Ecology and Evolution of Cancer

Ecology and Evolution of Cancer

Edited by

Beata Ujvari

Centre for Integrative Ecology, School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia

Benjamin Roche

UMMISCO (International Center for Mathematical and Computational Modeling of Complex Systems), UMI IRD/UPMC UMMISCO, Bondy, France

MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290, Montpellier, France

CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier, France

Frédéric Thomas

MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290, Montpellier, France

CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier, France

Table of Contents

Cover

Title page

Copyright

List of Contributors

Preface

Acknowledgments

Introduction: Five Evolutionary Principles for Understanding Cancer

Chapter 1: The Evolutionary Origins of Cancer and of Its Control by Immune Policing and Genetic Suppression

Abstract

Lineage selection

Immune system policing

Cancer suppression

Evolution and Peto’s paradox

Why does cancer persist?

Conclusions

Chapter 2: Cancer Prevalence and Etiology in Wild and Captive Animals

Abstract

Introduction

Cancer prevalence and etiology in wild vertebrates

Cancer etiology and prevalence in French zoological parks

Discussion

Concluding remarks

Acknowledgments

Chapter 3: Infection and Cancer in Nature

Abstract

Introduction

Infectious causes of cancer

Findings suggestive of pathogen-induced cancer in nature

Associations between nonmalignant neoplasia and cancer

Joint contributions to oncogenesis

A broadening scope for interventions

Acknowledgments

Chapter 4: Pseudohypoxia: Life at the Edge

Abstract

Introduction

Distinguishing pseudohypoxia from hypoxia

Pseudohypoxia: tumor edge versus core

Modeling of pseudohypoxia

Pseudohypoxia at the microscopic level

Tumor edge

Tumor core

Conclusions

Chapter 5: The Genomic Landscape of Cancers

Abstract

Introduction

Key features and challenges of the cancer genomic landscape

Genome theory of somatic cell evolution

Implications and future directions

Acknowledgments

Chapter 6: The Epigenetic Component in Cancer Evolution

Abstract

The genotype × environment concept

DNA methylation

Histone modifications

Nuclear topography and noncoding RNA

Conclusions

Chapter 7: Evolution of Cancer Defense Mechanisms Across Species

Abstract

Mechanisms of cancer suppression: organismal, microenvironmental, and molecular

A life history perspective: organismal level trade-offs in cancer suppression

Conclusions

Chapter 8: Coevolution of Tumor Cells and Their Microenvironment: Niche Construction in Cancer

Abstract

Introduction

The consequences of tumor-stroma metabolic compartmentation and collaboration

Conclusions

Chapter 9: Evolutionary Perspective of Tumorigenesis and Antitumor Immunity: A Comparative Approach

Abstract

Introduction

Immunology of cancer

Strategies of tumor immune evasion

Immunoediting

Tumors in invertebrates and ectothermic vertebrates

Evolution of immunity and tumor immunity

Immunotherapies

Overview of animal model system used to investigate the role of immune system in cancer

Amphibians as model systems to explore the evolutionary conservation of tumor immunity

The Xenopus immune system

Transplantable thymic lymphoid tumor cell lines

Tumor immunity in X. laevis

Conservation of antitumor properties of heat shock proteins

Conserved roles of nonclassical MHC and innate T cells in tumor immunity

Xenopus tadpole tumor model

Conclusions and perspectives

Acknowledgments

Chapter 10: The Response of Cancer Cell Populations to Therapies

Abstract

Introduction

Phenotypic plasticity

Tumor microenvironment

Summary and outlook on therapeutic strategies

Chapter 11: Ecology of the Metastatic Process

Abstract

Introduction

Introduction to metastasis

Introduction to invasion ecology

Metastasis and invasion ecology—a novel framework for clinical treatment?

What is special about the invasion ecology of cancer cells?

Filtering concepts as limits to metastatic success

Subsequent evolution and therapy

Conclusions

Chapter 12: Transmissible Cancer: The Evolution of Interindividual Metastasis

Abstract

Introduction

Contagious cancers with no underlying infectious etiologies

Mechanisms involved in cancer transmission

Tug-of-war: evolution of transmissible cancers and their hosts

The ecological impact of cancer cells on the hosts’ micro- and macroenvironment

Conclusions

Acknowledgments

Chapter 13: Cancer in Animals: Reciprocal Feedbacks Between Evolution of Cancer Resistance and Ecosystem Functioning

Abstract

Introduction

Cancer in wildlife: where are we?

How does natural selection deal with cancer risk?

Impact of cancer on ecological communities

Discussion

Chapter 14: Applying Tools From Evolutionary Biology to Cancer Research

Abstract

Introduction

Adapt or die (adaptive therapy)

All at once it is not always the best thing (the double bind theory)

No double pain, no double gain (the cost of being resistant)

Concluding remarks, drawbacks, and future directions

Section: Perspectives

Chapter 15: Understanding Ancient Legacies to Expose and Exploit Cancer’s Evolutionary Vulnerabilities

Abstract

A new light on old paradigms

Moving forward by looking back

Exposing and exploiting evolutionary vulnerabilities

Concluding remarks

Chapter 16: Atavism Theory—An Introductory Discourse

Abstract

Introduction

The nature of cancer

Therapeutic implications

Conclusions

Chapter 17: Toward an Ultimate Explanation of Intratumor Heterogeneity

Abstract

From cooperation to selfishness and back to (malignant) cooperation

De novo tumor development—from an individual cell to a cooperating organized system

