Overlooking Evolution: A Systematic Analysis of Cancer Relapse and Therapeutic Resistance Research

Department of Psychology, Arizona State University, Tempe, Arizona, United States of America.
PLoS ONE (Impact Factor: 3.23). 11/2011; 6(11):e26100. DOI: 10.1371/journal.pone.0026100
Source: PubMed

ABSTRACT Cancer therapy selects for cancer cells resistant to treatment, a process that is fundamentally evolutionary. To what extent, however, is the evolutionary perspective employed in research on therapeutic resistance and relapse? We analyzed 6,228 papers on therapeutic resistance and/or relapse in cancers and found that the use of evolution terms in abstracts has remained at about 1% since the 1980s. However, detailed coding of 22 recent papers revealed a higher proportion of papers using evolutionary methods or evolutionary theory, although this number is still less than 10%. Despite the fact that relapse and therapeutic resistance is essentially an evolutionary process, it appears that this framework has not permeated research. This represents an unrealized opportunity for advances in research on therapeutic resistance.

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Available from: C. Athena Aktipis, Sep 28, 2015
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    • "Despite broad acceptance of evolutionary theory as a useful conceptual framework to understand fundamental features of cancer behavior [1] [2] [3], evolutionary aspect of cancer is often overlooked in development of novel therapeutic strategies [4]. Although no disqualifying contradiction with evolutionary theory has been found, the dis-appreciation of therapeutic applicability of evolutionary theory might come from exaggerated expectations from too straightforward (or intuitive) applications of basic evolutionary concepts. "
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    ABSTRACT: Development of resistance limits transferability of most anticancer therapies into curative treatment and understanding mechanisms beyond it remains a big challenge. Many high resolution experimental observations show enormous intratumor heterogeneity at molecular, genetic and cellular levels which is made responsible for emerging resistance to therapy. Therefore, researchers search techniques to influence development of intratumor heterogeneity, which requires understanding its role within the context of integrative, logically consistent, framework, such as evolutionary theory. Although it is agreed that intratumor heterogeneity increases probability of the emergence of therapy resistant clones, more instructive role of its structure in the process of cancer dynamics and metastasis is needed. In the paper, intratumor heterogeneity is viewed as a product of two, in general stochastic, processes, evolutionary optimization and changing environment, respectively. In evolutionary theory, common risk-diversifying strategy displayed by isogenic populations in unpredictably changing environments is bet-hedging. We suggest, that the structure of intratumor heterogeneity is evolutionary trait evolving to maximize the clonal fitness in changing (or uncertain) environment and that its structure corresponds to bet-hedging strategy. We advocate our view by reviewing and combining important cancer relevant concepts.
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    • "In retrospect, it is remarkable that the evolution of cells within tumors was not recognized until the 1970s with Nowell's (1976) paper 'The clonal evolution of tumor cell populations.' Despite subsequent wide acceptance of evolutionary explanations for cancer progression, applications of evolutionary thinking remain limited; for instance, evolutionary terms are used in only about 1% of the abstracts of papers on therapeutic resistance (Aktipis et al. 2011). While applications of evolutionary principles to the problems of cancer are in their infancy, they are growing fast, as illustrated by many recent conferences across the world, and the creation of two centers for the study of evolution and cancer, the Center for Evolution and Cancer at the University of California, San Francisco, and the Centre for Ecological and Evolutionary Cancer Research at University of Montpellier. "
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    ABSTRACT: New applications of evolutionary biology are transforming our understanding of cancer. The articles in this special issue provide many specific examples, such as microorganisms inducing cancers, the significance of within-tumor heterogeneity, and the possibility that lower dose chemotherapy may sometimes promote longer survival. Underlying these specific advances is a large-scale transformation, as cancer research incorporates evolutionary methods into its toolkit, and asks new evolutionary questions about why we are vulnerable to cancer. Evolution explains why cancer exists at all, how neoplasms grow, why cancer is remarkably rare, and why it occurs despite powerful cancer suppression mechanisms. Cancer exists because of somatic selection; mutations in somatic cells result in some dividing faster than others, in some cases generating neoplasms. Neoplasms grow, or do not, in complex cellular ecosystems. Cancer is relatively rare because of natural selection; our genomes were derived disproportionally from individuals with effective mechanisms for suppressing cancer. Cancer occurs nonetheless for the same six evolutionary reasons that explain why we remain vulnerable to other diseases. These four principles-cancers evolve by somatic selection, neoplasms grow in complex ecosystems, natural selection has shaped powerful cancer defenses, and the limitations of those defenses have evolutionary explanations-provide a foundation for understanding, preventing, and treating cancer.
    Evolutionary Applications 02/2013; 6(1):144-59. DOI:10.1111/eva.12034 · 3.90 Impact Factor
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    • "Although our understanding of cancer biology and genetics has greatly improved since Richard Nixon's 1970s call to arms against cancer, the treatments developed have not lived up to the expectations (Jemal et al. 2009; Ryan et al. 2010; Colotta 2011; Drake 2011). For this reason, there has been a growing need for a shift in the way cancer is traditionally studied and treated (Merlo et al. 2006; Pienta et al. 2008; Aktipis et al. 2011). It is within this context that a fundamentally different approach to cancer research has emerged: the study of cancer as a process following Darwinian evolution (Cairns 1975; Nowell 1976; Crespi and Summers 2005; Merlo et al. 2006). "
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    ABSTRACT: Cancer is now understood to be a process that follows Darwinian evolution. Heterogeneous populations of cancerous cells that make up the tumor inhabit the tissue 'microenvironment', where ecological interactions analogous to predation and competition for resources drive the somatic evolution of cancer. The tumor microenvironment plays a crucial role in the tumor genesis, development, and metastasis processes, as it creates the microenvironmental selection forces that ultimately determine the cellular characteristics that result in the greatest fitness. Here, we explore and offer new insights into the spatial aspects of tumor-microenvironment interactions through the application of landscape ecology theory to tumor growth and metastasis within the tissue microhabitat. We argue that small tissue microhabitats in combination with the spatial distribution of resources within these habitats could be important selective forces driving tumor invasiveness. We also contend that the compositional and configurational heterogeneity of components in the tissue microhabitat do not only influence resource availability and functional connectivity but also play a crucial role in facilitating metastasis and may serve to explain, at least in part, tissue tropism in certain cancers. This novel work provides a compelling argument for the necessity of taking into account the structure of the tissue microhabitat when investigating tumor progression.
    Evolutionary Applications 01/2013; 6(1):82-91. DOI:10.1111/eva.12031 · 3.90 Impact Factor
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