Just as in the evolution of plants and animals, a kind of speciation often occurs: the original cancer cell lineage can diversify to give many genetically different vigorous subclones of cells. These may coexist in the same mass of tumor tissue; or they may migrate and colonize separate environments suited to their individual quirks, where they settle, thrive, and progress as independently evolving metastases. As new mutations arise within each tumor mass, different subclones may gain an advantage and come to predominate, only to be overtaken by others or outgrown by their own sub-subclones. The increasing genetic diversity as a cancer progresses is one of the chief factors that make cures difficult.
Figure 20–8 Stages of progression in the development of cancer of the epithelium of the uterine cervix. Pathologists use standardized terminology to classify the types of disorders they see, so as to guide the choice of treatment. (A) In a stratified squamous epithelium, dividing cells are confined to the basal layer. (B) In this low-grade intraepithelial neoplasia (right half of image), dividing cells can be found throughout the lower third of the epithelium; the superficial cells are still flattened and show signs of differentiation, but this is incomplete. (C) In high-grade intraepithelial neoplasia, cells in all the epithelial layers are proliferating and exhibit defective differentiation. (D) True malignancy begins when the cells move through or destroy the basal lamina that underlies the basal layer of epithelium and invade the underlying connective tissue. (Photographs courtesy of Andrew J. Connolly.)
Figure 20–9 Clonal evolution. In this schematic diagram, a tumor develops through repeated rounds of mutation and proliferation, giving rise eventually to a clone of fully malignant cancer cells. At each step, a single cell undergoes a mutation that either enhances cell proliferation or decreases cell death, so that its progeny become the dominant clone in the tumor. Proliferation of each clone hastens the occurrence of the next step of tumor progression by increasing the size of the cell population that is at risk of undergoing an additional mutation. The final step depicted here is invasion through the basement membrane, an initial step in metastasis. In reality, there are more than the three steps shown here, and a combination of genetic and epigenetic changes are involved. Not shown here is the fact that, over time, a variety of competing subclones will often arise in a tumor. As we will discuss later, this heterogeneity complicates cancer therapies (see Figure 20–30).
Most human cancer cells accumulate genetic changes at an abnormally rapid rate and are said to be genetically unstable. The extent of this instability and its molecular origins differ from cancer to cancer and from patient to patient, as we shall discuss in a later section. The basic phenomenon was evident even before modern molecular analyses. For example, the cells of many cancers show grossly abnormal sets of chromosomes, with duplications, deletions, and translocations that are visible at mitosis (Figure 20–10). When the cells are maintained in culture, these patterns of chromosomal disruption can often be seen to evolve rapidly and in a seemingly haphazard way. And for many years, pathologists have used an abnormal appearance of the cell nucleus to identify and classify cancer cells in tumor biopsies; in particular, cancer cells can contain an unusually large amount of heterochromatin—a condensed form of interphase chromatin that silences genes (see pp. 194–195). This suggested that epigenetic changes of chromatin structure can also contribute to the cancer cell phenotype, as recently confirmed by molecular analysis.
The genetic instability observed in cancer cells can arise from defects in the ability to repair DNA damage or to correct replication errors of various kinds. These alterations lead to changes in DNA sequence and produce rearrangements such as DNA translocations and duplications. Also common are defects in chromosome segregation during mitosis, which provide another possible source of chromosome instability and changes in karyotype.