Bet-hedging as evolutionary response to unpredictable tumor environment

Predictions and implications

Concluding remarks

Chapter 18: Obstacles to the Darwinian Framework of Somatic Cancer Evolution

Abstract

Introduction

Challenge #1: The dominance of gene and mutation-centric paradigms

Challenge #2: Complex inputs shaping the phenotypes of cancer cells

Challenge #3: Unique and powerful sources of phenotypic variability

Conclusions

Acknowledgments

Chapter 19: Cancer as a Disease of Homeostasis: An Angiogenesis Perspective

Abstract

Introduction to neovascularization

Pathological angiogenesis and musical chairs

Tumor-induced stromal stimulation and time to escape from tumor dormancy

Chapter 20: Dormancy: An Evolutionary Key Phenomenon in Cancer Development

Abstract

Introduction

Dormancy in tumor evolution

Dormancy in species evolution

Linking evolutionary concepts to the investigation of tumor dormancy

Conclusions

Chapter 21: Controlling Rogue Cells in Cancer and Bacterial Infections

Abstract

Killing the rogues—sparing the rest

Preventing resistance to treatment

Discussion

Acknowledgments

Chapter 22: Searching for a Cancer-Proof Organism: It’s the Journey That Teaches You About the Destination

Abstract

Insights from life history theory

Body size and cancer risk

Evolved cancer defenses

A macroevolutionary perspective

Since when has cancer been plaguing us?

Sex and cancer

Can a cancer-proof organism really exist?

Conclusions

Acknowledgments

Chapter 23: Ecology, Evolution, and the Cancer Patient

Acknowledgment

Index

Copyright

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List of Contributors

Jerôme Abadie,     LUNAM University, Oniris, AMaROC, Nantes, France

Ole Ammerpohl,     Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Audrey Arnal,     MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290; CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier, France

Maureen Banach,     Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States

Christa Beckmann,     Centre for Integrative Ecology, School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia

Florence Bernex

CREEC (Centre for Ecological and Evolutionary Research on Cancer)

Montpellier University

RHEM, IRCM, Institute of Cancer Research Montpellier, INSERM

ICM Regional Cancer Institute of Montpellier, Montpellier, France

Amy M. Boddy

Department of Psychology, Arizona State University, Tempe, AZ

Center for Evolution & Cancer, University of California San Francisco, San Francisco, CA, United States

Joel S. Brown

Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Department of Biological Sciences, University of Illinois at Chicago

Department of Evolutionary Biology, University of Illinois, Chicago, IL, United States

Sam P. Brown,     School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, United States

Francisco De Jesús Andino,     Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States

James DeGregori,     Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, United States

Eva-Stina Edholm,     Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States

Pedro M. Enriquez-Navas,     H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States

Paul W. Ewald,     Department of Biology; Department of Biology and the Program on Disease Evolution, University of Louisville, Louisville, KY, United States

Dominique Faugère

MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290

CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier, France

Jasmine Foo,     School of Mathematics, University of Minnesota, Minneapolis, MN, United States

Déborah Garcia

MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290

CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier, France

Colleen M. Garvey,     Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States

Robert A. Gatenby

Department of Integrated Mathematical Oncology

Department of Radiology

Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States

Cindy Gidoin,     MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290, Montpellier, France

Robert J. Gillies

Department of Cancer Imaging and Metabolism

Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States

Christoph Grunau,     University of Perpignan Via Domitia, IHPE UMR 5244, CNRS, IFREMER, University of Montpellier, Perpignan, France

Valerie K. Harris

Cancer and Evolution Lab, Arizona State University

School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States

Kirsten Hattermann,     Institute of Anatomy, Christian-Albrechts-University Kiel, Kiel, Germany

Janka Held-Feindt,     Department of Neurosurgery, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany

Henry H. Heng

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine

Department of Pathology, Wayne State University School of Medicine

Karmanos Cancer Institute, Detroit, MI, United States

Arig Ibrahim-Hashim,     Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States

Irina Kareva,     Simon A. Levin Mathematical, Computational and Modeling Sciences Center (SAL MCMSC), Arizona State University, Tempe, AZ, United States

Hanna Kokko,     Department of Evolutionary Biology and Environmental Studies, University of Zurich, Winterthurerstrasse, Zurich, Switzerland

Sophie Labrut,     LUNAM University, Oniris, AMaROC, Nantes, France

Karin Lemberger,     Vet Diagnostics, Lyon, France

Danika Lindsay,     School of Mathematics, University of Minnesota, Minneapolis, MN, United States

Mark C. Lloyd

Inspirata, Inc., Tampa, FL

Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, United States

Anders Pape Møller,     Ecology Systematic Evolution, CNRS UMR 8079, University Paris-Sud, Orsay, France

Thomas Madsen

School of Biological Sciences, University of Wollongong, Wollongong, NSW

Centre for Integrative Ecology, School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia

Andriy Marusyk,     Department of Cancer Imaging and Metabolism, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States

John F. McDonald

School of Biological Sciences

Integrated Cancer Research Center

Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States

Shannon M. Mumenthaler,     Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States

Aurora M. Nedelcu,     Department of Biology, University of New Brunswick, Fredericton, NB, Canada

Randolph M. Nesse,     The Center for Evolution and Medicine, Arizona State University, Tempe, AZ, United States

Leonard Nunney,     Department of Biology, University of California Riverside, Riverside, CA, United States

Andrew F. Read,     Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA, United States

Kun Hyoe Rhoo,     Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States

Christoph Röcken,     Department of Pathology, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Jacques Robert,     Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States

Benjamin Roche

UMMISCO (International Center for Mathematical and Computational Modeling of Complex Systems), UMI IRD/UPMC UMMISCO, Bondy

MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290, Montpellier

CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier, France

Shonagh Russell

Department of Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL

Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States

Heiner Schäfer,     Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Christian Schem,     Department of Obstetrics and Gynecology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Denis Schewe,     Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Joshua D. Schiffman,     Departments of Pediatrics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States

