Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy

To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional interventi...

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Veröffentlicht in:	Cancers Jg. 13; H. 22; S. 5817
Hauptverfasser:	Skibbe, Kerstin, Brethack, Ann-Kathrin, Sünderhauf, Annika, Ragab, Mohab, Raschdorf, Annika, Hicken, Maren, Schlichting, Heidi, Preira, Joyce, Brandt, Jennifer, Castven, Darko, Föh, Bandik, Pagel, René, Marquardt, Jens U., Sina, Christian, Derer, Stefanie
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Basel MDPI AG 19.11.2021 MDPI
Schlagworte:	Amino acids Antibodies Azoxymethane Carbohydrates Cell culture Cell differentiation Cell division Cell proliferation Colitis Colorectal cancer Colorectal carcinoma Dextran Down-regulation Drinking water Epidermal growth factor Epidermal growth factor receptors Glucose Glucose metabolism Glycolysis High protein diet Immune response Immunotherapy Inflammation Inflammatory bowel disease Kinases Lactic acid Metabolism Monoclonal antibodies Nutrition therapy Oxidative metabolism Oxidative phosphorylation PD-1 protein PD-L1 protein Physical fitness Proteins Rodents Signal transduction Spleen Tumor cells Tumorigenesis Tumors
ISSN:	2072-6694, 2072-6694
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Zusammenfassung:	To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an i.p. injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3ε, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this study.
ISSN:	2072-6694 2072-6694
DOI:	10.3390/cancers13225817