The Warburg effect drives cachectic states in patients with pancreatobiliary adenocarcinoma

Abstract

We have studied whether the Warburg effect (uncontrolled glycolysis) in pancreatobiliary adenocarcinoma triggers cachexia in the patient. After 74 pancreatobiliary adenocarcinomas were removed by surgery, their glucose transporter‐1 and four glycolytic enzymes were quantified using Western blotting. Based on the resulting data, the adenocarcinomas were equally divided into a group of low glycolysis (LG) and a group of high glycolysis (HG). Energy homeostasis was assessed in these cancer patients and in 74 non‐cancer controls, using serum albumin and C‐reactive protein and morphometrical analysis of abdominal skeletal muscle and fat on computed tomography scans. Some removed adenocarcinomas were transplanted in nude mice to see their impacts on host energy homeostasis. Separately, nude mice carrying tumor grafts of MiaPaCa‐2 pancreatic adenocarcinoma cells were treated with the glycolytic inhibitor 3‐bromopyruvate and with emodin that inhibited glycolysis by decreasing hypoxia‐inducible factor‐1α. Adenocarcinomas in both group LG and group HG impaired energy homeostasis in the cancer patients, compared to the non‐cancer reference. The impaired energy homeostasis induced by the adenocarcinomas in group HG was more pronounced than that by the adenocarcinomas in group LG. When original adenocarcinomas were grown in nude mice, their glycolytic abilities determined the levels of hepatic gluconeogenesis, skeletal muscle proteolysis, adipose‐tissue lipolysis, and weight loss in the mice. When MiaPaCa‐2 cells were grown as tumors in nude mice, 3‐bromopyruvate and emodin decreased tumor‐induced glycolysis and cachexia, with the best effects being seen when the drugs were administered in combination. In conclusion, the Warburg effect in pancreatobiliary adenocarcinoma triggers cancer cachexia.

Targeting the Warburg Effect in Cancer: Where Do We Stand?

“…The Cori cycle has been described to account for 50% of glucose turnover in cachectic cancer patients, compared to 20% in cancer patients without this condition [ 24 ]. In a study involving pancreaticobiliary adenocarcinoma patients, researchers demonstrated a correlation between cachexia and a high glycolytic index as measured by the expression levels of various glycolytic enzymes [ 5 ]. Furthermore, the same authors also show in a nude mice model that inhibiting the Warburg effect does attenuate cachexia [ 25 ], suggesting a potential causal link between the Warburg effect and cancer-induced cachexia.…”

“…Thus, the prevalence of a high rate of glucose catabolism into lactate is the most widespread metabolic phenotype observed in cancer cells [ 3 ]. The presence of the Warburg effect has been described in most tumor types, including, but not limited to, glioblastoma [ 4 ], pancreas [ 5 ], breast [ 6 , 7 ], and cervix [ 8 ].…”