Susanne Schindler,     Department of Evolutionary Biology and Environmental Studies, University of Zurich, Winterthurerstrasse, Zurich, Switzerland

Hinrich Schulenburg,     Department of Evolutionary Ecology Genetics, Zoological Institute, Christian-Albrechts-University Kiel, Kiel, Germany

Susanne Sebens,     Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Kathleen Sprouffske,     Department of Evolutionary Biology and Environmental Studies, University of Zurich, Winterthurerstrasse, Zurich, Switzerland

Holly A. Swain Ewald,     Department of Biology, University of Louisville, Louisville, KY, United States

Michael Synowitz,     Department of Neurosurgery, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany

Aurélie Tasiemski,     Lille1 University, UMR CNRS 8198, Evolution, Ecology and Paleontology Unit, Villeneuve d’Ascq, France

Frédéric Thomas

MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290, Montpellier

CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier, France

Sanjay Tiwari,     Department of Diagnostic Radiology and Neuroradiology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany

Arne Traulsen,     Department of Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Plön, Germany

Anna Trauzold,     Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Beata Ujvari,     Centre for Integrative Ecology, School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia

Thomas Valerius,     Department of Internal Medicine II, Section for Stem cell transplantation and Immunotherapy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Mark Vincent,     Department of Oncology, University of Western Ontario, London, ON, Canada

Marion Vittecoq

MIVEGEC (Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control), UMR IRD/CNRS/UM 5290, Montpellier

CREEC (Centre for Ecological and Evolutionary Research on Cancer), Montpellier

Research Center of the Tour du Valat, Arles, France

Kristofer Wollein Waldetoft,     School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, United States

Daniela Wesch,     Institute of Immunology, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

Preface

Cancer is not only a major cause of human death worldwide that touches nearly every family on the planet, but also a disease that affects all other multicellular organisms. Despite this, oncology and other biological sciences, such as ecology and evolution have until very recently developed in relative isolation. Although the first synergistic approaches to understand cancer were proposed in the mid-1970s by J. Cairns and P.C. Nowell, it is only during the last decade that the scientific community started to fully realize that adopting evolutionary principles and ecological approaches to cancer could greatly enhance our understanding of neoplastic progression, improve cancer prevention and therapies.

This view has transformed our understanding of cancer.

Today, most scientists accepts that cancer is a disease associated with clonal evolution and cell competition within the body, that appeared with the transition to multicellularity more than half a billion years ago. Specifically, somatic selection and adaptation to local and distant microenvironments are fundamental processes leading to malignancy, and its manifestations, that is, neoangiogenesis, immune system evasion, metastasis, resistance to therapies, and even contagion.

Although the congruence between the theory of cancer initiation, progression, and evolutionary and ecological concepts are increasingly accepted, this area of research is still in its infancy and a considerably enhanced research effort is urgently needed.

Applying evolutionary ecology to oncology is particularly crucial because treatment strategies have so far not lived up to expectations. Consequently, cancer research is now at a crossroad, needing novel ideas, major innovation, and new and unprecedented transdisciplinary approaches. The traditional separation between disciplines is more than ever a fundamental limitation that needs to be conquered if complex processes, such as oncogenesis, are to be understood.

Auspiciously, an increasing number of scientists and clinicians are now actively involved in pursuing interdisciplinary research and apply an evolutionary ecology view to cancer emergence and progression. This scientific community capitalizes on a panel of specialists using different, yet complementary approaches to cancer: mathematics, ecology, cell and evolutionary biology, and clinical research. This interdisciplinary field of study is also now moving beyond its descriptive phase and into the new dimensions of applying the theoretical understanding of cancer adaptations to treatment and prevention.

Apart from cancer being a problem of humanity, it also has, a so-far largely underestimated but significant impact on ecosystem functioning. Similar to humans, benign and malignant tumors are frequent in animals and prior to eventually causing death, cancer is likely to influence the organisms’ fitness by reducing competitive abilities, increasing susceptibility to pathogens, and vulnerability to predation.

Despite the potential importance of these ecological impacts, oncogenic phenomena are rarely incorporated into ecosystem modeling. Acknowledging that cancer incidence in animal species may experience an upsurge due to the cumulative effect of ever-increasing pollution of our ecosystems and the detrimental impact of ongoing climate change, it is essential to improve our knowledge of the reciprocal actions between oncogenic processes, intra-/interspecific interactions and animal behavior.

For all these reasons we felt that it was timely to provide an up-to-date, authoritative and challenging synopsis on the topic of ecology, evolution, and cancer that assesses the current state of developments in the field and importantly lays down a framework for future research.

We hope that this book presents materials that will be useful to a broad audience with a wide range of interest and expertise, from oncologists to ecologists. To achieve this goal, we assembled a team of experts to provide an overview of this engrossing topic, with the aim, above all, to provide an integrated understanding of cancer in Life.

Beata Ujvari

Benjamin Roche, Frédéric Thomas.

Acknowledgments

While compiling the book we lost dear friends and family members to cancer. The book grew out of desperation to unable to help and feeling impotent when facing the suffering of our loved ones. We sincerely hope that by laying down novel trajectories to understand the life history and evolution of cancer, we will eventually make an impact on tackling this devastating disease. We are grateful to our families and colleagues who patiently stood by us, provided endless support, and cheered us along the months of editing the book.

This work was supported by the Agence Nationale de la Recherche (Blanc project EVOCAN), the Centre National de la Recherche Scientifique (CNRS, Institute of Ecology and Evolution, INEE), the French National Research Institute for Sustainable Development (IRD), the University of Montpellier, the Labex CEMEB, the Australian Academy of Science’s French-Australian Science Innovation Collaboration Program Early Career Fellowship, André HOFFMANN and la Fondation MAVA, and an International Associated Laboratory Project France/Australia.

