ArticleProceedings of the National Academy of Sciences of the United States of America2015
Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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78 citing papers in PubMed, 170 citations in OpenAlex.
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- Improving neuroendocrine tumor treatments with mathematical modeling: lessons from other endocrine cancers.Endocrine oncology (Bristol, England) · 2025Review
- Density amplifiers of cooperation for spatial games.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Frequency-dependent returns in nonlinear public goods games.Journal of the Royal Society, Interface · 2024Article
- Modeling tumors as complex ecosystems.iScience · 2024Review
- Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies.Journal of clinical medicine · 2024Article
- Nonlinear social evolution and the emergence of collective action.PNAS nexus · 2024Article
- Dynamic altruistic cooperation within breast tumors.Molecular cancer · 2023Article
- Clonal cooperation through soluble metabolite exchange facilitates metastatic outgrowth by modulating Allee effect.Science advances · 2023Article
- The paradox of cooperation among selfish cancer cells.Evolutionary applications · 2023Review
18 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.