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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| Vydáno v: | Cancers Ročník 13; číslo 22; s. 5817 |
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19.11.2021
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| ISSN: | 2072-6694, 2072-6694 |
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| 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. |
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| AbstractList | Simple SummaryTo study the interplay between nutrition and intestinal metabolism in the context of colitis-driven colorectal carcinoma (CRC), we here investigated a nutritional therapy strategy in the presence or absence of EGFR-directed antibody therapy in mice to treat established colitis-driven CRCs in vivo. After CRC development, mice were fed a control diet or an isoenergetic glucose-free high-protein (GFHP) diet in the presence or absence of EGFR-directed antibody therapy. The GFHP diet was accompanied by a metabolic shift of the mice towards lower glycolysis activity. Both, GFHP diet or anti-EGFR antibody treatment, improved tumor differentiation and anti-tumor immune response, resulting in an efficient reduction of colonic tumor burden.AbstractTo 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. 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. 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.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. |
| Author | Ragab, Mohab Brethack, Ann-Kathrin Sünderhauf, Annika Schlichting, Heidi Derer, Stefanie Sina, Christian Preira, Joyce Föh, Bandik Castven, Darko Hicken, Maren Pagel, René Raschdorf, Annika Marquardt, Jens U. Skibbe, Kerstin Brandt, Jennifer |
| AuthorAffiliation | 2 1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; darko.castven@uksh.de (D.C.); Jens.Marquardt@uksh.de (J.U.M.) 3 Institute of Anatomy, University of Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; pagel@anat.uni-luebeck.de 1 Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; kerstin.skibbe@gmail.com (K.S.); annkathrin.brethack95@gmail.com (A.-K.B.); annika.suenderhauf@uksh.de (A.S.); mohab.ragab@uksh.de (M.R.); annika.raschdorf@uksh.de (A.R.); maren.hicken@uksh.de (M.H.); heidi.schlichting@uksh.de (H.S.); joyce.preira@icloud.com (J.P.); jennifer.brandt@student.uni-luebeck.de (J.B.); bandik.foeh@uksh.de (B.F.); Christian.Sina@uksh.de (C.S.) 4 1st Department of Medicine, Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany |
| AuthorAffiliation_xml | – name: 3 Institute of Anatomy, University of Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; pagel@anat.uni-luebeck.de – name: 4 1st Department of Medicine, Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany – name: 2 1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; darko.castven@uksh.de (D.C.); Jens.Marquardt@uksh.de (J.U.M.) – name: 1 Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; kerstin.skibbe@gmail.com (K.S.); annkathrin.brethack95@gmail.com (A.-K.B.); annika.suenderhauf@uksh.de (A.S.); mohab.ragab@uksh.de (M.R.); annika.raschdorf@uksh.de (A.R.); maren.hicken@uksh.de (M.H.); heidi.schlichting@uksh.de (H.S.); joyce.preira@icloud.com (J.P.); jennifer.brandt@student.uni-luebeck.de (J.B.); bandik.foeh@uksh.de (B.F.); Christian.Sina@uksh.de (C.S.) |
| Author_xml | – sequence: 1 givenname: Kerstin orcidid: 0000-0002-2517-0423 surname: Skibbe fullname: Skibbe, Kerstin – sequence: 2 givenname: Ann-Kathrin surname: Brethack fullname: Brethack, Ann-Kathrin – sequence: 3 givenname: Annika surname: Sünderhauf fullname: Sünderhauf, Annika – sequence: 4 givenname: Mohab surname: Ragab fullname: Ragab, Mohab – sequence: 5 givenname: Annika surname: Raschdorf fullname: Raschdorf, Annika – sequence: 6 givenname: Maren surname: Hicken fullname: Hicken, Maren – sequence: 7 givenname: Heidi surname: Schlichting fullname: Schlichting, Heidi – sequence: 8 givenname: Joyce surname: Preira fullname: Preira, Joyce – sequence: 9 givenname: Jennifer surname: Brandt fullname: Brandt, Jennifer – sequence: 10 givenname: Darko surname: Castven fullname: Castven, Darko – sequence: 11 givenname: Bandik surname: Föh fullname: Föh, Bandik – sequence: 12 givenname: René surname: Pagel fullname: Pagel, René – sequence: 13 givenname: Jens U. surname: Marquardt fullname: Marquardt, Jens U. – sequence: 14 givenname: Christian surname: Sina fullname: Sina, Christian – sequence: 15 givenname: Stefanie orcidid: 0000-0002-6142-5577 surname: Derer fullname: Derer, Stefanie |
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| CitedBy_id | crossref_primary_10_1186_s12885_023_10786_6 crossref_primary_10_1016_j_bcp_2023_115765 crossref_primary_10_1016_j_jnutbio_2025_110016 |
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| Title | Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy |
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