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细胞外基质降解产物下调食管肿瘤细胞表型。
DOI：
10.1089/ten.tea.2018.0105
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发表时间：
2019
影响因子：
--
通讯作者：
Turner,N
中科院分区：
文献类型：
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作者：
Saldin,LindseyT;Patel,Shil;Zhang,Li;Huleihel,Luai;Hussey,GeorgeS;Nascari,DavidG;Quijano,LinaM;Li,Xue;Raghu,Divya;Bajwa,AnantK;Smith,NicholasG;Chung,ChristopherC;Omstead,AshtenN;Kosovec,JuliannE;Jobe,BlairA;Turner,N
细胞外基质（ECsM）生物支架已成功用于治疗5例食管腺癌（EAC）患者切除肿瘤粘膜组织。本研究评价了从非恶性脱细胞组织中提取的ECM对EAC细胞表型的体外作用，以了解临床发现的分子机制。将非恶性（Het-1A）、化生性（CP-A）和肿瘤性（SK-GT-4、OE 33）食管上皮细胞暴露于从异源膀胱组织或同源食管粘膜组织制备的ECM降解产物（250 μg/mL），并评价细胞形态、细胞功能和EAC信号通路。两种ECM来源均下调肿瘤细胞表型，但具有独特的组织特异性作用。膀胱ECM降低了OE 33和SK-GT-4代谢，增加了CP-A凋亡。食管ECM降低SK-GT-4、CP-A和Het-1A增殖;在OE 33细胞中稳健地下调PI 3 K-Akt-mTOR、细胞周期/DNA复制信号传导，并上调自噬信号传导;在Het-1A细胞中增加细胞周期/DNA复制信号传导。两种ECM来源均降低了OE 33细胞的增殖和磷酸化AKT，相反，增加了Het-1A细胞的磷酸化AKT。结果支持的概念，在非恶性ECM的生化信号可以下调肿瘤细胞的表型与最小的，有时相反，对正常细胞的影响。PI 3 K-Akt信号转导与EAC进展有关，这些ECM介导的作用可能有利于癌症切除术后的食管治疗。影响声明细胞外基质（ECM）生物材料用于治疗癌症切除术后的食管癌患者，并促进正常粘膜的再生，而不会复发癌症。本研究探讨了这些材料成功预防癌表型的机制。ECM下调肿瘤食管细胞的功能（增殖，代谢），但正常食管上皮细胞在体外不受影响，并提出了有希望的临床结果的分子基础（下调PI 3 K-Akt，细胞周期）。使用同源食管ECM似乎增强了治疗效果。这项研究表明，ECM可以进一步研究，以治疗切除后的癌症患者或与靶向治疗相结合。
Extracellular matrix (ECsM) bioscaffolds have been successfully used to treat five esophageal adenocarcinoma (EAC) patients following resection of neoplastic mucosal tissue. The present study evaluated thein vitroeffect of ECM harvested from nonmalignant, decellularized tissue on EAC cell phenotype to understand the molecular mechanisms underlying the clinical findings. Nonmalignant (Het-1A), metaplastic (CP-A), and neoplastic (SK-GT-4, OE33) esophageal epithelial cells were exposed to ECM degradation products (250 μg/mL) prepared from heterologous urinary bladder tissue or homologous esophageal mucosa tissue, and evaluated for cell morphology, cell function, and EAC signaling pathways. Both the ECM sources downregulated neoplastic cell phenotype, but had distinctive tissue-specific effects. Urinary bladder ECM decreased OE33 and SK-GT-4 metabolism and increased CP-A apoptosis. Esophageal ECM decreased SK-GT-4, CP-A, and Het-1A proliferation; robustly downregulated PI3K-Akt-mTOR, cell cycle/DNA replication signaling, and upregulated autophagy signaling in OE33 cells; and increased cell cycle/DNA replication signaling in Het-1A cells. Both ECM sources decreased OE33 proliferation and phosphorylated AKT in OE33 cells, and in contrast, increased phosphorylated AKT in Het-1A cells. The results support the concept that the biochemical signals in nonmalignant ECM can downregulate neoplastic cell phenotype with minimal, and sometimes opposite, effects on normal cells. PI3K-Akt signaling has been implicated in EAC progression and these ECM-mediated effects may be favorable for an esophageal therapy following cancer resection.Impact StatementExtracellular matrix (ECM) biomaterials were used to treat esophageal cancer patients after cancer resection and promoted regrowth of normal mucosa without recurrence of cancer. The present study investigates the mechanisms by which these materials were successful to prevent the cancerous phenotype. ECM downregulated neoplastic esophageal cell function (proliferation, metabolism), but normal esophageal epithelial cells were unaffectedin vitro, and suggests a molecular basis (downregulation of PI3K-Akt, cell cycle) for the promising clinical results. The therapeutic effect appeared to be enhanced using homologous esophageal ECM. This study suggests that ECM can be further investigated to treat cancer patients after resection or in combination with targeted therapy.