Cancer cells acquire a variety of special properties as they evolve, multiply, and spread. Their mutant genomes enable them to grow and divide in defiance of the signals that normally keep cell proliferation under tight control. As part of the evolutionary process of tumor progression, cancer cells acquire a collection of additional abnormalities, including defects in the controls that permanently stop cell division or induce apoptosis in response to cell stress or DNA damage, and in the mechanisms that normally keep cells from straying from their proper place. All of these changes increase the ability of cancer cells to survive, grow, and divide in their original tissue and then to metastasize, founding new colonies in foreign environments. The evolution of a tumor also depends on other cells present in the tumor microenvironment, collectively called stromal cells, that the cancer attracts and manipulates.
Since many changes are needed to confer this collection of asocial behaviors, it is not surprising that most cancer cells are genetically and/or epigenetically unstable. This instability is thought to be selected for in the clones of aberrant cells that are able to produce tumors, because it greatly accelerates the accumulation of the further genetic and epigenetic changes that are required for tumor progression.
CANCER-CRITICAL GENES: hOW ThEY ARE FOUND AND WhAT ThEY DO
As we have seen, cancer depends on the accumulation of inherited changes in somatic cells. To understand it at a molecular level we need to identify the mutations and epigenetic changes involved and to discover how they give rise to cancerous cell behavior. Finding the relevant cells is often easy; they are favored by natural selection and call attention to themselves by giving rise to tumors. But how do we identify those genes with the cancer-promoting changes among all the other genes in the cancerous cells? A typical cancer depends on a whole set of mutations and epigenetic changes—usually a somewhat different set in each individual patient. In addition, a given cancer cell will also contain a large number of somatic mutations that are accidental by-products—so-called passengers rather than drivers—of its genetic instability, and it can be difficult to distinguish these meaningless changes from those changes that have a causative role in the disease. Despite these difficulties, many of the genes that are repeatedly altered in human cancers have been identified over the past 40 years. We will call such genes, for want of a better term, cancer-critical genes, meaning all genes whose alteration contributes to the causation or evolution of cancer by driving tumorigenesis.
In this section, we shall first discuss how cancer-critical genes are identified. We shall then examine their functions and the parts they play in conferring on cancer cells the properties outlined in the first part of the chapter. We shall end the section by discussing colon cancer as an extended example, showing how a succession of changes in cancer-critical genes enables a tumor to evolve from one pattern of bad behavior to another that is worse.
The Identification of Gain-of-Function and Loss-of-Function Cancer Mutations has Traditionally Required Different Methods
Cancer-critical genes are grouped into two broad classes, according to whether the cancer risk arises from too much activity of the gene product or too little. Genes of the first class, in which a gain-of-function mutation can drive a cell toward cancer, are called proto-oncogenes; their mutant, overactive or overexpressed forms are called oncogenes. Genes of the second class, in which a loss-of-function mutation can contribute to cancer, are called tumor suppressor genes. In either case, the mutation may lead toward cancer directly (by causing cells to proliferate when they should not) or indirectly—for example, by causing genetic or epigenetic instability and so hastening the occurrence of other inherited changes that directly stimulate tumor growth. Those genes whose alteration results in genomic instability represent a subclass of cancer-critical genes that are sometimes called genome maintenance genes.