Review
A two-front nutritional environment fuels colorectal cancer: perspectives for dietary intervention

https://doi.org/10.1016/j.tem.2021.11.002Get rights and content

Highlights

  • Colon epithelial and CRC cells are exposed to a unique two-front nutritional environment.

  • (Cancer) cells acquire nutrients from both sides for their bioenergetic and/or biosynthetic pathways.

  • The nutritional composition of the two fronts defines the tumor microenvironment, the preferred metabolic routes, and the rate of each energetic pathway.

  • Cancer cell bioenergetics may be steered by well-designed dietary interventions that can improve patient outcome.

Colorectal cancer (CRC) develops and progresses in a nutritional environment comprising a continuously changing luminal cocktail of external dietary and microbial factors on the apical side, and a dynamic host-related pool of systemic factors on the serosal side. In this review, we highlight how this two-front environment influences the bioenergetic status of colonocytes throughout CRC development from (cancer) stem cells to cancer cells in nutrient-rich and nutrient-poor conditions, and eventually to metastatic cells, which, upon entry to the circulation and during metastatic seeding, are forced to metabolically adapt. Furthermore, given the influence of diet on the two-front nutritional environment, we discuss dietary strategies that target the specific metabolic preferences of these cells, with a possible impact on colon cancer cell bioenergetics and CRC outcome.

Section snippets

The colonic microenvironment

A lifestyle change may prevent 30–50% of cancer deaths, including those from CRC [1]. Diet determines, directly and indirectly, the nutritional environment of colon epithelia and colon cancer cells. Food provides energetic fuel, building blocks, antioxidants, and cofactors, which are absorbed, circulated, stored, and metabolized in different tissues. At the cell level, intertwined metabolic pathways result in energy and building blocks. The balance between and rate of these pathways are

Two-front nutrient supply

The metabolism of colon (cancer) cells is influenced by the available nutrients at either the colonic lumen (apical) or blood and lymph vessels (serosal). This two-front nutrient supply is dictated by food intake, digestion, absorption, storage, metabolism, and release taking place in peripheral organs (Figure 1). At the level of the colon epithelium, these individual-level processes result in an interplay of luminal content, gut microbiota, and serosal nutrients.

On the serosal side,

The unique bioenergetics of the colon cell from cancer initiation to progression

CRC initiates and progresses at the intersection of the two-front nutritional environment. Different cell types are involved, which display differential metabolic routes. Here, we discuss the main metabolic differences between colon (cancer) cell types, which may expose their vulnerabilities. However, investigating colon (cancer) metabolism and the contribution of diet in the two-front nutritional environment with representative models and research methods remains challenging (Box 1).

Impact of dietary factors

The metabolic profile of each colonic cell type creates opportunities to target (colon) cancer bioenergetics by specific dietary interventions (Figure 3). So far, these diets are adapted at the macronutrient level and, consequently, target the demands for glucose, AAs, and FAs for rapid cell proliferation, either directly or indirectly.

Concluding remarks

During CRC initiation and progression, different cell types reside at specific tissue locations, and interact and adapt to the colonic nutritional two-front supply, which alters their bioenergetic status and cancer properties. In this context, nutritional intervention may offer novel therapeutic approaches but is hampered by the functional role of each nutrient of the complex cocktail of structurally different nutrients, which may contribute to CRC prevention or progression by diverse metabolic

Acknowledgments

E.A. is holder of a doctoral (PhD) grant Fundamental Research of Research Foundation-Flanders (FWO Vlaanderen; 1169420N).

Declaration of interests

No interests are declared.

Glossary

Anoikis
a type of cell death that is triggered when cells detach from their matrix and neighbor cells.
Autophagy
a regulated mechanism that allows the breakdown of dysfunctional cells and recycles cellular nutrients to surrounding cells [44].
Epithelial–mesenchymal transition (EMT)
process occurring in later cancer stages by which epithelial cells gain mesenchymal cell characteristics, including reduced cell–cell adhesion and increased invasiveness.
Glutaminolysis
metabolic process in which α-KG is

References (141)

  • D.G. Hardie

    AMPK: an energy-sensing pathway with multiple inputs and outputs

    Trends Cell Biol.

    (2016)
  • Z.R. Yu

    Cancer stem cells

    Int. J. Biochem. Cell Biol.

    (2012)
  • D. Zhang

    Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation

    Cell Rep.

    (2015)
  • I. Elia

    Metabolic hallmarks of metastasis formation

    Trends Cell Biol.

    (2018)
  • S.L. Qiu

    AMP-activated protein kinase alpha2 protects against liver injury from metastasized tumors via reduced glucose deprivation-induced oxidative stress

    J. Biol. Chem.

    (2014)
  • Z. Wu

    TPO-induced metabolic reprogramming drives liver metastasis of colorectal cancer CD110+ tumor-initiating cells

    Cell Stem Cell

    (2015)
  • J.M. Loo

    Extracellular metabolic energetics can promote cancer progression

    Cell

    (2015)
  • C.E. Mountford et al.

