Evolutionary game theory mathematically conceptualizes and analyzes biological interactions where one’s fitness not only depends on one’s own traits, but also on the traits of others. Typically, the individuals are not overtly rational and do not select, but rather inherit their traits. Cancer can be framed as such an evolutionary game, as it is composed of cells of heterogeneous types undergoing frequency-dependent selection. In this article, we first summarize existing works where evolutionary game theory has been employed in modeling cancer and improving its treatment. Some of these game-theoretic models suggest how one could anticipate and steer cancer’s eco-evolutionary dynamics into states more desirable for the patient via evolutionary therapies. Such therapies offer great promise for increasing patient survival and decreasing drug toxicity, as demonstrated by some recent studies and clinical trials. We discuss clinical relevance of the existing game-theoretic models of cancer and its treatment, and opportunities for future applications. Moreover, we discuss the developments in cancer biology that are needed to better utilize the full potential of game-theoretic models. Ultimately, we demonstrate that viewing tumors with evolutionary game theory has medically useful implications that can inform and create a lockstep between empirical findings and mathematical modeling. We suggest that cancer progression is an evolutionary competition between different cell types and therefore needs to be viewed as an evolutionary game.

/pdf/the-contribution-of-evolutionary-game-theory-to-xlzsb16526.pdf

The Contribution of Evolutionary Game Theory to Understanding and Treating Cancer

Nasopharyngeal carcinoma (NPC) is a particular entity of head neck cancer that is generally regarded as a genetic disease with diverse intertumor and intratumor heterogeneity. This perspective review mainly outlines the up-to-date knowledge of cancer ecology and NPC progression, and presents a number of conceptual stepping-stones. At the beginning, I explicitly advocate that the nature of NPC (cancer) is not a genetic disease but an ecological disease: a multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem. The hallmarks of cancer is proposed to act as ecological factors of population fitness. Subsequently, NPC cells are described as invasive species and its metastasis as a multidirectional ecological dispersal. The foundational ecological principles include intraspecific relationship (e.g. communication) and interspecific relationship (e.g. competition, predation, parasitism and mutualism) are interpreted to understand NPC progression. “Mulberry-fish-ponds” model can well illustrate the dynamic reciprocity of cancer ecosystem. Tumor-host interface is the ecological transition zone of cancer, and tumor buddings should be recognized as ecological islands separated from the mainland. It should be noted that tumor-host interface has a significantly molecular and functional edge effect because of its curvature and irregularity. Selection driving factors and ecological therapy including hyperthermia for NPC patients, and future perspectives in such field as “ecological pathology”, “multidimensional tumoriecology” are also discussed. I advance that “nothing in cancer evolution or ecology makes sense except in the light of the other”. The cancer ecology tree is constructed to comprehensively point out the future research direction. Taken together, the establishment of NPC ecology theory and cancer ecology tree might provide a novel conceptual framework and paradigm for our understanding of cancer complex causal process and potential preventive and therapeutic applications for patients.

/pdf/nasopharyngeal-carcinoma-ecology-theory-cancer-as-5i6nm8wb.pdf

Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem

Therapeutic strategies for tumor control have traditionally assumed that maximizing reduction in tumor volume correlates with clinical efficacy. Unfortunately, this rapid decrease in tumor burden is almost invariably followed by the emergence of therapeutic resistance. Evolutionary based treatment strategies attempt to delay resistance via judicious treatments that maintain a significant treatable subpopulation. While these strategies have shown promise in recent clinical trials, they often rely on biological conjecture and intuition to derive parameters. In this study we experimentally measure the frequency-dependent interactions between a gefitinib resistant non-small cell lung cancer (NSCLC) population and its sensitive ancestor via the evolutionary game assay. We show that cost of resistance is insufficient to accurately predict competitive exclusion and that frequency-dependent growth rate measurements are required. In addition, we show that frequency-dependent growth rate changes may ultimately result in a safe harbor for resistant populations to safely accumulate, even those with significant cost of resistance. Using frequency-dependent growth rate data we then show that gefitinib treatment results in competitive exclusion of the ancestor, while absence of treatment results in a likely, but not guaranteed exclusion of the resistant strain. Finally, using our empirically derived growth rates to constrain simulations, we demonstrate that incorporating ecological growth effects can dramatically change the predicted time to sensitive strain extinction. In addition, we show that higher drug concentrations may not lead to the optimal reduction in tumor burden. Taken together, these results highlight the potential importance of frequency-dependent growth rate data for understanding competing populations, both in the laboratory and the clinic.

/pdf/measuring-competitive-exclusion-in-non-small-cell-lung-174b4mc3q9.pdf

Measuring competitive exclusion in non-small cell lung cancer

DNA replication during cell proliferation is ‘vertical’ copying, which reproduces an initial amount of genetic information. Polyploidy, which results from whole-genome duplication, is a fundamental complement to vertical copying. Both organismal and cell polyploidy can emerge via premature cell cycle exit or via cell-cell fusion, the latter giving rise to polyploid hybrid organisms and epigenetic hybrids of somatic cells. Polyploidy-related increase in biological plasticity, adaptation, and stress resistance manifests in evolution, development, regeneration, aging, oncogenesis, and cardiovascular diseases. Despite the prevalence in nature and importance for medicine, agri- and aquaculture, biological processes and epigenetic mechanisms underlying these fundamental features largely remain unknown. The evolutionarily conserved features of polyploidy include activation of transcription, response to stress, DNA damage and hypoxia, and induction of programs of morphogenesis, unicellularity, and longevity, suggesting that these common features confer adaptive plasticity, viability, and stress resistance to polyploid cells and organisms. By increasing cell viability, polyploidization can provide survival under stressful conditions where diploid cells cannot survive. However, in somatic cells it occurs at the expense of specific function, thus promoting developmental programming of adult cardiovascular diseases and increasing the risk of cancer. Notably, genes arising via evolutionary polyploidization are heavily involved in cancer and other diseases. Ploidy-related changes of gene expression presumably originate from chromatin modifications and the derepression of bivalent genes. The provided evidence elucidates the role of polyploidy in evolution, development, aging, and carcinogenesis, and may contribute to the development of new strategies for promoting regeneration and preventing cardiovascular diseases and cancer.

/pdf/polyploidy-as-a-fundamental-phenomenon-in-evolution-1x4e222k.pdf

Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases

The majority of cancer-related deaths are the result of metastases (i.e., dissemination and establishment of tumor cells at distant sites from the origin), which develop through a multi-step process classically termed the metastatic cascade. The respective contributions of each step to the metastatic process are well described but are also currently not completely understood. Is there, for example, a critical phase that disproportionately affects the probability of the development of metastases in individual patients? Here, we address this question using a modified Drake equation, initially formulated by the astrophysicist Frank Drake to estimate the probability of the emergence of intelligent civilizations in the Milky Way. Using simulations based on realistic parameter values obtained from the literature for breast cancer, we examine, under the linear progression hypothesis, the contribution of each component of the metastatic cascade. Simulations demonstrate that the most critical parameter governing the formation of clinical metastases is the survival duration of circulating tumor cells (CTCs).

Is There One Key Step in the Metastatic Cascade

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.

/pdf/identifying-key-questions-in-the-ecology-and-evolution-of-4gliyk32kj.pdf

Jean Pascal Capp

Papers

Identifying key questions in the ecology and evolution of cancer.