Introduction: Five Evolutionary Principles for Understanding Cancer

Randolph M. Nesse    The Center for Evolution and Medicine, Arizona State University, Tempe, AZ, United States

Evolutionary perspectives are transforming our understanding of cancer. The plural is appropriate because evolution offers five somewhat separate principles useful for understanding cancer. Each is a landmark on a map of a new scientific territory. Descriptions of each principle and their relationships can help maintain orientation in an exponentially growing new field.

Three of the perspectives focus on how malignancies grow within the body. The greatest excitement is coming from recognition that cancers evolve within the body by somatic selection, by which the fastest reproducing malignant cells increase, their prevalence. In retrospect, it is amazing that this was not always obvious. The second perspective uses ecological principles to analyze how cancers create and interact with microenvironments that speed or slow tumor growth. The third uses principles from behavioral ecology to analyze how cancer clones compete and cooperate with each other. The final two perspectives focus on natural selection at the organismal level. The fourth uses principles of phylogeny and natural selection to understand why cancer is so rare. The ultimate perspective uses principles from evolutionary medicine to understand why we remain so vulnerable to cancer.

Five evolutionary principles for understanding cancer

1. Somatic selection shapes malignancies.

2. Ecological principles explain how cancers interact with microenvironments.

3. Behavioral ecological principles explain competition and cooperation among cancer clones.

4. Natural selection explains why cancer is rare.

5. Evolutionary medicine explains why cancer is common.

All of these principles have been well described in recent articles and books (Aktipis and Nesse, 2013; Greaves, 2000;  2007;  2015; Hochberg et al., 2012; Merlo et al., 2006; Nunney, 2013). Each of the chapters in this book elaborates details of one or another aspect. The bird’s eye overview of the landscape in this chapter cannot begin to summarize those details, it can only provide a rough map of this new exciting scientific territory.

Somatic selection and how cancers evolve

An older view envisioned cancer as resulting from a defective cell that replicated identical copies of itself out of control. Remnants of this preevolutionary view of cancer persist, but recognition that cancer is an evolutionary process (Nowell, 1976) is growing fast, thanks in large part to new data showing massive heterogeneity among the cells in a single malignancy, a theme in many chapters in this book. That heterogeneity turns out to be important not only theoretically, but also as a predictor of the future trajectory of premalignant and malignant cell lines (Andor et al., 2016; Maley et al., 2006). As would be expected by Fisher’s fundamental theorem, the rate of fitness change is proportional to the amount of variation, in this case, massive variation among individual cells in a tumor promotes rapid changes by somatic selection.

This revised view transforms our view of cancer (Aktipis and Nesse, 2013; Crespi and Summers, 2005; Greaves, 2015; Nunney, 2013; and many chapters in this book). The war on cancer encouraged thinking of it as one disease with one cause, but every decade of subsequent research has revealed new layers of complexity among related disorders that turn out to be diverse (Aktipis et al., 2011). Early studies looked for abnormalities in cancer cell lines, with little attention to selection that had taken place over the course of generations of replication in vitro. People still tend to think of cancers from each tissue as specific diseases: lung cancer, breast cancer, prostate cancer and so on. It’s now clear, however, that all cancers share deep similarities in the ways cell cycle control is disrupted, and that apparently similar cancers from the same tissue can be very different. There is continuing hope that distinct genotypes will define specific subtypes of cancer. Identifying such variations is certainly useful, especially for making decisions about chemotherapy, but an evolutionary perspective suggests it is unrealistic to expect to find a few genetically uniform specific subtypes. Instead, we should expect that almost all cancer clones, even those from different location in the same malignancy, will be to some extent distinct. Heterogeneity is intrinsic to cancer (see especially Chapters 5, 10, and 17).

This new perspective has, in combination with new sequencing technologies and phylogenetic methods, encouraged investigations into the sequence by which individual cancers develops. The order in which various driver and passenger mutations arise is important in changing the selection forces that shape subsequent tumor development. Mutations that disrupt DNA replication and repair have special significance because they vastly increase the variation on which somatic selection can act. Variation among cells in different parts of a tumor is the norm, and that variation is an important variable that predicts progression (Andor et al., 2016). For instance, the heterogeneity of cells in Barrett’s esophagus is a strong predictor of progression to cancer independent of information about individual cells (Maley et al., 2006).

The process of somatic selection acting on cells is, however, somewhat different from natural selection shaping species. The generic principle of selection explains changes in a group that inevitably result when variations between individuals influence their future prevalence in a group. For instance, the collection of items in a cottage cupboard will tend to shift over the years toward robust items because fragile glassware is more likely to break and be discarded. Natural selection is the same process, with the addition of reproduction and heritability. When variations in heritable factors influence the number of offspring who make it to maturity, the average characteristics of a group will change over time to be more like those of the individuals who had more offspring than average.

This process of natural selection shapes mechanisms that maintain and transmit the information code with extraordinary fidelity. Almost all new mutations are harmful, so selection shapes mechanisms that minimize them, repair them, and compensate for them. The process is different in somatic selection. Cancers arise from driver mutations that give a cell line a selective advantage. Some of them initiate mutations that cause genome chaos beyond the mutation rate that would maximize tumor growth. Somatic selection can be for or against cancer, and the direction of selection can shift as a malignancy develops in different loci (Michor et al., 2003).

Natural selection shapes phenotypes that maximize transmission of genes to future generations. For selection within the body, there is no surviving generation (with the informative exception of transmissible cancers (see Chapter 12). Whether somatic selection shapes traits that benefit the tumor as a whole at the expense of individual cells is a fascinating question, considered later.

