Lactate adversely affects the in vitro formation of endothelial cell tubular structures through the action of TGF-β1

Schmid, Stephan A.; Gaumann, Andreas; Wondrak, Marit; Eckermann, Christoph; Schulte, Stephanie; Mueller-Klieser, Wolfgang; Wheatley, Denys N.; Kunz-Schughart, Leoni A.

doi:10.1016/j.yexcr.2007.05.016

Cited by 26Angiogenesis and VEGF in CancerCancer, Hypoxia, and MetabolismTGF-β signaling in diseases

Lactate adversely affects the in vitro formation of endothelial cell tubular structures through the action of TGF-β1

Schmid, Stephan A., Gaumann, Andreas, Wondrak, Marit, Eckermann, Christoph, Schulte, Stephanie, Mueller-Klieser, Wolfgang, Wheatley, Denys N., Kunz-Schughart, Leoni A.·2007·Experimental Cell Research

DOI 10.1016/j.yexcr.2007.05.016

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Abstract

When lactate accumulation in a tumor microenvironment reaches an average concentration of 10-20 mM, it tends to reflect a high degree of malignancy. However, the hypothesis that tumor-derived lactate has a number of partially adverse biological effects on malignant and tumor-associated host cells requires further evidence. The present study attempted to evaluate the impact of lactate on the process of angiogenesis, in particular on the formation of tubular structures. The endothelial cell (EC) network in desmoplastic breast tumors is primarily located in areas of reactive fibroblastic stroma. We employed a fibroblast-endothelial cell co-culture model as in vitro angiogenesis system normally producing florid in vitro tubule formation to analyze this situation. In contrast to previous studies, we found that lactate significantly reduces EC network formation in a dose-dependent manner as quantified by semi-automated morphometric analyses following immunohistochemical staining. The decrease in CD31-positive tubular structures and the number of intersections was independent of VEGF supplementation and became more pronounced in the presence of protons. The number of cells, primarily of the fibroblast population, was reduced but cell loss could not be attributed to a decrease in proliferative activity or pronounced apoptotic cell death. Treatment with 10 mM lactate was accompanied by enhanced mRNA expression and release of TGF-beta1, which also shows anti-angiogenic activity in the model. Both TGF-beta1 and lactate induced myofibroblastic differentiation adjacent to the EC tubular structures. The lactate response on the EC network was diminished by TGF-beta1 neutralization, indicating a causal relationship between lactate and TGF-beta1 in the finely tuned processes of vessel formation and maturation which may also occur in vivo within tumor tissue.

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Lactate accumulation promotes angiogenesis.
“Furthermore, lactate accumulation is instrumental for the promotion of angiogenesis.”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Schmid et al., 2007

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Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis
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Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced tumor angiogenesis
Copetti, T., Saedeleer, C. J. D., Dhup, S., Dewhirst, M. W., Féron, O., & Sonveaux, P. (2011) · Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B))

Authors: Schmid, S. A., Gaumann, A., Wondrak, M., Eckermann, C., Schulte, S., Mueller-Klieser, W., Wheatley, D. N., & Kunz-Schughart, L. A.
Affiliations: University of Regensburg (DE)
OncoRay (DE)
Brigham and Women's Hospital (US)
ORCID: Schmid, Stephan A.
Wheatley, Denys N.
Venue: Experimental Cell Research
Publisher: Elsevier BV
Published: 2007-07
Volume: 313
Issue: 12
Pages: 2531-2549
ISSN: 0014-4827 (ISSN-L)
DOI: 10.1016/j.yexcr.2007.05.016
OpenAlex: W1964294317
Cited by: 26
References: 98
Citations by year: 2025: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2017: 1 · 2016: 3 · 2015: 2 · 2012: 2
FWCI: 0.53
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Experimental Cell Research (publishedVersion)
PubMed (publishedVersion)
University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
Funders: Deutsche Forschungsgemeinschaft (MU 576/14-3)
Bundesministerium für Bildung und Forschung (01ZZ0502)
Bayerisches Staatsministerium für Wissenschaft, Forschung und Kunst
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords: lactate, TGF-β1, angiogenesis, tumor microenvironment, myofibroblast differentiation, protons, antiangiogenic activity, VEGF-independent angiogenesis, CD31
MeSH terms: Actins, Cell Movement, Cell Survival, Fibroblasts, Gene Expression Regulation, Humans, Neutralization Tests, RNA, Messenger, Neovascularization, Physiologic, Coculture Techniques, Lactic Acid, Endothelial Cells, Cell Proliferation, Transforming Growth Factor beta1

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Lactate adversely affects the in vitro formation of endothelial cell tubular structures through the action of TGF-β1

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