From an evolutionary perspective, none of this should be a surprise: anything that increases the probability of random changes in gene function heritable from one cell generation to the next—and that is not too deleterious—is likely to speed the evolution of a clone of cells toward malignancy, thereby causing this property to be selected for during tumor progression.
epithelial cells growing on accidental production basal lamina of mutant cell cell with cell with
Figure 20–10 Chromosomes from a breast tumor displaying abnormalities in structure and number. Chromosomes were prepared from a breast tumor cell in metaphase, spread on a glass slide, and stained with (A) a general DNA stain or (B) a combination of fluorescently labeled DNA molecules that color each normal human chromosome differently (see Figure 4–10). The staining (displayed in false color) shows multiple translocations, including a doubly translocated chromosome (white arrow) that is made up of two pieces of chromosome 8 (green-brown) and a piece of chromosome 17 (purple). The karyotype also contains 48 chromosomes, instead of the normal 46. (Courtesy of Joanne Davidson and Paul Edwards.)
Cancer Cells Display an Altered Control of Growth
Mutability and large cell population numbers create the opportunities for mutations to occur, but the driving force for development of a cancer has to come from some sort of selective advantage possessed by the mutant cells. Most obviously, a mutation or epigenetic change can confer such an advantage by increasing the rate at which a clone of cells proliferates or by enabling it to continue proliferating when normal cells would stop. Cancer cells that can be grown in culture, or cultured cells artificially engineered to contain the types of mutations encountered in cancers, typically show a transformed phenotype. They are abnormal in their shape, their motility, their responses to growth factors in the culture medium, and, most characteristically, in the way they react to contact with the substratum and with one another. Normal cells will not divide unless they are attached to the substratum; transformed cells will often divide even if held in suspension. Normal cells become inhibited from moving and dividing when the culture reaches confluence (where the cells are touching one another); transformed cells continue moving and dividing even after confluence, and so pile up in layer upon layer in the culture dish (Figure 20–11). In addition, transformed cells no longer require all of the positive signals from their surroundings that normal cells require.
Their behavior in culture gives a hint of the ways in which cancer cells may misbehave in their natural environment, embedded in a tissue. But cancer cells in the body show other peculiarities that mark them out from normal cells, beyond those just described.
Given sufficient oxygen, normal adult tissue cells will generally fully oxidize almost all the carbon in the glucose they take up to CO2, which is lost from the body as a waste product. A growing tumor needs nutrients in abundance to provide the building blocks to make new macromolecules. Correspondingly, most tumors have a metabolism more similar to that of a growing embryo than to that of normal adult tissue. Tumor cells consume glucose avidly, importing it from the blood at a rate that can be as much as 100 times higher than neighboring normal cells. Moreover, only a small fraction of this imported glucose is used for production of ATP by oxidative phosphorylation. Instead, a great deal of lactate is produced, and many of the remaining carbon atoms derived from glucose are diverted for use as raw materials for synthesis of the proteins, nucleic acids, and lipids required for tumor growth (Figure 20–12).
This tendency of tumor cells to de-emphasize oxidative phosphorylation even when oxygen is plentiful, while at the same time taking up large quantities of glucose, can be shown to promote cancer cell growth and is called the Warburg contact-inhibited monolayer transformed cells foci of uninhibited of normal cells in lose contact inhibition transformed cells tissue-culture dish