Dietary fat stimulates pancreatic cancer growth and promotes fibrosis of the tumor microenvironment through the cholecystokinin receptor

Abstract

The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat to aid in digestion, and plasma CCK levels are elevated with the consumption of high-fat diets. CCK is also a trophic peptide for the pancreas and has also been shown to stimulate growth of pancreatic cancer. In the current investigation, we studied the influence of a diet high in saturated fat on the growth of pancreatic cancer in syngeneic murine models before the mice became obese to exclude the confounding factors associated with obesity. The high-fat diet significantly increased growth and metastasis of pancreatic cancer compared with the control diet, and the stimulatory effect was blocked by the CCK-receptor antagonist proglumide. We then selectively knocked out the CCK receptor on the pancreatic cancer cells using clustered regularly interspaced short palindromic repeats technology and showed that without CCK-receptors, dietary fat was unable to stimulate cancer growth. We next demonstrated that dietary fat failed to influence pancreatic cancer xenograft growth in genetically engineered CCK peptide knockout mice. The tumor-associated fibrosis that is so prevalent in the pancreatic cancer microenvironment was significantly decreased with CCK-receptor antagonist therapy because fibroblasts also have CCK receptors. The CCK-receptor antagonist proglumide also altered tumor metalloprotease expression and increased tumor suppressor genes by a PCR array. Our studies confirm that a diet high in saturated fat promotes growth of pancreatic cancer and the action is mediated by the CCK-receptor pathway. NEW & NOTEWORTHY Diets high in long-chain saturated fats promote growth of pancreatic cancer independent of obesity. The mechanism through which dietary fat promotes cancer is mediated through the cholecystokinin (CCK) receptor pathway. Therapy with a CCK-receptor antagonist altered the tumor microenvironment by reducing fibrosis, increasing cluster of differentiation 8 lymphocytes, increasing tumor suppressor genes, and thus decreasing metastases. Use of CCK-receptor antagonist therapy with standard chemotherapy for pancreatic cancer may improve response by altering the tumor microenvironment.

Ppard Is Essential in Acceleration of Pancreatic Ductal Adenocarcinoma Development by High-Fat Diet in MutantKrasMice

“…High-fat diets have been associated with increased risk for human PDAC [4][5][6] . In preclinical animal models, high-fat diets promote both chemically-induced and oncogenic KRAS-initiated pancreatic carcinogenesis [7][8][9][10][11][12][13][14] . Fatty acids in high-fat diets act as activating ligands of PPARD, a transcriptional factor that exerts a wide spectrum of effects on important molecular events 15 .…”

A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma

“…Human subjects that consumed a high-fat diet were found to have elevated CCK levels [22]. We previously documented that CCK blood levels were tenfold higher in mice consuming a high-saturated fat diet compared to controls [23,24]. CCK exerts its effects through the CCK receptor which is a G-protein-coupled receptor [25].…”

“…Apart from their proliferative role on cancer cells, CCK receptors have been identified on pancreatic stellate cells [40] and fibroblasts [41]. Proglumide treatment decreases tumor-associated fibrosis in mouse models of pancreatic cancer [24,36,42]. Although CCK receptors have not been reported on hepatic stellate cells, the liver and pancreas develop from endodermal epithelium of the embryonic foregut [43] and have many common features.…”

“…New genetically engineered animal models have been established that develop NASH, but most of these models have immune deficiencies [47]. A diet high in saturated fat that causes obesity is frequently used in experimental studies [23,24,48]; unfortunately, with this diet very extended periods (up to a year) are required to develop NASH with mild fibrosis and HCC frequently does not occur even under these protracted diet settings [44]. Most of the dietary animal models develop some fibrosis, but not cirrhosis.…”

Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma

“…Our results add to the growing body of evidence that obesity may be pro-tumorigenic through its microenvironmental rather than systemic consequences (Olson et al, 2017). Although evidence for a role for CCK signaling in PDAC progression exists (Nadella et al, 2018;Smith and Solomon, 2014), prior studies focused on intestinal-derived CCK, the physiologic source of systemic CCK. On the contrary, our work highlights a local source of CCK -induced by obesity within the pancreas itself -and offers the first example of endocrine-exocrine signaling beyond insulin in PDAC development.…”