Convergent evolution is prevalent in somatic selection, as it is in natural selection (see also Chapter 17). All cancers face the same set of constraints, and mutations that allow a tumor to escape from those constraints get a selective advantage and become more common. Thus, somatic selection increases the prevalence of mutations that disrupt apoptosis, preserve telomeres, stimulate angiogenesis, interfere with recognition by the immune system, and foster plasticity that enables coping with rapidly changing microenvironments (see Chapter 8). These ecological challenges faced by every cancer provide an evolutionary framework for understanding cancer that complements the well-known hallmarks of cancer (Hanahan and Weinberg, 2011).

Somatic selection and natural selection also differ in the role of epigenetics. In naturally selected species, epigenetic marks that inhibit, or stimulate gene expression can transmit information between one or a few subsequent generations; the extent to which this reflects adaptations or epiphenomena is an area of active study. Epigenetic changes that arise in the course of normal phenotype development influence gene expression patterns that tend to persist across the lifespan. They account for the differences between normal cell types in an individual, including the differences between germ cells and somatic cells, so it should not be surprising that they also account for many aspects of malignant transformation. Epigenetic changes are increasingly recognized as important and perhaps essential mediators that can prevent or speed transformation to cancer (see also Chapters 5 and 6).

Ecological environments influence cancer growth

There is no such thing as fitness for a gene or individual except in relation to a specific ecological environment. Fitness is a characteristic not of genotypes, but of phenotypes interacting with environments. The microenvironments inhabited by cancers influence their growth, as much as their genotypes. Furthermore, the growth of a tumor creates microenvironments that can speed or slow subsequent growth.

Of particular interest, and emphasized by several chapters in this book, is the hypoxia that results when a tumor has an inadequate blood supply (see especially Chapters 8 and 19). Even in tumors that stimulate angiogenesis, unregulated growth is likely to block arterial routes providing oxygen and nutrients to small or large parts of the tumor. This can severely restrain growth or even eliminate a tumor. More often, however, the resulting hypoxia creates a microenvironment that compromises the efficiency of the usual immunologic tumor control mechanisms. This may have major implications for treatment strategies (see also pseudohypoxia in Chapter 4).

The rapid changes in microenvironments also may select for plasticity in tumors. Clones gain an advantage if they have the capacity to adapt their metabolism to sudden changes in oxygen tension or nutrient availability without changes in their genomes (see also Chapter 6). When nutrient supply is limited, cells that can enter a dormant state get an advantage, with major implications for how best to use chemotherapy agents that preferentially attack rapidly dividing cells (see also Chapter 20). An ecological approach offers the foundation for adaptive therapy that adjusts chemotherapy doses to minimize tumor growth, instead of to attempt to kill every malignant cell (see Chapter 14).

Many other ecological principles are useful for understanding the ecological setting in which tumors grow (Daoust et al., 2013; Ducasse et al., 2015; Thomas et al., 2013). The limitations of blood supply and its availability only along widely separated routes creates riparian environments with selection forces that differ depending on the distance of a cell from the blood supply. Principles of island ecology are relevant to understanding isolated tumors and metastasis. Thinking of islands of cancer cells as if they were an endangered species provides suggestions for how to speed their extinction (Korolev et al., 2014). Chapters 8 and 11 provide more about ecological applications in cancer, as do several articles in a special issue of Evolutionary Applications on cancer (Thomas et al., 2013). Of particular interest is the possibility that tumors can create their own niches, perhaps even with different clones cooperating to construct and expand the niche (Barcellos-Hoff et al., 2013).

Behavioral ecology and cooperation among cancer clones

Heterogeneity in cancer is now well recognized, along with increasing understanding of its several possible origins. On the cutting edge is consideration of the possibility that different clones can provide resources that promote the survival and replication of other clones in a process that is something like cooperation (Aktipis et al., 2015, see also Chapter 17). There is no higher-level enforcement of cooperation in a tumor, and selection cannot shape persisting sophisticated coordinated systems like those that account for termite societies or the cooperation among cells in metazoan bodies. Nonetheless, it is important to consider how different clones may cooperate and compete with each other, and studies of such systems may yield new therapeutic strategies.

A simple example is when some malignant cells secrete substances that disrupt host cells and expand the ecological space while other cells manufacture angiogenesis factors that vascularize the space. Such interactions bring the principles from behavioral ecology into play. Somewhat separate groups of cells may well both benefit from mutualistic interactions. All clones are inevitably shaped, however, to maximize growth in whatever environment they exist in.

Hypoxia induces the transition of malignant cells from attached epithelial cells into mesenchymal forms that are free to circulate and initiate metastases. Many higher organisms have evolved behavior regulation mechanisms that monitor the environment and initiate movement elsewhere when conditions deteriorate. The analogy is attractive despite the major differences. It is also of special importance because of the possibility that treatments causing hypoxia might stimulate this transition in ways that influence metastasis.

Evolutionary explanations for why cancer is rare

From an evolutionary perspective, cancer is astoundingly rare. Controlling unrestrained cell growth is the original giant problem that multicellular life had to overcome before large complex organisms could evolve (Smith and Szathmáry, 1995). Attachment between cells is easy to explain; individuals with tendencies to attach to each other can increase their nutrition and safety in ways that increase their own replication. Shaping mechanisms that reduce the fitness of individual cells in ways that benefit a completely larger organism is a challenge more difficult by orders of magnitude. The process took billions of years for good reasons, a main one being the challenge of controlling the unregulated cell divisions that are the hallmark of cancer (see Chapter 1).

