Apoptosis and Cancer
Cancer is an important regulator of the Apoptosis pathway because it has the ability to control the apoptotic genes. More genes associated with apoptosis have been identified and continue to be discovered, and so the pathways involving all these genes can be potential targets for anti-cancer treatments in affected individuals. Research is constantly being done in these areas. The anti-apoptosis genes known most extensively are the Bcl-2 and Bcl-x1 genes that code for homologous proteins. The pro-apoptosis genes are p53, Bax, Bak, Bik, and C-myc, and the proteins they code for are considered cell death inducers.
Basically stated, the Bcl-2-like proteins can inhibit apoptosis and thus increase cell survival by blocking the apoptotic signal transmission system. The C-myc proteins are involved in a karyomitosis signal, a signal responsible for activating the transcription of genes related to cell proliferation. Bax and Bcl-2 interact together to determine whether the cell stays alive (increased expression of Bcl-2) or the cell dies (increase expression of Bax).
Mutations of proto-oncogenes, normal genes that have some kind of role in controlling mitosis or apoptosis, will turn them into oncogenes, which are genes that now cause the formation of cancers and tumors. Oncogenes active in liver cancer have been shown to increase the expression of Bcl-2 up to 22.73%, the expression of Bax up to 45.45%. Even though the percentage of Bax expression is higher than Bcl-2 expression, it was enough to break the balance between the two in favor of Bcl-2, and thus the proliferation of liver cancer.
In breast cancer, the following PCR and gel electrophoresis analysis between normal tissue and cancerous tissue shows the prevalence of certain apoptotic genes over others.
As you can see, the normal tissue has the pro-apoptotic gene Bax present, however the cancerous tissue does not. Also, in the cancerous tissue, the relative amounts of Bcl-2, Bcl-x1, and other anti-apoptotic genes outweigh the presence of Bax, thereby causing them to break the balance between the genes in favor of cell proliferation. Thus, breast cancer develops (Bargou).
In picture A of normal breast tissue, the expression of Bax is shown in red. However in picture B of malignant breast carcinoma, the expression of Bax is greatly reduced. Picture C shows the expression of the Bax protein in the ductal epithelium of breast tissue in a patient with fibrocystic disease. However, in picture D representing malignant epithelium of the same duct system, Bcl-2 expression is more detectable than Bax. In picture E, the tissue contains both malignant carcinoma of the breast tissue and carcinoma of the intraductal portions, and the resulting staining shows that NO Bax expression is present (Bargou).
Some viruses have the ability to infect their host's cells with certain genes that can cause cancer later on down the line. They do this by stopping the organism's cells from undergoing apoptosis, and therefore, any genetic changes caused by the virus or by normal DNA replication errors will be passed on because the cell has no way to keep itself from multiplying and passing on that genetic information.
One such virus is HPV, the human papilloma virus. This virus produces a protein known as E6, which binds to the organism's p53 gene (the infamous gene that helps activate the apoptosis pathway and thus control the development of cancer) and inactivates it, thereby inactivating apoptosis. The Epstein Barr Virus, EBV, produces a protein that is similar to Bcl-2. Since Bcl-2 is usually expressed by the cell in order to prevent apoptosis, an increase in this gene and its expression will make the cell even more immune to apoptosis. Thus, an increase expression of Bcl-2 will increase the chances cancer to develop.
This phenomenon also occurs in the B-cell leukemias and lymphomas in which the Bcl-2 gene is over expressed and the apoptotic pathway is ultimately inhibited. Extremely high levels of either condition result from the translocation of the Bcl-2 gene to areas usually designated for the enhancer regions adjacent to antibody genes.
In Melanomas, the cells inhibit the expression of the Apaf-1 gene, thereby avoiding the apoptotic pathway. Other cancers, such as lung cancer and color cancer, are able to increase the production of a protein that mimics that of FasL but does not activate the Fas receptors on cell membrane. Therefore, this protein essentially blocks the action of normal FasL proteins from stimulating cells and activating the apoptotic pathway. As you can see, since the cytotoxic T cells express the FasL protein, they cannot even stimulate the apoptotic pathway, and thus all apoptotic pathways are blocked.
References
"Apoptosis" Oct 2005. Retrieved from: http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html#CTL
Bargou, Ralf C., Christian Wagener, Kurt Bommert, Markus Y. Mapara, Peter T. Daniel, Wolfgang Arnold, Manfred Dietel, Hans Guski, Alfred Feller, Hans D. Royer, and Bernd Dorken. "Overexpression of the Death-promoting Gene bax-alpha Which is Downregulated in Breast Cancer Restores Sensitivity to Different Apoptotic Stimuli and Reduces Tumor Growth in SCID Mice." Journal of Clinical Investigation, Vol 97, No 11, June 1996, 2651-2659. Retrieved on April 27, 2006 from: http://www.jci.org/cgi/reprint/97/11/2651
Xu, Hong Yu, You Lin Yang, Xi LI Guan, Guang Song, Ai Min Jiang, and Li Jun Shi. "Expression of regulating apoptosis gene and apoptosis index in primary liver cancer." World Journal of Gastroenterology, 2000;6(5): 721-724. Retrieved on April 27, 2006 from: http://www.wjgnet.com/1007-9327/6/721.pdf