Über die Autorin bzw. den Autor

Steven A. Frank is professor of biology at the University of California, Irvine. He is the author of Immunology and Evolution of Infectious Disease and Foundations of Social Evolution (both Princeton).

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"As Frank observes, 'Cancer is the failure of controls over cellular birth and death.' Although a vast amount of work has gone into describing the molecular and cellular processes involved, an understanding of the overall dynamics of these processes is less advanced. This book combines empirical information with insights into the nonlinear dynamics of multistage progression, in ways that both illuminate and have practical implications. Anyone with serious interests in cancer research should read it."--Robert M. May, University of Oxford

"This is an excellent book on a very difficult but important subject. It does a superb job of introducing the various models for observed cancer frequencies and explaining their assumptions, conclusions, and weaknesses."--Darryl Shibata, University of Southern California

"This is a book of relentless scholarship, precise organization, and fundamental, interdisciplinary insights into the biology of cancer. It provides the first truly comprehensive theory for the epidemiological/genetic incidence curves that characterize cancer, the first solid integration of evolutionary genetics with cancer biology, and a rigorous, well-reasoned approach to progress in understanding the genetic and environmental bases of cancer."--Bernard Crespi, Simon Fraser University

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Dynamics of Cancer

Princeton University Press

Chapter One

Through failure we understand biological design. Geneticists discover the role of a gene by studying how a mutation causes a system to fail. Neuroscientists discover mental modules for face recognition or language by observing how particular brain lesions cause cognitive failure.

Cancer is the failure of controls over cellular birth and death. Through cancer, we discover the design of cellular controls that protect against tumors and the architecture of tissue restraints that slow the progress of disease.

Given a particular set of genes and a particular environment, one cannot say that cancer will develop at a certain age. Rather, failure happens at different rates at different ages, according to the age-specific incidence curve that defines failure.

To understand cancer means to understand the genetic and environmental factors that determine the incidence curve. To learn about cancer, we study how genetic and environmental changes shift the incidence curve toward earlier or later ages.

The study of incidence means the study of rates. How does a molecular change alter the rate at which individuals progress to cancer? How does an inherited genetic change alter the rate of progression? How does natural selection shape the design of regulatory processes that govern rates of failure?

Over fifty years ago, Armitage and Doll (1954) developed a multistage theory to analyze rates of cancer progression. That abstract theory turned on only one issue: ultimate system failure-cancer-develops through a sequence of component failures. Each component failure, such as loss of control over cellular death or abrogation of a critical DNA repair pathway, moves the system one stage along the progression to disease. Rates of component failure and the number of stages in progression determine the age-specific incidence curve. Mutations that knock out a component or increase the rate of transition between stages shift the incidence curve to earlier ages.

I will review much evidence that supports the multistage theory of cancer progression. Yet that support often remains at a rather vague level: little more than the fact that progression seems to follow through multiple stages. A divide separates multistage theory from the daily work of cancer research.

The distance between theory and ongoing research arose naturally. The theory follows from rates of component failures and age-specific incidence in populations; most cancer research focuses on the mechanistic and biochemical controls of particular components such as the cell cycle, cell death, DNA repair, or nutrient acquisition. It is not easy to tie failure of a particular pathway in cell death to an abstract notion of the rate of component failure and advancement by a stage in cancer progression.

In this book, I work toward connecting the great recent progress in molecular and cellular biology to the bigger problem: how failures in molecular and cellular components determine rates of progression and the age-specific incidence of cancer. I also consider how one can use observed shifts in age-specific incidence to analyze the importance of particular molecular and cellular aberrations. Shifts in incidence curves measure changes in failure rates; changes in failure rates provide a window onto the design of molecular and cellular control systems.

1.1 Aims

The age-specific incidence curve reflects the processes that drive disease progression, the inheritance of predisposing genetic variants, and the consequences of carcinogenic exposures. It is easy to see that these various factors must affect incidence. But it is not so obvious how these factors alter measurable, quantitative properties of age-specific incidence.

My first aim is to explore, in theory, how particular processes cause quantitative shifts in age-specific incidence. That theory provides the tools to develop the second aim: how one can use observed changes in age-specific incidence to reveal the molecular, cellular, inherited, and environmental factors that cause disease. Along the way, I will present a comprehensive summary of observed incidence patterns, and I will synthesize the intellectual history of the subject.

I did not arbitrarily choose to study patterns of age-specific incidence. Rather, as I developed my interests in cancer and other age-related diseases, I came to understand that age-specific incidence forms the nexus through which hidden process flows to observable outcome. In this book, I address the following kinds of questions, which illustrate the link between disease processes and age-related outcomes.

Faulty DNA repair accelerates disease onset-that is easy enough to guess-but does poor repair accelerate disease a little or a lot, early in life or late in life, in some tissues but not in others?

Carcinogenic chemicals shift incidence to earlier ages: one may reasonably measure whether a particular dosage is carcinogenic by whether it causes a shift in age-specific incidence, and measure potency by the degree of shift in the age-incidence curve. Why do some carcinogens cause a greater increase in disease if applied early in life, whereas other carcinogens cause a greater increase if applied late in life? Why do many cancers accelerate rapidly with increasing time of carcinogenic exposure, but accelerate more slowly with increasing dosage of exposure? What processes of disease progression do the chemicals affect, and how do changes in those biochemical aspects of cells and tissues translate into disease progression?

Inherited mutations sometimes abrogate key processes of cell cycle control or DNA repair, leading to a strong predisposition for cancer. Why do such mutations shift incidence to earlier ages, but reduce the rate at which cancer increases (accelerates) with age?

Why do the incidences of most diseases, including cancer, accelerate more slowly later in life? What cellular, physiological, and genetic processes of disease progression inevitably cause the curves of death to flatten in old age?

Inherited mutations shift incidence to earlier ages. How do the particular changes in age-specific incidence caused by a mutation affect the frequency of that mutation in the population?

How do patterns of cell division, tissue organization, and tissue renewal via stem cells affect the accumulation of somatic mutations in cell lineages? How do the rates of cell lineage evolution affect disease progression? How do alternative types of heritable cellular changes, such as DNA methylation and histone modification, affect progression? How can one measure cell lineage evolution within individuals?

I will not answer all of these questions, but I will provide a comprehensive framework within which to study these problems.

Above all, this book is about biological reliability and biological failure. I present a full, largely novel development of reliability theory that accounts for biological properties of variability, inheritance, and multiple pathways of disease. I discuss the consequences of reliability and failure rates for evolutionary aspects of organismal design. Cancer provides an ideal subject for the study of reliability and failure, and through the quantitative study of failure curves, one gains much insight into cancer progression and the ways in which to develop further studies of cancer biology.

1.2 How to Read

Biological analysis...