Cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice.
Cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice.
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DOI：
10.1097/mpa.0000000000000194
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发表时间：
2014-10
期刊：
影响因子：
2.9
通讯作者：
Matters GL
中科院分区：
文献类型：
--
作者：
Smith JP;Cooper TK;McGovern CO;Gilius EL;Zhong Q;Liao J;Molinolo AA;Gutkind JS;Matters GL
外源性给予胆囊收缩素（CCK）会诱导胰腺肥大和增生，并增加 DNA 含量。我们假设内源性 CCK 与胰腺上皮内瘤变 (PanIN) 病变的恶性进展以及与胰腺癌相关的纤维化有关。通过免疫组织化学检查小鼠和人胰腺中早期 PanIN 病变中 CCK 受体的存在。 Pdx1-Cre/LSL-KrasG12D 转基因小鼠被随机分配接受未经处理的饮用水或补充有 CCK 受体拮抗剂（丙谷胺，0.1mg/ml）的水。拮抗剂治疗1、2或4个月后，取出小鼠胰腺并进行组织学检查PanIN的数量和等级。 CCK-A 和 CCK-B 受体均在小鼠和人胰腺的早期 PanIN 中被鉴定。与对照组相比，丙谷胺治疗小鼠的 PanIN 病变程度发生逆转，晚期病变的进展也被阻止 (p=0.004)。此外，与媒介物相比，拮抗剂治疗的动物的胰腺纤维化显着减少（pitalic>0.001）。这些发现表明，内源性 CCK 在一定程度上导致了胰腺癌的发生和进展。使用 CCK 受体拮抗剂可能在高危受试者的癌症预防中发挥作用，并可能减少微环境中的纤维化。
Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved with the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-KrasG12D transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK-receptor antagonist (proglumide, 0.1mg/ml). Pancreas from mice were removed and examined histologically for number and grade of PanINs after 1, 2 or 4 months of antagonist therapy. Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed and progression to advanced lesions arrested in mice treated with proglumide compared to controls (p=0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared to vehicle (pitalic>0.001). These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. Use of CCK-receptor antagonists may have a role in cancer prophylaxis in high risk subjects, and may reduce fibrosis in the microenvironment.