The earth is about 4.5 billion years old. Life emerged, in the form of bacteria that leave their traces in stone about 3.7 billion years ago, about within the first 20% of time from earth’s origin. Multicellular organisms didn’t appear until over 3 billion years later. Complex multicellular organisms have existed for only the most recent 10% of the history of the planet. The fast emergence of life, and the extended delay until the emergence of complex multicellular organisms, suggests that simple life forms may exist on many other planets, but complex multicellular organisms are likely to be rare.

Why did it take about 75% of the time of earth’s existence for simple life to evolve into complex multicellular life (see also Chapter 1)? Among several obstacles overcome by major transitions, difficulty of evolving mechanisms to enforce cell cooperation was crucial. As cells united to begin to form early multicellular organisms, their generation times increased, so faster-evolving smaller organisms could overcome their defenses. However, being larger also offers protection against predators, and ecosystems had open niches for larger organisms (Bonner, 2011). The related challenge was the need to inhibit cell division, foster division of labor, and create ways to purge cells that nonetheless replicated at the expense of the whole organism (Smith and Szathmáry, 1995).

The Cambrian explosion, in which small simple organisms evolved into large complex ones, was but an eye blink in the history of life (Chapter 16). It started 542 million years ago, and gave rise to the main phyla of metazoans in as little as 25 million years. This speed has been attributed to the emergence of predators whose presence created strong selection for larger prey in a rapid process of coevolution that also rapidly made predators larger (Niklas, 2014). These larger bodies required new mechanisms to enforce cooperation. It is fascinating to consider that external threats may have been a crucial factor that shaped cells go sacrifice their own reproduction for the benefit of larger bodies, and that there is still much debate about this (Erwin and Valentine, 2013).

Multicellular species in which all cells are capable of reproduction cannot become complex with division of labor because there is no way to enforce cooperation. The differentiation of a sterile line of somatic cells was the key innovation that made the transition to complex multicellular life possible (Buss, 1987; Smith and Szathmáry, 1995). Sterile cell lines can advance their genetic interests only by advancing the interests of the whole organism, or rather, the organism’s genes. Once a sequestered germ line is separated from a sterile somatic cell line, selection can shape specialized kinds of somatic cells with separate functions, including enforcing cooperation among other cells. The dynamics of this transition have been the focus of intense study (Queller, 2000).

Any cell potentially capable of independent reproduction poses a threat that must be carefully monitored and controlled. For organisms as complex as vertebrates, somatic cells cannot establish their own continuing separate lineages, with the dramatic exception of transmissible cancers (see Chapter 12). Even stem cells cannot get out of the body and reproduce on their own. However, because they lack the controls that strictly limit replication of all normal somatic cells, stem cells are capable of indefinite replication, and thus cancer.

This helps to explain many curious aspects of stem cells (Greaves and Maley, 2012). They are relatively rare, for the good reason that they are vulnerable to malignant transformation. They tend to be sequestered in locations away from toxins and damage. The sequence with which they differentiate into descendent cells is strictly controlled. This means that mutations that immortalize cells are essential to malignant transformation.

This perspective distinguishes the several factors necessary to control aberrant cell division (Aktipis et al., 2015). First, there must be a restraint on division. Second, there must be policing to eliminate or dissociate cells that try to divide at a cost to the group. Third, there must be policing to prevent individual cells from taking advantage of group resources for their own benefit. Finally, there must be a mechanism to eliminate cells that go rogue. Chapter 7 provides comprehensive details in a comparative perspective.

These different factors have varied requirements and impacts in different species, making comparative studies valuable. The idea that cancer is only a disease of humans is contradicted by evidence for cancer in animals in the wild (see also Chapter 2) and an overview of cancer across the breadth of the living world (Aktipis et al., 2015). The similarity in rates of cancer in organisms with orders of magnitude different numbers of cells is Peto’s paradox (Nunney et al., 2015; Peto, 1977). The solution to the paradox is that natural selection shaped mechanisms that provide protection against cancer that are adequate to however, many cells a phenotype has; the effectiveness of these mechanisms is limited not by the number of cells, but mainly by tradeoffs with their costs. This perspective has inspired research that has predicted and confirmed increased number and expression of tumor suppression genes in large organisms (Caulin and Maley, 2011; Nagy et al., 2007; Sulak et al., 2016).

The application of biological theories of sociality to cancer is opening up whole new realms of cancer biology. Who could have anticipated that deep thinking about altruistic behavior in bees (Hamilton, 1964) would develop into an elaborated and still-developing body of theory crucial for understanding cancer (Aktipis et al., 2015; Frank, 2007; Nunney, 2013)?

Why is cancer so common? Evolutionary medicine

Even as we marvel at the ability of natural selection to shape mechanisms to prevent cancer, the reality is that about one half of us will have cancer at sometime during our lives. Explaining such vulnerabilities to disease is a primary focus for evolutionary medicine (Nesse and Williams, 1994). A list of possible kinds of evolutionary explanations for apparent maladaptations helps to avoid the tendency to overemphasize one explanation (Crespi, 2000; Nesse, 2005). For instance, a kerfuffle was aroused by a recent publication showing that variation in vulnerability to cancer across species is directly proportional to the number of stem cells and the number of their divisions (Tomasetti and Vogelstein, 2015). Journalists took the implication that most cancer is a result of just bad luck, arousing rebuttals that emphasized the role of environmental factors, and the difference between explaining variations in cancer rates and causes of cancer (Couzin-Frankel, 2015).

Two kinds of questions need to be distinguished. First is the usual question about why some individuals get a disease and others do not. Such questions are answered by descriptions of individual differences in mechanisms at a reductionist level, and factors that influence those mechanisms. Evolutionary medicine asks a different question about why all members of a species are the same in ways that leave them vulnerable to disease. Such questions have six possible kinds of answers, each of which is summarized briefly later.

