Colorectal Cancer and Metabolism

Brown, Rachel E.; Short, Sarah P.; Williams, Christopher S.

doi:10.1007/s11888-018-0420-y

Cited by 77 publications

(89 citation statements)

References 192 publications

(256 reference statements)

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“…We also found FASN, ACLY, ACACA, and SCD are significantly up-regulated, which indicated an increased fatty acid biosynthesis. It is clinically well-known that fatty acid synthesis is increased in colorectal cancer (25), and this could help the cancer cell to produce lipid metabolites crucial to cell membranes, cell signaling, post-translational modifications of proteins, neutralization of toxic reactive oxygen species, and energy storage (26). In addition, we found GLS2 is also significantly up-regulated, which indicated an increased uptake of glutamine and suggested increased glutaminolysis in the cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling

et al. 2019

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Colorectal cancer is the third most incidental cancer worldwide, and the response rate of current treatment for colorectal cancer is very low. Genome-scale metabolic models (GEMs) are systems biology platforms, and they had been used to assist researchers in understanding the metabolic alterations in different types of cancer. Here, we reconstructed a generic colorectal cancer GEM by merging 374 personalized GEMs from the Human Pathology Atlas and used it as a platform for systematic investigation of the difference between tumor and normal samples. The reconstructed model revealed the metabolic reprogramming in glutathione as well as the arginine and proline metabolism in response to tumor occurrence. In addition, six genes including ODC1, SMS, SRM, RRM2, SMOX, and SAT1 associated with arginine and proline metabolism were found to be key players in this metabolic alteration. We also investigated these genes in independent colorectal cancer patients and cell lines and found that many of these genes showed elevated level in colorectal cancer and exhibited adverse effect in patients. Therefore, these genes could be promising therapeutic targets for treatment of a specific colon cancer patient group.

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Section: Resultsmentioning

confidence: 99%

Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling

et al. 2019

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“…Phosphatidylinositol 3-kinases (PI3Ks) are a family of enzymes, which are important for intracellular signal transduction. They are activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors after binding growth factors like epidermal growth factor (EGF) or by oncogenes like RAS [ 76 , 77 ]. While growth factors interact with the regulatory subunit p85, RAS directly activates the catalytic subunit p110 of PI3K [ 77 ].…”

Section: Mitochondrial Metabolism Of Colorectal Cancermentioning

confidence: 99%

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

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“…Aberrant metabolism, which is a salient feature of colon tumor cells, involves the alteration of metabolic pathways to increase macromolecules and energy for cell growth. Metabolic pathways known to be affected in tumor cells include glycolysis, glutaminolysis, one-carbon metabolism, and fatty acid synthesis 19,20 . With advancements in high-throughput analytical techniques for metabolomics research, there are emerging studies that have revealed metabolic signatures in colon cancer 21,22 .…”

mentioning

confidence: 99%

Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype

Cai

Rattray

Zhang

et al. 2020

Sci Rep

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Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrientdeplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and the second leading cause of cancer-related deaths for cancers that affect both men and women 1. In 2019, there will be an estimated 145,600 new cases and 51,020 deaths attributed to the disease 2. Cancers of the colorectum can be categorized by anatomic location. Right-sided colon cancers (RCCs) occur in the cecum, ascending colon and hepatic flexure, and left-sided colon cancers (LCCs) occur in the splenic flexure, descending, sigmoid and rectosigmoid colon. Mid and lower rectal cancers are sometimes grouped as LCCs 3. Tumors in different anatomic locations have differing clinical outcomes, and recent epidemiologic studies have shown that patients with RCC have the poorest survival, even when adjusted for confounding factors, including clinical stage 4-6. This suggests that differences exist in the underlying tumor biology based on anatomic location. Distinguishing molecular features of RCCs include high microsatellite instability (MSI-H), valine to glutamate BRAF mutations at codon 600, cytosine-guanosine (CpG) island methylation phenotype (CIMP) 7,8 , and diploid cells 9. In contradistinction, patients with LCCs more frequently have chromosomal instability, mutations in the TP53 and APC genes, and aneuploidy 10. Recently, expression arrays have revealed four molecular subtypes of CRCs, called "consensus molecular subtypes" which tend to occur more frequently in either the right-or left-sides of the colon. Consensus molecular subtype 1, for example, has a 77% frequency in RCCs and is enriched for high MSI, CIMP, and BRAF mutations. In addition, gene set enrichment analysis shows molecular pathways related to immune infiltration and PD-1 activation for this subtype 10,11. In addition to genetic variance in colorectal subsites, RCCs ...

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Colorectal Cancer and Metabolism

Cited by 77 publications

References 192 publications

Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling

Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype

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