Evidence for the cancer stem-cell phenomenon comes chiefly from experiments in which individual cells from a cancer are tested for their ability to give rise to fresh tumors: a standard assay is to implant the cells into an immunodeficient mouse (Figure 20–33). It has been known for half a century that there is usually only a small chance—typically much less than 1%—that a tumor cell chosen at random and tested in this way will generate a new tumor. This by itself does not prove that
Figure 20–32 Cancer stem cells can be responsible for tumor growth and yet remain only a small part of the tumor-cell population. (A) how stem  cells produce transit amplifying cells.
(B) how a small proportion of cancer stem cells can maintain a tumor. Suppose, for example, that each daughter of a cancer stem cell has a probability slightly greater than 50% of retaining stem-cell potential and a probability slightly less than 50% of becoming a transit amplifying cell that is committed to a program of cell divisions that stops after 10 division cycles. While the number of cancer stem cells will increase slowly but steadily to give a growing tumor, the non-stem cells that they give rise to will always outnumber the stem cells by a large factor—in this example, by a factor of about 1000. (If the cell-divisioncycle and survival times for the two classes of cells are equal.) the tumor cells are heterogeneous: like seeds scattered on difficult ground, each of them may have only a small chance of finding a spot where it can survive and grow. Modern technologies for sorting cells have shown, however, that in some cancers at least, the rate of success in founding new tumors is even lower than it would otherwise be because the cancer cells are heterogeneous in their state of differentiation, and only a small subset of them—the cancer stem cells—have the special properties needed for tumor propagation. For example, in several types of cancer, including breast cancers and leukemias, one can fractionate the tumor cells using monoclonal antibodies that recognize a particular cell-surface marker that is present on the normal stem cells in the tissue of origin of the cancer. The purified cancer cells expressing this marker are found to have a greatly enhanced ability to found new tumors. And the new tumors consist of mixtures of cells that express the marker and cells that do not, all generated from the same founder cell that expressed the marker.
Experiments with breast cancer cells have revealed that, instead of following a rigid program from stem cell to transit amplifying cell to terminally differentiated cell, these cancer cells can randomly switch to and fro—with a certain low transition probability—between different states of differentiation that express different molecular markers. In one state, they behave like stem cells, dividing slowly but capable of founding new tumors; in other states, they behave like transit amplifying cells, dividing rapidly but unable to found new tumors in a standard transplant assay. But a single cell in any of these states—given time in culture, or a congenial environment in the body—will give rise to a mixed population that includes all the other states as well.
The cancer stem-cell phenomenon, whatever its basis, implies that even when the tumor cells are genetically similar, they are phenotypically diverse. A treatment that wipes out those in one state is likely to allow survival of others that remain a danger. Radiotherapy or a cytotoxic drug, for example, may selectively kill off the rapidly dividing cells, reducing the tumor volume to almost nothing, and yet spare a few slowly dividing cells that go on to resurrect the disease. This greatly adds to the difficulty of cancer therapy, and it is part of the reason why treatments that seem at first to succeed often end in relapse and disappointment.
Colorectal Cancers Evolve Slowly Via a Succession of Visible Changes
At the beginning of this chapter, we saw that most cancers develop gradually from a single aberrant cell, progressing from benign to malignant tumors by the accumulation of a number of independent genetic and epigenetic changes. We have discussed what some of these changes are in molecular terms and seen how they contribute to cancerous behavior. We now examine one of the common human cancers more closely, using it to illustrate and enlarge upon some of the general principles and molecular mechanisms we have introduced. We take colorectal cancer as our example.