Impact of diabetes type II and chronic inflammation on pancreatic cancer

Abstract

BackgroundWe explored if known risk factors for pancreatic cancer such as type II diabetes and chronic inflammation, influence the pathophysiology of an established primary tumor in the pancreas and if administration of metformin has an impact on tumor growth.MethodsPancreatic carcinomas were assessed in a syngeneic orthotopic pancreas adenocarcinoma model after injection of 6606PDA cells in the pancreas head of either B6.V-Lepob/ob mice exhibiting a type II diabetes-like syndrome or normoglycemic mice. Chronic pancreatitis was then induced by repetitive administration of cerulein. Cell proliferation, cell death, inflammation and the expression of cancer stem cell markers within the carcinomas was evaluated by immunohistochemistry. In addition, the impact of the antidiabetic drug, metformin, on the pathophysiology of the tumor was assessed.ResultsDiabetic mice developed pancreatic ductal adenocarcinomas with significantly increased tumor weight when compared to normoglycemic littermates. Diabetes caused increased proliferation of cancer cells, but did not inhibit cancer cell necrosis or apoptosis. Diabetes also reduced the number of Aldh1 expressing cancer cells and moderately decreased the number of tumor infiltrating chloracetate esterase positive granulocytes. The administration of metformin reduced tumor weight as well as cancer cell proliferation. Chronic pancreatitis significantly diminished the pancreas weight and increased lipase activity in the blood, but only moderately increased tumor weight.ConclusionWe conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma.

Use of statins offsets insulin‐related cancer risk

“…The latter finding is in line with previous studies [2] and could be caused by lower testosterone levels in diabetic men [23,24]. There is evidence to support diabetes as a genuine risk factor in the pathogenesis of liver and pancreatic cancers beyond the complex interplay of different risk factors, detection bias, cancer treatment and the effects of reverse causality as these cancers can also impair glucose metabolism [25][26][27][28][29][30]. In a metaanalysis, a twofold higher risk of hepatocellular carcinoma was seen in diabetic compared to nondiabetic subjects, with potential mechanisms including inflammation, cellular proliferation stimulated by hyperinsulinemia, high IGF-1 levels, and We found significantly increased cancer risks for sulfonylureas and decreased risks for oral glucose-lowering drugs, glitazones, simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin for female and male patients, as well as decreased risks for metformin in men.…”

“…In a meta‐analysis, a twofold higher risk of hepatocellular carcinoma was seen in diabetic compared to nondiabetic subjects, with potential mechanisms including inflammation, cellular proliferation stimulated by hyperinsulinemia, high IGF‐1 levels, and hyperglycaemia favouring development of steatosis and cirrhosis . Pancreatic cancer was also reported to be more common in diabetic subjects in whom it was suspected that hyperglycaemia may be the major mechanistic driver for this interrelation . Indeed, a dose–response meta‐analysis revealed that every 0.56 mmol L −1 increase in fasting glucose was associated with a 14% increase in the rate of pancreatic cancer .…”

“…hyperglycaemia favouring development of steatosis and cirrhosis [25,26]. Pancreatic cancer was also reported to be more common in diabetic subjects in whom it was suspected that hyperglycaemia may be the major mechanistic driver for this interrelation [27,28]. Indeed, a dose-response metaanalysis revealed that every 0.56 mmol L À1 increase in fasting glucose was associated with a 14% increase in the rate of pancreatic cancer [29].…”

Obesity and Cancer: An Angiogenic and Inflammatory Link

“…One such agent, currently under intense clinical investigation, is metformin, the most widely prescribed anti-diabetic generic drug that is also frequently administered to diabetic PDAC patients [47]. Metformin can improve treatment outcomes in preclinical models of cancer, particularly in the obese setting [1,3,58,86,112,118,127,152,164,170,178,181]. In addition, it reduces the incidence of cancer in diabetic patients as well as improves survival in newly diagnosed cases [28,94,97,102,144,152].…”

The advanced glycation end‐product Nϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

“…Studies designed to unravel the mechanistic link between DM and PaC are complicated by the fact that type 2 DM, the most common form of DM, could promote PaC through a variety of factors, including hyperglycaemia itself, dyslipidaemia, chronic inflammation, and insulin resistance/hyperinsulinaemia . Recently, a tumour‐promoting role has been suggested for receptor for advanced glycation end‐products (RAGE), a single transmembrane receptor of the immunoglobulin superfamily.…”