9.8Cancer and Cancer Genes
Cancer cells are generally considered to grow rapidly. However, their cell cycle turns no more quickly than that of normal cells. They grow fast because in cancer tissues, many cells exist within the cell cycle, whereas in normal tissues, a higher proportion of cells are in the G0 phase. Cancer cells overgrow because their cell growth does not arrest in the G0 phase - in other words, their growth regulation mechanism is defective.
As shown in Figure. 9-10A, it has been demonstrated that normal cells can be transformed into cancer cells if DNA extracted from the latter is fragmented and incorporated into the DNA of the former. The incorporated genetic information caused malignant transformation, and the genes identified were named oncogenes. The oncogene first discovered in humans was ras*1. As shown in Figure. 9-5, Ras*1 (a G protein) acts at the early stage of the signal transduction pathway for cell growth, and if mutation occurs in this gene (thus triggering the production of the activated Ras protein without the presence of growth factors), the signal transduction pathway starts acting continuously. The difference between normal Ras and Ras that turns cells cancerous is one amino acid caused by a single base mutation. The cancer-causing Ras, bound with GTP, is constantly activated, and maintains activation without the presence of growth factors, thus causing uncontrolled cell growth. As exemplified by the constant activation of MAP kinase kinase kinase (Fig. 9-2B (c)) and early genes produced in large amounts (Fig. 9-7), it has been shown that many of the oncogenes known today have a mutation that causes the runaway of the signal transduction pathway for cell growth.
Fig. 9-10. Discovery of cancer genes and tumor suppressor genes
A) Cancer genes were discovered by fragmenting DNA extracted from cancer cells and identifying the DNA fragments that transform cultured cells into cancer cells.
B) In a family line characterized by a high rate of hereditary retinal cancer, one of the two copies of the tumor-suppressing Rb gene is mutated, and the cancer develops when the other copy is mutated.
Genes are basically expressed by three italic letters, while the proteins encoded by the genes are expressed by three regular letters with the first letter capitalized. However, there are many exceptions.
Tumor Suppressor Genes
The negative regulation of cell growth stops functioning if genes, such as Rb and p53, are damaged or mutated, thereby halting the functions of the proteins encoded by the genes. Cell growth is initiated not only in this way; it also occurs as a result of slight stimuli. Such genes in the normal state suppress cancer, and are called tumor suppressor genes. The first tumor suppressor gene discovered in humans was identified in a study of a family with frequent occurrence of hereditary retinal cancer in childhood (Fig. 9-10B), which found a mutation in the Rb gene. It was shown that one copy of the Rb gene in this family line is inherently defective, and that the cancer occurs if there is a mutation in the other normal Rb gene. On the other hand, in nonhereditary retinal cancer that occurs in adulthood, the possibility of mutation occurring in both copies of the Rb gene is extremely low. In the case of the p53 gene, mutation in one gene copy is often enough for cancer to develop (even if the other copy is normal), and the defective p53 gene has been identified in over fifty percent of human cancer cases. Other examples of tumor suppressor genes can also be found in various proteins that form part of the signal transduction pathway (e.g., signals from cell adhesion) that negatively regulates cell growth.
Independent Growth of Cancer
It has been shown that in many cancer cells in humans, both cancer genes and tumor suppressor genes are mutated, resulting in the abnormal growth regulation of cells. This is the cause of the independent growth of cancer cells. The term “independent” here means that cells grow in an uncontrolled manner without being subjected to the homeostasis of the number of cells - an important cellular regulation mechanism for individuals. Cancer cells also have the ability to translocate and escape from immune surveillance mechanisms.