What, if anything, distinguishes the survivors from the failures? A clue may come from the fact that in many types of tumors, the cancer cells show a kind of heterogeneity that resembles the heterogeneity seen among the cells of those normal tissues that renew themselves continually by a stem-cell strategy, as we discuss next.
A Small Population of Cancer Stem Cells May Maintain Many Tumors
Self-renewing tissues, where cell division continues throughout life, are the breeding ground for the great majority of human cancers. They include the epidermis
Figure 20–31 The barriers to metastasis.
Studies of labeled tumor cells leaving a tumor site, entering the circulation, and establishing metastases show which steps in the metastatic process, outlined in Figure 20–16, are difficult or “inefficient,” in the sense that they are steps in which large numbers of cells fail and are lost. It is in these difficult steps that cells from highly metastatic tumors are observed to have much greater success than cells from a nonmetastatic source. It seems that the ability to escape from the parent tissue, and an ability to survive and grow in the foreign tissue, are key properties that cells must acquire to become metastatic. (Adapted from A.F. Chambers et al., Breast Cancer Res. 2:400–407, 2000. With permission from BioMed Central Ltd.) (the outer epithelial layer of the skin), the lining of the digestive and reproductive tracts, and the bone marrow, where blood cells are generated (see Chapter 22). In almost all these tissues, renewal depends on the presence of stem cells, which divide to give rise to terminally differentiated cells, which do not divide. This creates a mixture of cells that are genetically identical and closely related by lineage, but are in different states of differentiation. Many tumors seem likewise to consist of cells in varied states of differentiation, with different capacities for cell division and self-renewal.
To see the implications, it is helpful to consider how normal stem-cell systems operate. When a normal stem cell divides, each daughter cell has a choice—it can remain a stem cell, or it can commit to a pathway leading to differentiation. A stem-cell daughter remains in place to generate more cells in the future. A committed daughter typically undergoes some rounds of cell proliferation (as a so-called transit amplifying cell) but then stops dividing, terminally differentiates, and eventually is discarded and replaced (it may die by apoptosis, with recycling of its materials, or be shed from the body). On average, the two fates—stem cell or differentiating cell—normally occur with equal probability, so that half the daughters of stem-cell divisions take the one path and half take the other. In a healthy body, feedback controls regulate the process, adjusting this balance of cell-fate choices to correct for any departure from the proper cell population numbers. Thus, the number of stem cells remains approximately constant, and the terminally differentiated cells are continually replaced at a steady rate. Because of the divisions undergone by the transit amplifying cells, the stem cells may be vastly outnumbered by the cells that are committed to terminal differentiation and have lost the capacity for self-renewal. But the stem cells, though few and far between and often relatively slowly dividing, carry the whole responsibility for maintenance of the tissue in the long term.
Some cancers seem to be organized in a similar way: they consist of rare cancer stem cells capable of dividing indefinitely, together with much larger numbers of dividing transit amplifying cells that are derived from the cancer stem cells but have a limited capacity for self-renewal (Figure 20–32). These non-stem cells appear to constitute the great majority of the cell population in some tumors.
The Cancer Stem-Cell Phenomenon Adds to the Difficulty of Curing Cancer