Traditionally, cancer was (and often still is) first detected in humans, cats, dogs, and horses by clinicians feeling for an unusual mass of cells, tumor cells.

Thus, cancer is quite intuitively a disease affecting cellular growth. In the last 20 years, enormous progress has been made in under­standing several normal control pathways that regulate cell growth, as well as how these “Rube Goldberg^v pathways (see Chapter 1) go wrong in cancer.

The first path to be unraveled, long thought to play a major role in cancer, was the pathway controlling cellular proliferation. Cellular proliferation was known to occur by a regular clocklike cycle of chromosomal doubling followed by mitotic division, called the cell cycle. However, almost nothing was known about molecular control of the cell cycle. Progress arose from the study of cancer cells, but importantly also from the study of the proteins synthesized by fertilized sea urchin eggs, how frogs ovulate, and how yeast cells divide. Cell growth depends not only on new cells being formed by cell division, but also on cells dying. As a result of studying in detail the history and fate of every cell that arises during embryonic development to form a soil roundworm (a nematode), it was discovered that cells are programmed to commit “suicide." That is, cells can actively kill themselves using metabolic machinery if the cell has internal damage, such as mutations or oxidative stress. This surprising discovery quickly led to the realization that not only do cancer cells divide inappropriately, but they are also resistant to programmed death and thus continue to divide despite the internal damage. The final general process affecting cellular growth is that normal cells, like the organisms they are part of, have a characteristic life span. However, cancer cells were long known to be “immortal,” being able to divide indefinitely. How cells age, or become immortal, was not understood until the process of chromosomal duplication was studied in a ciliated protozoan, similar to the familiar Paranieciuin of college biology laboratories.

As these examples illustrate, our understanding of cellular proliferation, cellular life span, and cell suicide came in large part from the study of problems that first seemed distant from the cancer seen in the clinic. As such, the recent progress on cancer is an unusually dramatic example of the importance of understanding basic biology to understand medicine. The vast majority of cancer studies are conducted on humans and in mice, the animal model for cancer, and using cultured cells derived from human and mouse tumors. The much smaller number of studies on domestic animals strongly indicate that the principles derived from humans and mice are generally applicable. However, it is also clear that humans and mice differ in a few aspects of cancer, and thus there are likely to be “special” aspects of cancer for each species.