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. 2017 Mar 28;8(13):20543-20557.
doi: 10.18632/oncotarget.16129.

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

Mart Dela Cruz  1 , Sarah Ledbetter  1 , Sanjib Chowdhury  1 , Ashish K Tiwari  1 , Navneet Momi  1 , Ramesh K Wali  1 , Charles Bliss  1 , Christopher Huang  1 , David Lichtenstein  1 , Swati Bhattacharya  1 , Anisha Varma-Wilson  1 , Vadim Backman  2 , Hemant K Roy  1
Affiliations

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

Mart Dela Cruz et al. Oncotarget. .

Abstract

Background: Colorectal 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.

Methods: Rectal 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.

Results: We 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 HIF1α, 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-α (biogenesis), UCP2 (uncoupling) and mtND1 (copy number). Similar results were observed in the two different animal models.

Conclusions: These 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.

Keywords: Warburg effect; colorectal carcinoma; field carcinogenesis; metabolic reprogramming; metabolism.

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Conflict of interest statement

CONFLICTS OF INTEREST

Drs. Roy and Backman are co-founders and shareholders in Nanocytomics LLC and American BioOptics LLC which has licensed the PWS and PGS technologies. All other authors do not have any competing interests.

Figures

Figure 1
Figure 1. Metabolic and mitochondrial changes in patient rectal biopsies from uninvolved mucosa
Messenger RNA (mRNA) expression of A. metabolic markers - HIF1α, GLUT-1, PKM2 and LDHA and B. mitochondrial markers - DRP1, OPA-1, PGC1-α and UCP2 was measured in rectal uninvolved mucosal biopsies collected from patients with (n = 38) or without (n = 43) any adenomas. The error bar represents standard error of mean (SEM). Statistical significance is denoted as * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
Figure 2
Figure 2. Representative animal model images showing colonoscopy and tumors
A.-D. Colonoscopy images from animals with tumors and control animals; E. AOM-induced tumor images and F. PIRC rat tumor images in the colon.
Figure 3
Figure 3. Metabolic and mitochondrial changes in PIRC rat model
Messenger RNA (mRNA) expression of A. metabolic markers - HIF1α, GLUT-1, PKM2 and LDHA and B. mitochondrial markers - DRP1, OPA-1, PGC1-α and UCP2 was measured in rectal uninvolved mucosal biopsies collected from PIRC rats with tumors (n = 6) or age-matched control rats (n = 6). The error bar represents standard error of mean (SEM). Statistical significance is denoted as * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
Figure 4
Figure 4. Metabolic and mitochondrial changes in AOM rat models
Messenger RNA (mRNA) expression of A. metabolic markers - HIF1α, GLUT-1, PKM2 and LDHA and B. mitochondrial markers - DRP1, OPA-1, PGC1-α and UCP2 was measured in rectal uninvolved mucosal biopsies collected from AOM-treated rats (n = 6) or control saline-treated rats (n = 6). The error bar represents standard error of mean (SEM). Statistical significance is denoted as * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
Figure 5
Figure 5. Metabolic changes in uninvolved mucosa by IHC in AOM model
Expression of HIF1α, GLUT-1, PKM2 and LDHA by immunohistochemical staining was performed as described in Materials and Methods Section. Ten optical fields from each specimen were scored (0-3; with 0 being no intensity and 3 very strong). The error bar represents standard error of mean (SEM). Statistical significance is denoted as * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
Figure 6
Figure 6. Changes in mitochondrial copy number mt-ND1 in premalignant field in patients and animal models
Messenger RNA (mRNA) expression of mitochondrial gene mtND1 was measured in patient rectal biopsies, PIRC and AOM models. The error bar represents standard error of mean (SEM). Statistical significance is denoted as * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
Figure 7
Figure 7. Schematic representation of the metabolic and mitochondrial alterations in early colon carcinogenesis
See this image and copyright information in PMC

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