Metabolic modelling links Warburg effect to collagen formation, angiogenesis and inflammation in the tumoral stroma.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Collagen*/metabolism ; Inflammation*/metabolism ; Inflammation*/pathology ; Neovascularization, Pathologic*/metabolism ; Neovascularization, Pathologic*/pathology ; Models, Biological*; Humans ; Neoplasms/metabolism ; Neoplasms/pathology ; Warburg Effect, Oncologic ; Cell Line, Tumor ; Glutamine/metabolism ; Stromal Cells/metabolism ; Stromal Cells/pathology ; Glycolysis ; Angiogenesis

Cancer cells are known to express the Warburg effect-increased glycolysis and formation of lactic acid even in the presence of oxygen-as well as high glutamine uptake. In tumors, cancer cells are surrounded by collagen, immune cells, and neoangiogenesis. Whether collagen formation, neoangiogenesis, and inflammation in cancer are associated with the Warburg effect needs to be established. Metabolic modelling has proven to be a tool of choice to understand biological reality better and make in silico predictions. Elementary Flux Modes (EFMs) are essential for conducting an unbiased decomposition of a metabolic model into its minimal functional units. EFMs can be investigated using our tool, aspefm, an innovative approach based on logic programming where biological constraints can be incorporated. These constraints allow networks to be characterized regardless of their size. Using a metabolic model of the human cell containing collagen, neoangiogenesis, and inflammation markers, we derived a subset of EFMs of biological relevance to the Warburg effect. Within this model, EFMs analysis provided more adequate results than parsimonious flux balance analysis and flux sampling. Upon further inspection, the EFM with the best linear regression fit to cancer cell lines exometabolomics data was selected. The minimal pathway, presenting the Warburg effect, collagen synthesis, angiogenesis, and release of inflammation markers, showed that collagen production was possible directly de novo from glutamine uptake and without extracellular import of glycine and proline, collagen's main constituents.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Mahout et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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9007-34-5 (Collagen)
0RH81L854J (Glutamine)

Date Created: 20241203 Date Completed: 20241203 Latest Revision: 20241205

20241209

PMC11614220

10.1371/journal.pone.0313962

39625899