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

Abstract

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 with 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-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. 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 to controls (p=0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared to vehicle (pitalic>0.001). Conclusions 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.

Distribution of Cholecystokinin-B Receptor Genotype Between Patients With Pancreatic Cancer and Controls and Its Impact on Survival

“…22 Furthermore, the expression of the CCK-BR has recently been identified in early human pancreatic epithelial neoplasms (PanINs) and blockade of this receptor with a CCK receptor antagonist blocks PanIN progression in the Kras transgenic mouse model. 23 These investigations support the role of the CCK-BR in pancreatic carcinogenesis.…”

Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

“…However, unlike human pancreatic cancer, Panc02 cells express wild-type KRAS and CCK-A receptors. Since CCK-B receptors become expressed in the Pdx1-Cre/LSL-Kras G12D mouse under the influence of mutated KRAS [21], it is not surprising that the mT3 cells derived from this model also express the CCK-B receptors and more closely resemble human pancreatic cancer. Findings from our work may influence cell lines used in future studies in immune-competent murine models of PDAC.…”

“…The other CCKR antagonist used was proglumide (Tocris) which is an orally bioavailable nonselective antagonist that blocks both the CCK-A and CCK-B receptors but has greater affinity for the CCK-B receptor [39]. Proglumide is water soluble and was administered orally in the drinking water at a concentration of 0.1 mg/mL, or approximately 30 mg/kg/d per mouse, a dose we previously found was effective in blocking the CCKR in vivo [21]. …”

“…The CCK-A receptor is the predominant type found in normal rodent pancreas [17], whereas the CCK-B receptor is the form found in the normal human pancreas [18, 19]. Of interest, when the rodent pancreas undergoes malignant transformation as a result of azaserine treatment [20] or under the influence of mutant KRAS [21], the rodent pancreas expresses the CCK-B receptor type. The third variety of CCK receptor, the CCK-C receptor, is a splice variant of the CCK-B receptor that occurs only in human PDAC patients with a germline single nucleotide polymorphism (rs1800843) [22, 23].…”

“…Evidence that CCKRs play a role in the dense fibrosis of the pancreas cancer microenvironment was demonstrated when CCKR blockade with proglumide inhibited fibrosis in the mutant KRAS murine model [21]. …”