Studies in animals show that typically far fewer than one in every thousand malignant tumor cells that enter the bloodstream will colonize a new tissue so as to produce a detectable tumor at a new site.
wall of a blood or lymphatic vessel. Lymphatic vessels, being larger and having more flimsy walls than blood vessels, allow cancer cells to enter in small clumps; such clumps may then become trapped in lymph nodes, giving rise to lymph-node metastases. The cancer cells that enter blood vessels, in contrast, seem to do so singly. With modern techniques for sorting cells according to their surface properties, it has become possible in some cases to detect these circulating tumor cells (CTCs) in samples of blood from cancer patients, even though they are only a minute fraction of the total blood-cell population. These cells, in principle at least, provide a useful sample of the tumor-cell population for genetic analysis.
Of the cancer cells that enter the lymphatics or bloodstream, only a tiny proportion succeed in making their exit, settling in new sites, and surviving and proliferating there as founders of metastases. Experiments show that fewer than one in thousands, perhaps one in millions, manage this feat. The final step of colonization seems to be the most difficult: like the Vikings who landed on the inhospitable shores of Greenland, the migrant cells may fail to survive in the alien environment; or they may only thrive there for a short while to found a little colony—a micrometastasis—that then dies out (Movie 20.3).
Many cancers are discovered before they have managed to found metastatic colonies and can be cured by destruction of the primary tumor. But on occasion, an undetected micrometastasis will remain dormant for many years, only to reveal its presence by erupting into growth to form a large secondary tumor long after the primary tumor has been removed.
Many Properties Typically Contribute to Cancerous Growth
Clearly, to produce a cancer, a cell must acquire a range of aberrant properties—a collection of subversive new skills—as it evolves. Different cancers require different combinations of these properties. Nevertheless, cancers all share some common features. By definition, they all ignore or misinterpret normal social controls so as to proliferate and spread where normal cells would not. These defining properties are commonly combined with other features that help the miscreants to arise and thrive. A list of the key attributes of cancer cells in general would include the following, all of which we have just discussed: 1.
They grow (biosynthesize) when they should not, aided by a metabolism shifted from oxidative phosphorylation toward aerobic glycolysis.
2.
They go through the cell-division cycle when they should not.
3.
They escape from their home tissues (that is, they are invasive) and survive and proliferate in foreign sites (that is, they metastasize).
4.
They have abnormal stress responses, enabling them to survive and continue dividing in conditions of stress that would arrest or kill normal cells, and they are less prone than normal cells to commit suicide by apoptosis.
5.
They are genetically and epigenetically unstable.
6.
They escape replicative cell senescence, either by producing telomerase or by acquiring another way of stabilizing their telomeres.
In the next section of the chapter, we examine the mutations and molecular mechanisms that underlie these and other properties of cancer cells.
Cancer cells, by definition, grow and proliferate in defiance of normal controls (that is, they are neoplastic) and are able to invade surrounding tissues and colonize distant organs (that is, they are malignant). By giving rise to secondary tumors, or metastases, they become difficult to eradicate by surgery or local irradiation. Cancers are thought to originate from a single cell that has experienced an initial mutation, but the progeny of this cell must undergo many further changes, requiring additional mutations and epigenetic events, to become cancerous. Tumor progression usually takes many years and reflects the operation of a Darwinian-like process of evolution, in which somatic cells undergo mutation and epigenetic changes accompanied by natural selection.