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.
Originalsprache | Englisch |
---|---|
Aufsatznummer | 5817 |
Zeitschrift | Cancers |
Jahrgang | 13 |
Ausgabenummer | 22 |
ISSN | 2072-6694 |
DOIs | |
Publikationsstatus | Veröffentlicht - 01.11.2021 |
Strategische Forschungsbereiche und Zentren
- Profilbereich: Lübeck Integrated Oncology Network (LION)
- Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)
DFG-Fachsystematik
- 2.22-15 Gastroenterologie
- 2.22-05 Ernährungswissenschaften
- 2.22-14 Hämatologie, Onkologie