Page 16 - 20dynamics of cancer

1 Introduction

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 lan-
guage 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 can-
not say that cancer will develop at a certain age. Rather, failure happens
at different rates at different ages, according to the age-specific inci-
dence curve that defines failure.
To understand cancer means to understand the genetic and environ-
mental factors that determine the incidence curve. To learn about can-
cer, 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 molec-
ular 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