Constraints

The traditional explanation for traits that leave bodies vulnerable to disease is that natural selection has limits. Mutations happen. Natural selection tends to eliminate deleterious ones, but the process takes time and is subject to the vagaries of any stochastic process. Useful mutations tend to increase, but genetic drift makes the process uncertain. The limits of selection offer a powerful and correct explanation that is only part of the picture. It is often framed using an outmoded model of the body as a designed machine whose robustness depends only on redundancies, instead of the complex networks that make bodies stable (Nesse, 2016). Explanations that refer to mere chance are also unwelcome. People who have cancer want to know what caused it; understanding a specific cause gives hope of a specific cure, or at least better prevention. Few people are willing to accept the reality that natural selection is incapable of shaping mechanisms to prevent all cancers. However, there are five other good reasons why selection has not shaped better protections against cancer.

Tradeoffs

A second closely related explanation is that trade-offs limit the perfection of all traits shaped by natural selection. In the case of cancer, tradeoffs are present in abundance. Tighter controls on cell division would decrease risk of cancer but would also decrease the ability of wounds to heal, and of cells in organs, such as the liver to divide in order to replace losses. Shorter telomeres, and increased sensitivity of apoptosis regulation mechanisms, would decrease rates of cancer, but they would increase rates of aging. More aggressive immune systems would likewise decrease cancer, at the cost of increased tissue damage and possible autoimmune disease. On a macro level, tall people get many advantages in life, especially in mating, but every 10 cm increase in height increases the cancer risk by at least 10% because of increased cell number and the associated extra growth factor stimulation (Green et al., 2011). Light skin increases Vitamin D synthesis, but at the cost of increased vulnerability to skin cancer (Greaves, 2014). There is no free lunch; trade-offs are intrinsic to all cancer prevention mechanisms (Aktipis et al., 2013; Boddy et al., 2015, see also Chapter 1).

Mismatch

Natural selection can change a species only slowly, so many aspects of bodies become vulnerable to disease when environments change rapidly, as they have dramatically for humans in recent generations. The American Cancer Society estimates that more than half of all human cancers could be prevented by modifying environmental factors (Fontham et al., 2009). The big one is tobacco use, which accounts for a third of all cancers. Other environmental factors, including sun exposure, modern diets, and obesity also increase risks substantially. Much research looks at specific factors, such as the multiple aspects of modern environments that can increase rates of breast cancer. High levels of nutrition and leisure induce high levels of reproductive hormones that are correlated with breast cancer rates (Jasieńska and Thune, 2001). They also lead to early menarche, which combines with delayed first pregnancy to create an interval in which breast cells are particularly vulnerable to metaplastic transformation (Russo et al., 2005). Furthermore, in ancestral environments the average woman had only about 100 menstrual cycles because of lactation induced amenorrhea while in modern societies the number is over 400 per lifetime (Strassmann, 1997), driving the system with endocrine stimulation unprecedented in the history of our species. Finally, exposure to light at night is also associated with higher rates of breast cancer (Stevens, 2009). Combinations of aspects of modern environments help to explain increased vulnerability to other kinds of cancer, and offer a potent prescription for prevention (Hochberg et al., 2013).

These environmental factors interact with genes to influence cancer risk. Common genetic variations found to strongly influence risk are likely to be those with few deleterious effects in ancestral environments, otherwise, they would have been selected out. Such variations associated with cancer should not be assumed to be deleterious; they may be quirks that were harmless in the environments in which we evolved.

Benefits to Genes at the Expense of Health

Natural selection shapes maximum health and longevity only to the extent that they contribute to increased reproduction. An allele that increases reproduction will tend to spread, even if it increases the risk of cancer. Such variations that have gone to fixation are very hard to identify, because they would need to be compared to some alternative that would be hard or impossible to recognize. However, some of the increased vulnerability of males to cancer may be explained, because they get a relatively greater reproductive payoff for investments in competition, while females get a relatively greater payoff for tissue maintenance and repair (Kruger and Nesse, 2006). Also, specific alleles have been suggested to perhaps increase reproduction at the cost of cancer; for instance, BRCA1, seems to be correlated with increased fecundity in some studies (Smith et al., 2012), although it is hard to control for confounding factors that could potentially explain this finding. Transmission of cancers between individuals is a dramatic example that is rare for good evolutionary reasons.

Coevolution

That infectious agents cause cancer has long been recognized, but the phenomenon is increasingly studied in evolutionary perspective. The role of papilloma virus in causing cervical cancer is well-established, as is the efficacy of vaccine prevention. An evolutionary view of why infection causes cancer begins with the general observation that tissues subject to chronic inflammation are also subject to genetic damage that can increase the risk of cancer. However, Ewald and others have suggested, and shown, that certain pathogens get reproductive advantages in the body by disrupting cell junctions and other manipulations that allow them to persist within hosts (Ewald, 2009; Ewald and Swain Ewald, 2012, see also Chapter 3). This is a classic example of coevolution, in which every improvement in the body’s ability to resist infection is countered by the rapid evolution in pathogens of mechanisms to get around the defenses. The resulting arms races are extremely expensive, leaving hosts with defenses that decrease the risk of infection but increase the risk of cancer.

Defenses

Many defenses are facultative adaptations shaped by natural selection that are aroused when needed, such as fever, pain, vomiting, and inflammation. Defenses against cancer provide similar protection, but only some are aroused by specific threats, more are continuously preventing malignant transformation and eliminating rouge clades. The long-recognized special role of the immune system in controlling cancer has led to dramatic new therapeutic options now under intense study (see also Chapter 9).

