Mitochondrial dysregulation: early Warburg effect as a means of risk stratification in colon cancer
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There exists a profound need for biomarkers that will allow for better screening and risk stratification for colorectal cancer (CRC). With the advent of the newly termed "metabolic syndrome", CRC prevalence is trending upwards even with much improved screening protocols and remains the second leading cause of cancer related morbidity. The "metabolic syndrome" refers to a range of environmental risk factors, including diabetes and obesity, thought to be increasing the prevalence of CRC. An altered metabolism is seen in metabolic syndrome, which affects cancer through changes in the relationship between glycolysis, the Krebs cycle, and mitochondrial oxidative phosphorylation (OXPHOS). Specifically, it has been observed that highly proliferative tumorigenic cells are undergoing a shift away from the energy efficient OXPHOS and toward aerobic glycolysis even under normoxic conditions. This effect has been termed, the Warburg Effect. As a consequence of endogenous (e.g. genetic, diabetes etc.) and exogenous (e.g. diet, smoking etc.) factors, alterations in cell proliferation/death have been shown to occur throughout the colon reflecting the diffuse "field of injury" (field carcinogenesis). Also due to high energy demands it is recognized that the hyper-proliferative mucosa contiguous to colonic tumors may be hyper-metabolic. Our group has been interested in elucidating the biological nature of field carcinogenesis and assesses expression of key metabolic markers in the rectal biopsies from patients who harbor neoplasia elsewhere in their colon. We found key indications of a glycolytic shift toward aerobic glycolysis with upregulation of glucose transporter (GLUT1) as well as pyruvate shunting away from OXPHOS via pyruvate kinase muscle 2 (PKM2). These changes were further corroborated by an increase in hypoxia inducible factor 1 alpha (HIF1alpha), which is normally seen to increase glycolytic function in hypoxic conditions. Along with these glycolytic changes we also found mitochondrial dysfunction in patients with adenomas. Specifically, mitochondrial mass was found to be increased, with increases in mtDNA as well as upregulation of mitochondrial fusion via optic atrophy 1 (OPA1). Uncoupling protein 2, which decouples OXPHOS from ATP synthesis in the mitochondria, was also found to be upregulated. These findings represent a novel panel of biomarkers for assessing CRC risk via analysis of metabolic dysfunction in the easily accessible rectal epithelium.