Metabolic cooperation between co-cultured lung cancer cells and lung fibroblasts
Open accessAbstract
Cooperation of cancer cells with stromal cells, such as cancer-associated fibroblasts (CAFs), has been revealed as a mechanism sustaining cancer cell survival and growth. In the current study, we focus on the metabolic interactions of MRC5 lung fibroblasts with lung cancer cells (A549 and H1299) using co-culture experiments and studying changes of the metabolic protein expression profile and of their growth and migration abilities. Using western blotting, confocal microscopy and RT-PCR, we observed that in co-cultures MRC5 respond by upregulating pyruvate dehydrogenase (PDH) and the monocarboxylate transporter MCT1. In contrast, cancer cells increase the expression of glucose transporters (GLUT1), LDH5, PDH kinase and the levels of phosphorylated/inactivated pPDH. H1299 cells growing in the same culture medium with fibroblasts exhibit a 'metastasis-like' phenomenon by forming nests within the fibroblast area. LDH5 and pPDH were drastically upregulated in these nests. The growth rate of both MRC5 and cancer cells increased in co-cultures. Suppression of LDHA or PDK1 in cancer cells abrogates the stimulatory signal from cancer cells to fibroblasts. Incubation of MRC5 fibroblasts with lactate resulted in an increase of LDHB and of PDH expression. Silencing of PDH gene in fibroblasts, or silencing of PDK1 or LDHA gene in tumor cells, impedes cancer cell's migration ability. Overall, a metabolic cooperation between lung cancer cells and fibroblasts has been confirmed in the context of direct Warburg effect, thus the fibroblasts reinforce aerobic metabolism to support the intensified anaerobic glycolytic pathways exploited by cancer cells.
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CAFs stimulate proliferation and growth of tumor cells by metabolic cooperation.
“CAFs interact actively with cancer cells, and not only enhance their survival and invasion capacity but also remodel the ECM and stimulate the proliferation/growth of tumor cells by metabolic cooperation [42,43].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [43]
The Discussion concludes that metabolic cooperation increased cancer-cell proliferation in co-culture with lung fibroblasts. However, the experiments used MRC5 lung fibroblasts rather than specifically testing cancer-associated fibroblasts, so the claim extends the experimental finding to CAFs. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCAFs enhance cancer cell survival and invasion capacity.
“CAFs interact actively with cancer cells, and not only enhance their survival and invasion capacity but also remodel the ECM and stimulate the proliferation/growth of tumor cells by metabolic cooperation [42,43].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [43]
CAFs remodel the ECM.
“CAFs interact actively with cancer cells, and not only enhance their survival and invasion capacity but also remodel the ECM and stimulate the proliferation/growth of tumor cells by metabolic cooperation [42,43].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [43]
The Abstract and Discussion describe fibroblast–cancer-cell metabolic cooperation, growth, and migration, but do not address extracellular matrix remodeling. Searches for ECM remodeling and extracellular matrix found no passage stating that CAFs remodel the ECM. (LLM, conf=0.72)
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- Authors
- Koukourakis, M. I., Kalamida, D., Mitrakas, A. G., Liousia, M., Pouliliou, S., Sivridis, E., & Giatromanolaki, A.
- Affiliations
- Democritus University of Thrace (GR)
- Corresponding author
- Koukourakis, Michael I
- ORCID
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 97
- Issue
- 11
- Pages
- 1321-1331
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2746285571
- Cited by
- 54
- References
- 20
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 10 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 5 · 2018: 2
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Trakya Üniversitesi
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- lung cancer, cancer-associated fibroblasts, tumor microenvironment, metabolic cooperation, Warburg effect, aerobic glycolysis, pyruvate dehydrogenase, pyruvate dehydrogenase kinase 1, lactate dehydrogenase, MCT1, glucose transporter 1, tumor cell migration, MRC-5 fibroblasts, A549 cells, H1299 cells
- MeSH terms
- Cancer-Associated Fibroblasts, Cell Line, Cell Movement, Energy Metabolism, Humans, Lung, Lung Neoplasms, Neoplasm Proteins, Phosphorylation, Protein Processing, Post-Translational, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Spheroids, Cellular, Coculture Techniques, Paracrine Communication, Gene Expression Profiling, RNA Interference, Cell Line, Tumor, Cell Proliferation
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