Conclusions

All five evolutionary perspectives offer useful insights about cancer. Keeping them separate encourages clear thinking. They are, however, intimately related. For instance, comparative studies looking at different rates of cancer among species need to be informed by both consideration of the role of chance mutations resulting from stem cell divisions, and also different life history patterns, and body designs with different compartments. Behavioral ecological approaches that analyze why cooperation sometimes breaks down among metazoan cells are closely connected with analyses of tradeoffs, and the costs and benefits of different strategies. These behavioral and ecological principles are also essential for understanding how cancers may shape their own ecological environments, and be shaped by those environments.

The transition to a fully evolutionary view of cancer offers huge promise, and many challenges (see Chapter 18). A description of five relevant principles provides useful landmarks as the territory continues to expand.

Acknowledgments

Thanks to Karla Moeller, Manfred Laubichler, Frédéric Thomas, and Beata Ujvari.

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Chapter 1

The Evolutionary Origins of Cancer and of Its Control by Immune Policing and Genetic Suppression

Leonard Nunney    Department of Biology, University of California Riverside, Riverside, CA, United States

Abstract

Cancer is a disease of multicellular animals that arises from conflicting effects of natural selection acting at the cellular and individual levels. Over the long term, this conflict can be resolved in favor of individuals through the evolution of cancer suppression (e.g., by tumor suppressor genes) and/or policing (by the immune system) as a result of lineage selection. Our understanding of the role of immune policing in cancer prevention is reviewed in light of the recent surge of interest in immunotherapy; however, it is argued that cancer suppression is likely to be the major mechanism limiting cancer in nature. Predictions regarding the evolution of cancer suppression, derived from a simple model of multistage carcinogenesis, are discussed. These predictions combined with the success of a recent study of rodents suggest that comparative analyses of animal clades differing in size and longevity may provide important insight into novel mechanisms of cancer suppression.

Keywords

adaptation

multistage carcinogenesis

lineage selection

Peto’s paradox

immunotherapy

tumor suppressor genes

Cancer is a malignant growth of cells capable of invading other tissues. As such, cancer is a disease of multicellular organisms and disrupts organismal function so severely that it is generally fatal. Based on this definition, cancer is restricted to animals because the cell walls of plants, algae, and fungi prevent cellular invasion (Doonan and Sablowski, 2010). In contrast, benign tumors, which do not invade other tissues, are relatively common across multicellular life and are generally not life-threatening, although by virtue of their location or abundance, their growth can cause serious problems, including death. However, sometimes it can be difficult to distinguish malignant and nonmalignant forms, leading to a category of cancer-like tumors (Aktipis et al., 2015). For example, crown galls, which are bacteria-induced benign tumors of plants, can produce secondary tumors nearby, but these additional tumors are due to a diffusible factor rather than cell movement (White, 1951; White and Braun, 1942). Despite these distinctions, an understanding of such noncancerous tumors can provide valuable insight into the unregulated cell division that is a prerequisite of all cancers.

Multicellularity is one of the major transitions of life (Maynard Smith and Szathmary, 1995), creating individual organisms, each made up of a society of cells that persists for a significant period of time and within which there is a division of labor between cells that are reproductive (in the sense that they contribute directly to the next generation of individuals) and nonreproductive cells. In animals, this division corresponds to the germline versus the soma. A critical component in the origin of such a society is the evolution of reproductive altruism in the cells that are nonreproductive. These cells can transmit only copies of their genes to future generations indirectly via the success of the reproductive cells.

At first sight, this division of labor does not seem to be a significant evolutionary barrier: the cells of a multicellular organism are clonal derivatives of a single fertilized egg, so discounting somatic mutation, the germline and somatic cells are 100% related. The theory of kin selection (Hamilton, 1964) predicts that, given a minimal benefit to multicellularity, such high relatedness would make the barrier to the evolution of reproductive altruists almost nonexistent. So why did the transition to multicellularity not occur until about 1 billion years after the first appearance of eukaryotes? One of the factors that may have contributed to this delay is the problem of cheating.

All societies are vulnerable to antisocial cheats that fail to conform to their assigned role, and societies will fail to persist if they lack mechanisms for limiting the effect of cheating (Maynard Smith, 1964; Nunney, 1985). In the case of multicellularity, these cheats are tumor cells that, in the worst-case scenario, become cancerous. Cells can become antisocial in two ways: their behavior can be disrupted through infection by a pathogen (see Ewald and Swain Ewald, 2015, and Chapter 3) or via somatic mutation. Furthermore, these possibilities are nonexclusive in driving the occurrence of cancer. For example, infection with certain types of human papillomavirus (HPV) does not lead directly to cervical cancer, but it reduces the number of mutational changes needed to induce it (McLaughlin-Drubin and Münger, 2009).

There appear to have been five independent origins of multicellular life (Knoll, 2011). Each origin has required the evolution of reproductive altruism, which, once evolved, raises the problem of cheating. In plants, algae, and fungi an incidental benefit of a structural cell wall is that cancer is completely suppressed, although cheats that form noninvasive tumors often arise (Aktipis et al., 2015; Doonan and Sablowski, 2010). In large long-lived animals, cancer is a never-ending problem with the incidence of a given cancer resulting from a balance between the fitness advantage gained by preventing that cancer and its fitness cost (Nunney, 1999a,  2003). I will now consider how that balance is achieved.

Lineage selection

Natural selection can occur whenever there exist reproduction and heritability, and can act at any level of biological organization. Viewed in this way, cancer is the result of natural selection favoring proliferating cells within an individual, selection that has the incidental effect of lowering fitness at the next organizational level, the level of the individual. Thus a conflict is created between natural selection acting at the cell and individual levels. The success of