From simple histology, looking at stained tissue sections, it is clear that some tumors contain distinct sectors, all clearly cancerous, but differing in appearance because they differ genetically: the cancer cell population is heterogeneous. Evidently, within the initial clone of cancerous cells, additional mutations have arisen and thrived, creating diverse subclones. Today, the ability to analyze cancer genomes lets us look much deeper into the process.
One approach involves taking samples from different regions of a primary tumor and from the metastases that it has spawned. With modern methods, it is even possible to take representative single cells and analyze their genomes. Such studies reveal a classic picture of Darwinian evolution, occurring on a time scale of months or years rather than millions of years, but governed by the same rules of natural selection (Figure 20–30).
One such investigation compared the genomes of 100 individual cells from different regions of a primary tumor of the breast. A large fraction—just over half—of the chosen cells was genetically normal or nearly so: these were connective-tissue cells and other cell types, such as those of the immune system, that were mixed up with the cancer cells. The cancer cells themselves were distinguished by their severely disrupted genomes. The detailed pattern of gene deletions and amplifications in each such cell revealed how closely it was related to the others, and from this data one could draw up a family tree (Figure 20–30B). In this case, three main branches of the tree were seen; that is, the cancer consisted of three major mammary appearance of most epithelial recent common ancestor development number of cells subclones. From the shared abnormalities, one could deduce that their last common ancestor—the presumed founder of the cancer—was already very different from a normal cell, but that the first split between branches occurred early, when the tumor was small. This was followed by a large amount of additional change within each branch. A hint of the future could be seen in the smallest of the three major subclones: its cells were distinguished by a massive amplification of a Ras oncogene. Given more time, perhaps they would have out-competed the other cancer cells and taken over the whole tumor.
Similar results have been obtained with other cancers. Clearly, cancer cells are constantly mutating, multiplying, competing, evolving, and diversifying as they exploit new ecological niches and react to the treatments that are used against them (Figure 20–30C). Diversification accelerates as they metastasize and colonize new territories, where they encounter new selection pressures. The longer the evolutionary process continues, the harder it becomes to catch them all in the same net and kill them.
The Changes in Tumor Cells That Lead to Metastasis Are Still Largely a Mystery
Perhaps the most significant gap in our understanding of cancer concerns invasiveness and metastasis. For a start, it is not clear exactly what new properties a cancer cell must acquire to become metastatic. In some cases, it is possible that invasion and metastasis require no further genetic changes beyond those needed to violate the normal controls on cell growth, cell division, and cell death. On the other hand, it may be that, for some cancers, metastasis requires a large number of additional mutations and epigenetic changes. Clues are coming from comparisons of the genomes of cells of primary tumors with the cells of metastases that they have spawned. The results appear complex and variable from one cancer to another. Nevertheless, some general principles have emerged.
As we discussed earlier, it is helpful to distinguish three phases of tumor progression required for a carcinoma to metastasize (see Figure 20–16). First, the cells
Figure 20–30 How cancers progress as a series of subclones. (A) Schematic illustration of the pattern of mutation and natural selection in a clone of tumor cells.