Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada.
Neoplasia. 2012 Jul;14(7):624-33. doi: 10.1593/neo.12486.
Higher cyclooxygenase 2 (COX-2) expression is often observed in aggressive colorectal cancers (CRCs). Here, we attempt to examine the association between COX-2 expression in therapy-refractory CRC, how it affects chemosensitivity, and whether, in primary tumors, it is predictive of clinical outcomes. Our results revealed higher COX-2 expression in chemoresistant CRC cells and tumor xenografts. In vitro, the combination of either aspirin or celecoxib with 5-fluorouracil (5-FU) was capable of improving chemosensitivity in chemorefractory CRC cells, but a synergistic effect with 5-FU could only be demonstrated with celecoxib. To examine the potential clinical significance of these observations, in vivo studies were undertaken, which also showed that the greatest tumor regression was achieved in chemoresistant xenografts after chemotherapy in combination with celecoxib, but not aspirin. We also noted that these chemoresistant tumors with higher COX-2 expression had a more aggressive growth rate. Given the dramatic response to a combination of celecoxib + 5-FU, the possibility that celecoxib may modulate chemosensitivity as a result of its ability to inhibit MDR-1 was examined. In addition, assessment of a tissue microarray consisting of 130 cases of CRCs revealed that, in humans, higher COX-2 expression was associated with poorer survival with a 68% increased risk of mortality, indicating that COX-2 expression is a marker of poor clinical outcome. The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy.
环氧化酶 2(COX-2)的表达水平在侵袭性结直肠癌(CRC)中通常较高。在此,我们试图探讨治疗抵抗型 CRC 中 COX-2 表达与化疗敏感性之间的关系,以及其是否能预测原发性肿瘤的临床结局。我们的研究结果显示,在化疗抵抗型 CRC 细胞和肿瘤异种移植中 COX-2 表达水平较高。体外研究发现,阿司匹林或塞来昔布联合氟尿嘧啶(5-FU)能够提高化疗抵抗型 CRC 细胞的化疗敏感性,但仅塞来昔布与 5-FU 具有协同作用。为了检验这些观察结果的潜在临床意义,我们进行了体内研究,结果也显示,化疗联合塞来昔布治疗后,化疗抵抗型异种移植中的肿瘤退缩最为显著,但联合阿司匹林则不然。我们还注意到,这些 COX-2 表达水平较高的化疗抵抗型肿瘤具有更高的侵袭性生长速度。鉴于塞来昔布联合 5-FU 治疗的显著疗效,我们研究了塞来昔布是否通过抑制多药耐药蛋白 1(MDR-1)来调节化疗敏感性。此外,我们还评估了由 130 例 CRC 组成的组织微阵列,结果显示,在人类中,COX-2 表达水平较高与较差的生存率相关,死亡风险增加 68%,表明 COX-2 表达是预后不良的标志物。本研究的结果表明,联合 COX-2 抑制剂与当前治疗方案可能有助于改善治疗抵抗型 CRC 的治疗反应,并将 COX-2 表达作为预后标志物,以帮助确定最需要密切随访和更积极治疗的患者。