    Organization of lipids in the plasma membranes of malignant and stimulated cells: a new model

    Trends Biochem. Sci.

    (1988)
  • D.R. Donohoe

    The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation

    Mol. Cell

    (2012)
  • Q. Li

    Butyrate suppresses the proliferation of colorectal cancer cells via targeting pyruvate kinase M2 and metabolic reprogramming

    Mol. Cell. Proteomics

    (2018)
  • M. Butler

    Amino acid depletion therapies: starving cancer cells to death

    Trends Endocrinol. Metab.

    (2021)
  • R. Riscal

    Chromatin-bound MDM2 regulates serine metabolism and redox homeostasis Independently of p53

    Mol. Cell

    (2016)
  • S. Chaturvedi

    Exploiting methionine restriction for cancer treatment

    Biochem. Pharmacol.

    (2018)
  • S.J. Dixon

    Ferroptosis: an iron-dependent form of nonapoptotic cell death

    Cell

    (2012)
  • M.Y. Song et al.

    Preventable incidence and mortality of carcinoma associated with lifestyle factors among white adults in the United States

    JAMA Oncol.

    (2016)
  • S.J. O'Keefe

    Fat, fibre and cancer risk in African Americans and rural Africans

    Nat. Commun.

    (2015)
  • A. Vulcan

    High blood glucose levels are associated with higher risk of colon cancer in men: a cohort study

    BMC Cancer

    (2017)
  • J.D. Rabinowitz et al.

    Lactate: the ugly duckling of energy metabolism

    Nat. Metab.

    (2020)
  • C. Jang

    Metabolite exchange between mammalian organs quantified in pigs

    Cell Metab.

    (2019)
  • C. Harmon

    Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis

    Cancer Immunol. Res.

    (2019)
  • Z. Wei

    Metabolism of amino acids in cancer

    Front. Cell Dev. Biol.

    (2021)
  • W. Zhang

    Gut microbiota-derived metabolites in colorectal cancer: the bad and the challenges

    Front. Oncol.

    (2021)
  • M.A. Farhangi et al.

    Novel findings of the association between gut microbiota-derived metabolite trimethylamine N-oxide and inflammation: results from a systematic review and dose-response meta-analysis

    Crit. Rev. Food Sci. Nutr.

    (2020)
  • L. Liu

    Deoxycholic acid disrupts the intestinal mucosal barrier and promotes intestinal tumorigenesis

    Food Funct.

    (2018)
  • M.S. Attene-Ramos

    Hydrogen sulfide induces direct radical-associated DNA damage

    Mol. Cancer Res.

    (2007)
  • D.G.A.J. Hebels

    Radical mechanisms in nitrosamine- and nitrosamide-induced whole-genome gene expression modulations in Caco-2 cells

    Toxicol. Sci.

    (2010)
  • Y. Xi

    Analysis of prognosis, genome, microbiome, and microbial metabolome in different sites of colorectal cancer

    J. Transl. Med.

    (2019)
  • T.H. Pan

    ANKRD22, a novel tumor microenvironment-induced mitochondrial protein promotes metabolic reprogramming of colorectal cancer cells

    Theranostics

    (2020)
  • J.C. Schell

    Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism

    Nat. Cell Biol.

    (2017)
  • L. Chen

    HNF4 regulates fatty acid oxidation and is required for renewal of intestinal stem cells in mice

    Gastroenterology

    (2020)
  • D. Sun

    Influence of the microbiota on epigenetics in colorectal cancer

    Natl. Sci. Rev.

    (2018)
  • Y. Tang

    G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer

    Int. J. Cancer

    (2011)
  • Z.T. Schug

    The metabolic fate of acetate in cancer

    Nat. Rev. Cancer

    (2016)
  • R. Yang

    Propionic acid targets the TLR4/NF-kappaB signaling pathway and inhibits LPS-induced intestinal barrier dysfunction: in vitro and in vivo studies

    Front. Pharmacol.

    (2020)
  • Y.Q. Zhao

    Colorectal cancers utilize glutamine as an anaplerotic substrate of the TCA cycle in vivo

    Sci. Rep.

    (2019)
  • J.R. Mayers

    Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development

    Nat. Med.

    (2014)
  • M. Kodama

    A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer

    Nat. Commun.

    (2020)
  • N. Koundouros et al.

    Reprogramming of fatty acid metabolism in cancer

    Br. J. Cancer

    (2020)
  • X.J. Xu

    Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

    Int. J. Cancer

    (2009)
  • N. Shibuya

    Augmented pentose phosphate pathway plays critical roles in colorectal carcinomas

    Oncology

    (2015)
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