Jiménez Pilar, Chueca Eduardo, Arruebo María, Strunk Mark, Solanas Estela, Serrano Trinidad, García-González María A, Lanas Ángel
CIBERehdMadrid, Spain.
Instituto de Investigación Sanitaria Aragón (IIS Aragón)Zaragoza, Spain.
Front Pharmacol. 2017 May 30;8:321. doi: 10.3389/fphar.2017.00321. eCollection 2017.
The cancer stem cell (CSC) model suggests that there are subsets of cells within a tumor with increased proliferation and self-renewal capacity, which play a key role in therapeutic resistance. The importance of cyclooxygenase-2 () in carcinogenesis has been previously established and the use of inhibitors as celecoxib has been shown to exert antitumor effects. The present study investigated whether treatment of esophageal adenocarcinoma (EAC) cells with 5-fluorouracil (5-FU) or the growth of tumor spheres increased the proportion of CSCs and also if treatment with celecoxib was able to reduce the putative CSC markers in this tumor. OE19 and OE33 EAC cells surviving 5-FU exposure exhibited an increase in CSC markers and and also an increased resistance to apoptosis. EAC cell lines had the capacity to form multiple spheres displaying typical CSC functionalities such as self-renewal and increased levels. In addition, after the induction of differentiation, cancer cells reached levels of similar to those observed in the parental cells. Treatment with celecoxib alone or in combination with 5-FU also resulted in a reduction of expression. Moreover, celecoxib inhibited the growth of tumor spheres. These findings showing a reduction in CSC markers induced by celecoxib suggest that the inhibitor might be a candidate for combined chemotherapy in the treatment of EAC. However, additional clinical and experimental studies are needed.
癌症干细胞(CSC)模型表明,肿瘤内存在具有增强增殖和自我更新能力的细胞亚群,这些细胞亚群在治疗抗性中起关键作用。环氧化酶-2(COX-2)在致癌作用中的重要性先前已得到证实,并且已证明使用塞来昔布等COX-2抑制剂可发挥抗肿瘤作用。本研究调查了用5-氟尿嘧啶(5-FU)处理食管腺癌(EAC)细胞或肿瘤球的生长是否会增加CSC的比例,以及用塞来昔布治疗是否能够降低该肿瘤中假定的CSC标志物。在5-FU暴露后存活的OE19和OE33 EAC细胞表现出CSC标志物CD44和CD133的增加以及对凋亡的抗性增加。EAC细胞系有能力形成多个显示典型CSC功能(如自我更新和增加的ALDH1水平)的球体。此外,在诱导分化后,癌细胞达到的ALDH1水平与亲代细胞中观察到的水平相似。单独使用塞来昔布或与5-FU联合使用也导致ALDH1表达降低。此外,塞来昔布抑制肿瘤球的生长。这些结果表明塞来昔布诱导的CSC标志物减少,提示COX-2抑制剂可能是EAC联合化疗的候选药物。然而,还需要额外的临床和实验研究。