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

Alderweireldt, Elien; Grootaert, Charlotte; Wever, Olivier De; Camp, John Van

doi:10.1016/j.tem.2021.11.002

Cited by 8 publications

(6 citation statements)

References 136 publications

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“…In the past decade, the role of diet has caught the attention of scientists because metabolites and biomolecules in the blood can significantly influence tumor growth, especially in CRC [ 314 ]. Dietary intervention is cheap, available, and could synergize with standard therapy to enhance the therapeutic effect [ 315 ].…”

Section: Glycolytic Metabolism Is a Therapeutic Target In Crcmentioning

confidence: 99%

Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

Zhong

Wang

et al. 2022

J Hematol Oncol

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Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy.

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Section: Glycolytic Metabolism Is a Therapeutic Target In Crcmentioning

confidence: 99%

Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

Zhong

Wang

et al. 2022

J Hematol Oncol

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“…It is widely known that the tumor environment via altered perfusion, hypoxia, and alterations in metabolic pathways and transporters, plays a crucial role in determining the metabolic phenotype and may be a key driver of the observed PET differences in our study ( 44–46 ). The colon possesses a unique nutritional environment with varying levels of amino acids, sugars, and acetate, which could be relevant to the metabolic phenotypes observed in colon cancer ( 47 ). Although we were unable to measure all models intracolonically due to resource constraints, our findings indicate that cell extrinsic mechanisms play a significant role in imaging phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging

Malviya,

Lannagan,

Johnson

et al. 2024

Clinical Cancer Research

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Purpose: The current approach for molecular subtyping of colon cancer relies on gene expression profiling, which is invasive and has limited ability to reveal dynamics and spatial heterogeneity. Molecular imaging techniques, such as PET, present a noninvasive alternative for visualizing biological information from tumors. However, the factors influencing PET imaging phenotype, the suitable PET radiotracers for differentiating tumor subtypes, and the relationship between PET phenotypes and tumor genotype or gene expression–based subtyping remain unknown. Experimental Design: In this study, we conducted 126 PET scans using four different metabolic PET tracers, [18F]fluorodeoxy-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), and [11C]acetate ([11C]ACE), using a spectrum of five preclinical colon cancer models with varying genetics (BMT, AKPN, AK, AKPT, KPN), at three sites (subcutaneous, orthograft, autochthonous) and at two tumor stages (primary vs. metastatic). Results: The results demonstrate that imaging signatures are influenced by genotype, tumor environment, and stage. PET imaging signatures exhibited significant heterogeneity, with each cancer model displaying distinct radiotracer profiles. Oncogenic Kras and Apc loss showed the most distinctive imaging features, with [18F]FLT and [18F]FET being particularly effective, respectively. The tissue environment notably impacted [18F]FDG uptake, and in a metastatic model, [18F]FET demonstrated higher uptake. Conclusions: By examining factors contributing to PET-imaging phenotype, this study establishes the feasibility of noninvasive molecular stratification using multiplex radiotracer PET. It lays the foundation for further exploration of PET-based subtyping in human cancer, thereby facilitating noninvasive molecular diagnosis.

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“…Finally, the precise mechanism by which the cholesterol pathway regulates tumorigenesis can be multifaceted 20 – 22 . Cholesterol biosynthesis is not only responsible for cholesterol as an end product but also creates isoprenoids as intermediate metabolites that can be the source of geranylgeranyl pyrophosphate (GGPP) and ubiquinone, contributing to protein prenylation, glycosylation, and the response to oxidative stress 21 , 24 .…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, a relatively unexplored area of research in CRC is metabolism, which could provide a rich source of new therapeutics targeting phenotypic dependencies created by non-oncogenic vulnerabilities. In this context, cholesterol metabolism is particularly vital because it not only provides energy sources and essential structural molecules for cell membranes but also modulates various signal transduction pathways, thereby mediating cell survival, tumor growth, and drug resistance 20 – 22 . Furthermore, cumulative evidence suggests that reversal of a dysregulated lipid metabolism has synergistic tumor-suppressive effects, offering potential therapeutic opportunities for cancers refractory to conventional treatments 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis

Muta,

Linares,

Martinez-Ordoñez

et al. 2023

Nat Commun

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The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

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

Cited by 8 publications

References 136 publications

Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis

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