Cholecystokinin Receptor Antagonist Halts Progression of Pancreatic Cancer Precursor Lesions and Fibrosis in Mice

被引:33
|
作者
Smith, Jill P. [1 ,2 ]
Cooper, Timothy K. [3 ]
McGovern, Christopher O. [2 ]
Gilius, Evan L. [2 ]
Zhong, Qing [3 ]
Liao, Jiangang [4 ]
Molinolo, Alfredo A. [5 ]
Gutkind, J. Silvio [5 ]
Matters, Gail L. [2 ,6 ]
机构
[1] NIDDKD, NIH, Bethesda, MD USA
[2] Penn State Univ, Coll Med, Dept Med, Hershey, PA USA
[3] Penn State Univ, Coll Med, Dept Comparat Med & Pathol, Hershey, PA USA
[4] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Hershey, PA USA
[5] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA USA
[6] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA
关键词
transgenic; proglumide; Kras; PanIN lesions; fibrosis; STELLATE CELLS; STIMULATES GROWTH; GENE-EXPRESSION; DOWN-REGULATION; MOUSE MODELS; GASTRIN; IDENTIFICATION; PEPTIDE; ADENOCARCINOMA; PROLIFERATION;
D O I
10.1097/MPA.0000000000000194
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Objectives: 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 in the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. Methods: The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-Kras(G12D) transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK receptor antagonist (proglumide, 0.1 mg/mL). Pancreas from the mice were removed and examined histologically for number and grade of PanINs after 1, 2, or 4 months of antagonist therapy. Results: 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 with the controls (P = 0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared with vehicle (P < 0.001). Conclusions: These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. The use of CCK receptor antagonists may have a role in cancer prophylaxis in high-risk subjects and may reduce fibrosis in the microenvironment.
引用
收藏
页码:1050 / 1059
页数:10
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