A family tree of cancer cells sampled from different regions of a single breast tumor, showing how the cells have evolved and diversified from a common ancestor, the cancer founder cell. The genome of each of the indicated 100 cells from a human breast tumor was sequenced to produce an evolutionary tree. About half of these cells were normal cells from the stroma (blue cells). The red cells have greatly amplified their K-Ras gene. Note that many subclones appear to have died out, including the one that contained the founder cells for the three subclones that survive.
A depiction of how driver mutations are thought to cause cancer progression over long periods of time, before producing a large enough clone of proliferating cells to be detected as a tumor. The data indicate that driver mutations occur only rarely in a background of long-lived subclones of cells that continually accumulate passenger mutations without gaining a growth advantage. (A, adapted from M. Greaves, Semin. Cancer Biol. 20:65–70, 2010; B, adapted from N. Navin et al., Nature 472:90–94, 2011; C, adapted from
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Nik-Zainal et al., Cell 149:994–1007, 2012.) invasiveness survival in the arrest in exit into survival of initial growth persistence causes circulation capillary or remote tissue cells in of cells in of growth entry into other small or organ foreign foreign vessel vessel tissue tissue must escape the normal confines of their parent epithelium and begin to invade the tissue immediately beneath. Second, they must travel via the blood or lymph to lodge in distant sites. Third, they must survive there and multiply. It is the first and last steps in this sequence that are the most difficult to accomplish for most cancers (Figure 20–31).
The first step, local invasiveness, requires a relaxation of the mechanisms that normally hold epithelial cells together. As mentioned earlier, this step resembles the normal developmental process known as the epithelial–mesenchymal transition (EMT ), in which epithelial cells undergo a shift in character, becoming less adhesive and more migratory (discussed in Chapter 19). A key part of the EMT process involves switching off expression of the E-cadherin gene. The primary function of the transmembrane E-cadherin protein is in cell–cell adhesion, binding epithelial cells together through adherens junctions (see Figure 19–13). In some carcinomas of the stomach and of the breast, E-cadherin has been identified as a tumor suppressor gene, and a loss of E-cadherin may promote cancer development by facilitating local invasiveness.
The initial entry of tumor cells into the circulation is helped by the presence of a dense supply of blood vessels and sometimes lymphatic vessels, which tumors attract to themselves as they grow larger and become hypoxic in their interior. This process, called angiogenesis, is caused by the secretion of angiogenic factors that promote the growth of blood vessels, such as vascular endothelial growth factor (VEGF; see Figure 22–26). An abnormal fragility and leakiness of the new vessels that form may help the cells that have become invasive to enter and then move through the circulation with relative ease.
The remaining steps in metastasis, involving exit from a blood or lymphatic vessel and the effective colonization of remote sites, are much harder to study. To discover which of the later steps in metastasis present cancer cells with the greatest difficulties, one can label the cells with a fluorescent dye or green fluorescent protein (GFP), inject them into the bloodstream of a mouse, and then monitor their fate (Movie 20.5). In such experiments, one observes that many cells survive in the circulation, lodge in small vessels, and exit into the surrounding tissue, regardless of whether they come from a tumor that metastasizes or one that does not. Some cells die immediately after they enter foreign tissue; others survive entry into the foreign tissue but fail to proliferate. Still others divide a few times and then stop, forming micrometastases containing ten to several thousand cells. Very few establish full-blown metastases.