Colorectal cancer progression is potently reduced by a glucose-free, high-protein diet: Comparison to anti-egfr therapy

Kerstin Skibbe, Ann Kathrin Brethack, Annika Sünderhauf, Mohab Ragab, Annika Raschdorf, Maren Hicken, Heidi Schlichting, Joyce Preira, Jennifer Brandt, Darko Castven, Bandik Föh, René Pagel, Jens U. Marquardt, Christian Sina, Stefanie Derer*

*Korrespondierende/r Autor/-in für diese Arbeit

Abstract

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.

OriginalspracheEnglisch
Aufsatznummer5817
ZeitschriftCancers
Jahrgang13
Ausgabenummer22
ISSN2072-6694
DOIs
PublikationsstatusVeröffentlicht - 01.11.2021

Strategische Forschungsbereiche und Zentren

  • Profilbereich: Lübeck Integrated Oncology Network (LION)
  • Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)

DFG-Fachsystematik

  • 205-15 Gastroenterologie
  • 205-05 Ernährungswissenschaften
  • 205-14 Hämatologie, Onkologie

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