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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/22/5817 |
| _version_ | 1797510934894215168 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kerstin Skibbe |
| collection | DOAJ |
| description | 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>i.p.</i> 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. |
| first_indexed | 2024-03-10T05:38:15Z |
| format | Article |
| id | doaj.art-5cd64188174e4c99bfdca3d7276a666f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T05:38:15Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5cd64188174e4c99bfdca3d7276a666f2023-11-22T22:43:44ZengMDPI AGCancers2072-66942021-11-011322581710.3390/cancers13225817Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR TherapyKerstin Skibbe0Ann-Kathrin Brethack1Annika Sünderhauf2Mohab Ragab3Annika Raschdorf4Maren Hicken5Heidi Schlichting6Joyce Preira7Jennifer Brandt8Darko Castven9Bandik Föh10René Pagel11Jens U. Marquardt12Christian Sina13Stefanie Derer14Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Anatomy, University of Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyInstitute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, GermanyTo 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>i.p.</i> 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.https://www.mdpi.com/2072-6694/13/22/5817EGFRcolorectal canceramino acid metabolismPD-L1PD-1AOM/DSS |
| spellingShingle | 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 Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy Cancers EGFR colorectal cancer amino acid metabolism PD-L1 PD-1 AOM/DSS |
| title | Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy |
| title_full | Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy |
| title_fullStr | Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy |
| title_full_unstemmed | Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy |
| title_short | Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy |
| title_sort | colorectal cancer progression is potently reduced by a glucose free high protein diet comparison to anti egfr therapy |
| topic | EGFR colorectal cancer amino acid metabolism PD-L1 PD-1 AOM/DSS |
| url | https://www.mdpi.com/2072-6694/13/22/5817 |
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