Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity
Abstract Background Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Cancer & Metabolism |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40170-022-00288-7 |
| _version_ | 1811287367004192768 |
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| author | Daniela D. Weber Sepideh Aminzadeh-Gohari Maheshwor Thapa Anna-Sophia Redtenbacher Luca Catalano Tânia Capelôa Thibaut Vazeille Michael Emberger Thomas K. Felder René G. Feichtinger Peter Koelblinger Guido Dallmann Pierre Sonveaux Roland Lang Barbara Kofler |
| author_facet | Daniela D. Weber Sepideh Aminzadeh-Gohari Maheshwor Thapa Anna-Sophia Redtenbacher Luca Catalano Tânia Capelôa Thibaut Vazeille Michael Emberger Thomas K. Felder René G. Feichtinger Peter Koelblinger Guido Dallmann Pierre Sonveaux Roland Lang Barbara Kofler |
| author_sort | Daniela D. Weber |
| collection | DOAJ |
| description | Abstract Background Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system. Methods Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo. Results We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors. Conclusions Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy. |
| first_indexed | 2024-04-13T03:17:15Z |
| format | Article |
| id | doaj.art-2d1d742289f44a19bbc1d95c27545516 |
| institution | Directory Open Access Journal |
| issn | 2049-3002 |
| language | English |
| last_indexed | 2024-04-13T03:17:15Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj.art-2d1d742289f44a19bbc1d95c275455162022-12-22T03:04:52ZengBMCCancer & Metabolism2049-30022022-07-0110112010.1186/s40170-022-00288-7Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticityDaniela D. Weber0Sepideh Aminzadeh-Gohari1Maheshwor Thapa2Anna-Sophia Redtenbacher3Luca Catalano4Tânia Capelôa5Thibaut Vazeille6Michael Emberger7Thomas K. Felder8René G. Feichtinger9Peter Koelblinger10Guido Dallmann11Pierre Sonveaux12Roland Lang13Barbara Kofler14Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityBiocrates Life Sciences AGResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityInstitut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain)Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain)Patholab SalzburgDepartment of Laboratory Medicine, University Hospital of the Paracelsus Medical UniversityResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityDepartment of Dermatology and Allergology, University Hospital of the Paracelsus Medical UniversityBiocrates Life Sciences AGInstitut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain)Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical UniversityResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityAbstract Background Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system. Methods Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo. Results We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors. Conclusions Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy.https://doi.org/10.1186/s40170-022-00288-7Ketogenic dietMelanomaCancer metabolismMetabolomics |
| spellingShingle | Daniela D. Weber Sepideh Aminzadeh-Gohari Maheshwor Thapa Anna-Sophia Redtenbacher Luca Catalano Tânia Capelôa Thibaut Vazeille Michael Emberger Thomas K. Felder René G. Feichtinger Peter Koelblinger Guido Dallmann Pierre Sonveaux Roland Lang Barbara Kofler Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity Cancer & Metabolism Ketogenic diet Melanoma Cancer metabolism Metabolomics |
| title | Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity |
| title_full | Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity |
| title_fullStr | Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity |
| title_full_unstemmed | Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity |
| title_short | Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity |
| title_sort | ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity |
| topic | Ketogenic diet Melanoma Cancer metabolism Metabolomics |
| url | https://doi.org/10.1186/s40170-022-00288-7 |
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