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. 2025 Jun 19;14(12):931.
doi: 10.3390/cells14120931.

Free Methylglyoxal and Lactate Produced and Released by Cultured Cancer and Non-Cancer Cells: Implications for Tumor Growth and Development

Dominique Belpomme  1   2 , Philippe Irigaray  2   3 , Jean-Marc Alberto  4 , Clément Poletti  5 , Charlotte Hinault-Boyer  6   7 , Stéphanie Lacomme  8
Affiliations

Free Methylglyoxal and Lactate Produced and Released by Cultured Cancer and Non-Cancer Cells: Implications for Tumor Growth and Development

Dominique Belpomme et al. Cells. .

Abstract

We have previously shown that in cancer patients, free methylglyoxal (MG), a side-product of glycolysis, is recovered from tumors at significantly higher levels than from their corresponding non-cancerous tissues. We also recently confirmed our initial experimental finding that in these patients, free MG peripheral blood levels correlate positively with tumor growth, making free MG levels a new metabolic biomarker of tumor growth of interest to detect cancer and clinically follow cancer patients with no available biomarkers. Now we measure free MG and lactate produced by different cancer and normal cells cultured at low or high glucose concentration and in normoxic or hypoxic conditions to question whether cancer cells and non-cancer cells in tumors produce and release free MG and lactate. Surprisingly, we found that normal fibroblastic and endothelial cell lines grown in normoxic conditions produce and release high free MG levels, which we confirmed for non-transformed normal fibroblasts, albeit at significantly lower levels. Cancer cells generally significantly increased their free MG production and release when cultured in high glucose concentration, while normal cells generally did not. Furthermore, in normoxic conditions, normal fibroblastic cells, in addition to free MG, may produce and release lactate. From this data, we propose that in malignant tumors, both cancer and fibroblastic stromal cells may contribute to tumor growth and development by producing via glycolysis both free MG and D-lactate, which, in addition to L-lactate, may be part of the core hallmark of cell metabolic reprogramming in cancer.

Keywords: Warburg effect; cancer cells; cancer-associated fibroblasts; cell metabolic reprogramming; glycolysis; lactate; methylglyoxal; stromal cells; tumor growth; tumor microenvironment.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Free MG release from cancer cell lines cultured in normoxic low ☐ or high ⬛ glucose concentration. *: p = 0.001; **: p < 0.0001.
Figure 2
Figure 2
Free MG release from normal cell lines in comparison with mean free MG release from cancer cell lines, in normoxic low ☐ or high ⬛ glucose concentration. **: p < 0.0001.
Figure 3
Figure 3
Fluorescent staining using a specific anti-MG probe (A) in NDF normal fibroblast line, and (B) NFB-1 and NFB-2 normal fibroblasts. LG: low glucose concentration; HG: high glucose concentration.
Figure 4
Figure 4
Representation of free MG ☐ and lactate ▧ release by PCS 201-012 normal fibroblasts in normoxic or hypoxic conditions and glucose concentrations. LG, low glucose concentration; HG, high glucose concentration.
Figure 5
Figure 5
Representation of free MG release from non-transformed normal fibroblasts and normal fibroblastic cell lines in normoxic low ☐ or high ⬛ glucose concentration. *: p < 0.001; **: p < 0.0001.
Figure 6
Figure 6
Free MG release from normal fibroblasts and cancer cell lines cultured in different conditions. Normoxic low glucose ☐, normoxic high glucose ⬛, hypoxic low glucose ▧, or hypoxic high glucose ▥ conditions. **: p < 0.0001.
Figure 7
Figure 7
Lactate production from normal (A) and cancer cell (B) lines in normoxic low ☐ or high ⬛ glucose concentration. **: p < 0.0001.
Figure 8
Figure 8
Lactate release from cancer cell lines in aerobic ☐ or anaerobic ▥ low (A) or high (B) glucose concentration.
See this image and copyright information in PMC

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