Cancer encompasses a set of genetic diseases that lead to uncontrolled cell proliferation in multicellular organisms. The discussion of cancer also happens to be useful in a cell biology course, because it ties together many of the concepts that you just spent most of the semester learning. Although it can be caused in part by an outside agent, the development of cancer is essentially a series of uncorrected mistakes by a cell’s regular processes. It can strike plants as well as animals, and because of intense research and subsequent deeper understanding of the cellular events that lead to cancer, it can now be treated in humans with some degree of success, depending on the type, location, and progression of the tumor.
Figure 9. (left) A tumor on a cypress branch. (right) A tumor of the small intestine. Cypress tumor photo by W. Calder, cc licensed 2009. Small bowel tumor by E. Uthman, public domain 1999.
Abnormal replication of a cell generally leads to the formation of a tumor, which is simply a solid mass of abnormally growing cells, usually clonal colonies of one or a few original tumorigenic cells. However, a tumor is not necessarily cancerous. A benign tumor is one that is ensconced within an extracellular matrix sheath, does not spread beyond that sheath, and whose growth is slow or limited. In contrast, a cancerous or malignant tumor grows quickly due to uncontrolled proliferation, expands significantly beyond its original boundaries, invading new tissue, and can metastasize, spreading through the circulatory system. Once this happens, not only is it no longer possible to remove all of the cancerous cells by surgical excision of the primary tumor, it is also nearly impossible to know how many secondary tumors have formed or where they formed, since the metastatic cancer cells in the bloodstream may theoretically exit almost anywhere. However, in reality, certain tumors metastasize preferentially to particular target tissues/organs, presumably based on molecular markers on the surface of the cells or in the extracellular matrix. Metastasis is considered the greatest medical problem with respect to cancer treatment. If cancer is detected after metastasis has occurred, the chances of survival drop dramatically.
At the cellular level, cancerous cells differ from normal cells in a number of important ways. Normal cells are regulated by the cells around them, and by adulthood, most cells are inhibited from proliferation by contact with their neighboring cells. In vitro, this can be demonstrated by the observation that non-cancerous proliferative cells such as epithelial cells can proliferate until the culture dish bottom is completely covered (confluence), but once that happens, proliferation stops. This phenomenon is known as contact inhibition. If cancerous cells are allowed to proliferate in culture, they do not stop after the surface is covered, and instead can mound up on one another. The cell surface and internal cellular organization of cancer cells is often disorganized in comparison to normal cells. Finally, cancer cells usually appear de-differentiated in comparison to their original cell type. If the original cell type was a at cell, the cancerous cell would be more rounded and three-dimensional. This is an expected consequence of becoming a cancerous cell. Not only is proliferation deregulated, cell surface protein expression is altered to promote metastasis.
Figure 10. Normal human breast cells in culture at left. At right, similar cultured cells that have been transformed (i.e. they are now cancerous). Note the irregularity of both cell and nuclear morphology. Membranes are arbitrarily stained in different colors; chromosomes are stained blue in both panels. Photos from Ince et al, Cancer Cell 12:160-170, 2007.
Differentiation is a key part of normal metazoan development. All cells come from the fertilized egg, and even after several divisions, the cells are very similar. Eventually, though, they begin to specialize for their particular physiological functions, whether as lung cells, brain cells, or bone cells, and that process of specialization is differentiation. In cancer cells, this process is partially reversed, as the cell reverts to a less specialized, more primitive state.
Cancer is considered a genetic disease because it is caused by alterations to the DNA. However, it is rarely an inherited disease. An inherited disease would mean a disease that can be passed from one generation to the next, implying that the disease-causing DNA mutation is found in the gametes (sperm or egg) of the stricken adult. Most cancers are due to spontaneously arising mutation in the DNA of one or a few somatic cells, and not a systemic aberration. Spontaneous mutation in the germ cells are possible, but most potentially cancer-causing ones lead to non-viable offspring. So, although it is exceedingly rare for cancer to be inherited, however, it is much more common to inherit a predisposition or increased chance of developing a cancer.
Figure 11. Development of colon cancer takes time and multiple mutations.
An individual cancer-causing mutation generally creates a problem that can be corrected by some other cellular mechanism. Therefore, development of cancer comes about through the accumulation of multiple mutations and not the acquisition of just one. The best studied example of this gradual development of cancer is colon cancer (fig.11). There is a fairly characteristic progression of mutations in the genes APC, RAS, DCC, TP53, and PRL3. Note that the progression depicted here is not inevitable: the presence of polyps does not lead invariably to colon cancer. Furthermore, intervention can be highly successful if it occurs early in the progression, so oncologists need to consider a range of risk factors in weighing the cost and benefits of medical intervention. RAS and PRL3 are oncogenes, while APC, TP53, and DCC are tumor suppressor genes.