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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/5cd64188174e4c99bfdca3d7276a666f |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:5cd64188174e4c99bfdca3d7276a666f |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:5cd64188174e4c99bfdca3d7276a666f2021-11-25T17:04:24ZColorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy10.3390/cancers132258172072-6694https://doaj.org/article/5cd64188174e4c99bfdca3d7276a666f2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5817https://doaj.org/toc/2072-6694To 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.Kerstin SkibbeAnn-Kathrin BrethackAnnika SünderhaufMohab RagabAnnika RaschdorfMaren HickenHeidi SchlichtingJoyce PreiraJennifer BrandtDarko CastvenBandik FöhRené PagelJens U. MarquardtChristian SinaStefanie DererMDPI AGarticleEGFRcolorectal canceramino acid metabolismPD-L1PD-1AOM/DSSNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5817, p 5817 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
EGFR colorectal cancer amino acid metabolism PD-L1 PD-1 AOM/DSS Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
EGFR colorectal cancer amino acid metabolism PD-L1 PD-1 AOM/DSS Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
colorectal cancer progression is potently reduced by a glucose-free, high-protein diet: comparison to anti-egfr therapy |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/5cd64188174e4c99bfdca3d7276a666f |
| work_keys_str_mv |
AT kerstinskibbe colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT annkathrinbrethack colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT annikasunderhauf colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT mohabragab colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT annikaraschdorf colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT marenhicken colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT heidischlichting colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT joycepreira colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT jenniferbrandt colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT darkocastven colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT bandikfoh colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT renepagel colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT jensumarquardt colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT christiansina colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy AT stefaniederer colorectalcancerprogressionispotentlyreducedbyaglucosefreehighproteindietcomparisontoantiegfrtherapy |
| _version_ |
1718412713856598016 |