Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Ann Surg Oncol. 2012 May;19(5):1402-9. doi: 10.1245/s10434-012-2242-5.
Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei (PMP) promotes an inflammatory/fibrotic reaction that progresses to bowel obstruction and eventual patient demise. Cytokines and inflammation-associated transcription factor binding sites, such as glucocorticoid response elements and COX-2, regulate secretory mucin, specifically MUC2, production. We hypothesized that anti-inflammatory drugs targeting inflammation-associated pathways may reduce mucin production and subsequent disease morbidity in PMP.
The effects of dexamethasone and Celebrex were assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements, MUC2 transcripts via real-time RT-PCR, and MUC2 protein expression via immunofluorescence assays.
Dexamethasone significantly inhibited basal MUC2 mRNA levels in LS174T cells, inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model, and prolonged survival in a subcutaneous LS174T xenograft model. Celebrex significantly inhibited sodium butyrate-stimulated MUC2 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models. MUC2 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count.
Inflammatory mediators are known to regulate mucin production and may promote overexpression of MUC2 by neoplastic cells with goblet cell phenotype in PMP. Anti-inflammatory drugs, dexamethasone and Celebrex, could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and, therefore, may decrease compressive symptoms, increase the disease-free interval, and reduce the extent or frequency of morbid cytoreductive surgeries.
腹膜假黏液瘤（PMP）中的腹腔内黏液性腹水积聚会引发炎症/纤维化反应，进而导致肠梗阻和患者死亡。细胞因子和炎症相关转录因子结合位点，如糖皮质激素反应元件和 COX-2，调节分泌性黏蛋白，特别是 MUC2 的产生。我们假设针对炎症相关途径的抗炎药物可能会减少 PMP 中的黏蛋白产生，并降低随后的疾病发病率。
我们通过连续参数测量、实时 RT-PCR 检测 MUC2 转录本和免疫荧光检测 MUC2 蛋白表达，在体外培养的分泌黏蛋白的人结肠癌细胞 LS174T 细胞以及体内 LS174T 和人阑尾 PMP 的异种移植模型中评估地塞米松和西乐葆的作用。
地塞米松显著抑制 LS174T 细胞中基础 MUC2 mRNA 水平，抑制腹腔内 PMP 异种移植模型中的黏液性肿瘤积聚，并延长皮下 LS174T 异种移植模型中的存活时间。西乐葆显著抑制 LS174T 细胞中丁酸钠刺激的 MUC2 mRNA 水平，并且在异种移植模型中显示出肿瘤生长减少和存活时间延长的统计学上无显著趋势。免疫荧光分析 MUC2 蛋白表明地塞米松对黏蛋白产生和肿瘤细胞计数具有双重作用。
已知炎症介质可调节黏蛋白的产生，并可能通过 PMP 中具有杯状细胞表型的肿瘤细胞过度表达 MUC2。抗炎药物地塞米松和西乐葆可通过靶向炎症级联反应抑制 PMP 中的细胞外黏蛋白产生，从而可能减轻压迫症状、增加无病间隔期，并减少恶性细胞减灭术的程度或频率。
