Metabolic reprogramming of the premalignant colonic mucosa is an early event in carcinogenesis

Abstract

BackgroundColorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. There is an increasing need for the identification of biomarkers of pre-malignant and early stage CRC to improve risk-stratification and screening recommendations. In this study, we investigated the possibility of metabolic and mitochondrial reprogramming early in the pre-malignant colorectal field.MethodsRectal biopsies were taken from 81 patients undergoing screening colonoscopy, and gene expression of metabolic and mitochondrial markers were assessed using real time quantitative PCR. Validation studies were performed in two different animal models of colon carcinogenesis: Pirc rats and AOM-treated rats.ResultsWe found evidence of a Warburg effect in the normal-appearing rectal mucosa of patients harboring precancerous lesions elsewhere in the colon compared to control patients, with a significant increase in HIF1a, SLC2A1 (referred to as GLUT1), PKM2, and LDHA. We also found evidence of early mitochondrial changes in the colorectal field of patients harboring pre-cancerous lesions, with significantly increased mitochondrial gene expression of DRP1 (fission), OPA1 (fusion), PGC1-a (biogenesis), UCP2 (uncoupling) and mtND1 (copy number). Similar results were observed in the two different animal models.ConclusionsThese results demonstrate for the first time evidence of early Warburg-like metabolic changes as well as changes in mitochondrial function, dynamics and mtDNA copy number in endoscopically normal premalignant colorectal mucosal field. These findings provide an opportunity for the development of metabolic biomarkers that could be used for improving screening recommendations and risk-stratification. This also provides a potential target for novel chemopreventive strategies in the pre-malignant colorectal field.

Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

“…Percent of low oxidative capacity of mitochondrion demonstrates the metabolic shift to glycolytic state in all colon polyps, but not in KRAS mutated and wild-type tumors compared to control tissue ( Table 1, Tables S1 and S2). The changes in glycolytic markers have been observed in the early premalignant colorectal mucosal field and these changes would be expected to promote increased glycolysis [19]. The K m (ADP) values in polyp molecular groups were 55.3 ± 7.4 µM, 52.5 ± 4.7 µM and 60.1 ± 6.3 µM for KRAS mutated, BRAF mutated and wild-type group, respectively.…”

“…Normal cells exhibit only glycolytic and oxidative states [16][17][18]. Premalignant polyps and arising adenocarcinomas are still regarded as highly glycolytic tumors of the Warburg phenotype [19][20][21]. Previous studies indicate that although polyps have higher inclination to aerobic glycolysis, the metastatic carcinomas maintain high rates of O 2 consumption (much more than adjacent normal tissues) and exhibit obvious signs of stimulated mitochondrial biogenesis [6,[22][23][24].…”

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

“…Several factors have been proposed to drive oncogenesis from inflammatory diseases (Galandiuk et al ., ; Leedham et al ., ). In sporadic colon cancer, a field effect has been reported in the normal mucosa surrounding the tumor based on changes in methylation patterns (Shen et al ., ), chromosomal instability, copy number alterations (Hawthorn et al ., ), or even in Warburg metabolism (Cruz et al ., ). T2DM has also been proposed as a factor for field cancerization in in vitro experiments (Rubin, ).…”

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…As previously mentioned, the metabolic profile of cancer cells is switched toward anaerobic glycolysis to support their rapid proliferation and survival, and precancerous lesions in the gut mucosa also exhibit increased markers of this metabolic reprogramming (Cruz Dela et al, 2017). Thus, C. albicansinduced metabolic shift could be linked to a more pathogenic state, which may include excessive inflammation and even, oncogenesis.…”