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Cancer and Gene Alterations

As we know, cancer is a disease of unregulated cell growth. Although we looked at some of the features of cancer when we discussed mitosis checkpoints, it is helpful to revisit cancer from the perspective of gene alteration.

Some cancers develop when the gene regulators are defective, and in all cancers, gene expression is defective. As we saw earlier, normal differentiation limits cell and tissue growth, but in cancers, these normal regulations are inactive, so that abnormal growth and tumor formation can result. In cancers, the abnormal growth can spread to other areas of the body, or metastasize. By definition, cancer cells are cells that lack normal cell division control mechanisms. Once a cell line becomes cancerous, cell division cannot be stopped, and will continue until the individual in whom the cancer cells reside dies, unless the cancer cells can be successfully destroyed or excised surgically.

The current estimates are that 1/3 of the children born now will get some form of cancer in their lifetime. By far, the most deaths from cancer are still lung cancer, and the cause of most lung cancers is straightforward: smoking. The three most common cancers are breast cancer (an assortment of cancers), prostate cancer and colon cancer.

There are many different types of cancers. The categories or types of cancers are derived from their originating tissue. For example:


A substance that causes a change in DNA that can lead to cancer is a carcinogen and exposure to a carcinogen is the first step in cancer.

From what we know today, the steps in cancer development are:
As discussed previously (with mutations), the Ames test is a standard used for predicting the potential mutagenic (and carcinogenic) property of chemicals. A strain of Salmonella that is histidine-dependent (requires histidine in its growth medium) is exposed to the chemical and the rate of backward mutations (a mutation that corrects the histidine coding gene) is measured when the salmonella is cultured on a growth medium lacking histidine. The more mutagenic the chemical, the greater the number of mutant colonies that grow.

Most believe that the onset of cancer is an accumulation of mutations rather than one single alteration. Research today focuses on the things that cause changes in the DNA that result in alteration of the genes that control normal cell division.

Ionizing radiation and combustion products of tobacco are two of the most common carcinogens. Asbestos and many heavy metals in particulate form are also carcinogens, as are any number of other chemicals found in our environment. Steroids in higher than normal concentrations are carcinogenic, and a high fat, low fiber diet is also suspected as being cancer promoting. Viruses can also promote gene mutations that result in cancers.

Chemical Carcinogens
The evidences for chemical carcinogens is compelling, both from laboratory study of controlled chemical exposure and population studies that correlate to chemicals in the environment and/or workplace.

Dr. John Hill proposed in the 1700's that the nose tumors common in those who used snuff was caused by chemicals in the tobacco. It was also noted during that time period that chimney sweeps were more likely to get tumors, and a probable cause of those tumors was the constant exposure to soot. That coal tars induce cancer in rabbits was shown by Yamigawa in 1915. Cancers caused from cigarette tars was documented in 1949.

Over the past half-century the list of known chemical carcinogens has grown. Some of the common chemical carcinogens found in the workplace are listed in your text.

Cancer and Viruses
There are also some known human cancer-causing viruses. Liver cancer is related to the Hepatitis B virus, and Burkitt's lymphoma is related to the Epstein-Barr virus. One form of leukemia is linked to a virus, as is cervical cancer. Cat leukemia is also caused by a virus.

Peyton Rouse identified the first known cancer-causing virus in 1911. This virus, the Rous avian sarcoma virus, or RSV, was isolated from cultured chicken sarcoma tissue. The isolated virus was then used to infect normal chicken connective tissue.

RSV is a RNA virus, identical to a non-carcinogenic virus (called RAV-1) except for one gene. This gene is known as the src (sarcoma) gene. Once identified, researchers were able to discover how this gene works. This research led to one of the most important cancer research breakthroughs in the 1970's – the discovery of the oncogene, or cancer-causing gene.

Because this was such an important discovery (as discussed in your text), let's look at how src works. Specifically, src codes for an enzyme that functions as a membrane receptor that phosphorylates a tyrosine-kinase signal transduction pathway for a growth factor that signals the initiation of cell division. Therefore, RSV (the virus that carries the src gene) acts to promote a normally non-dividing cell to start dividing by supplying the receptor enzyme for the signal molecule.

Research also showed that the origin of the RSV src gene is the chicken – where it is one of the regulatory genes for cell division, subject to the chicken's normal regulatory controls. The gene was, at some time, incorporated into the RAV-O virus which transformed that virus into RSV. When RSV infects a chicken, the src gene it contains is not under the chicken's transcription controls, so this cancer promoting gene, or oncogene is transcribed and the chicken gets cancer.

So there is good evidence that viruses activate oncogenes that code for growth factors and growth factor receptor molecules involved with mitosis and the cell cycle. Similar genes, called proto-oncogenes, exist in non-cancer cells but are not active. Some viruses can activate proto-oncogenes. Oncogenes work collaboratively with other carcinogens. Oncogenes, by themselves, cannot produce cancers.

Targets for Cancer Promoters in the Cell Cycle
To identify specific gene targets cancer promoters, researchers use specific DNA fragments from existing tumor cells and track, in tissue culture, what cell processes are altered. The research shows that many, if not most, tumors result from mutations in genes that regulate the cell cycle.

Mutation and Oncogenes
Mutation in genes that normally regulate the cell cycle by repressing cell division can result in tumor formation and cancer. Several such proto-oncogenes have been identified. When activated, the result is the over-production of the gene's product or increased activity of each molecule synthesized.

Remember, a proto-oncogene is one that is repressed in a normal cell. When a mutation occurs so that the proto-oncogene is not repressed, it becomes an oncogene.

"Something" causes a proto-oncogene to mutate into an active oncogene, one that results in abnormal cell division, no longer subject to normal controls. There are many suspect ways in which proto-oncogenes can be changed into oncogenes:

Research to date has focused on identifying proto-oncogenes and tracking what happens when they are altered. There are several classes of proto-oncogenes identified to date that affect:


Growth Factors Identified in Mammalian Cancers

Role of Tumor Suppressor Genes in Cancer
In addition to activating oncogenes, we need to inactivate tumor suppressing genes to trigger the uncontrolled growth associated with cancer.


Normal tumor-suppressor genes can be inactivated by mutation. Mutations in genes that normally suppress cell division can result in abnormal growth, since the gene can no longer suppress growth activity. A tumor-suppressor gene can also be considered a proto-oncogene in the sense that when mutated, cancer can result. Most such mutations occur in somatic cells, and are not inherited.

A good example of a tumor-suppressor gene is the gene that codes for the ras G-protein, a protein that activates a tyrosine-kinase pathway that results in the synthesis of a protein that stimulates the cell cycle. The ras G-protein, therefore, can control the rate of cell division. If the ras proto-oncogene mutates to become "hyperactive", cell division occurs at an uncontrolled rate. The ras proto-oncogene mutation was first identified in cancer cells.

A second tumor-suppressor gene is the myc gene, the gene that promotes the production of cyclins and the cyclin-dependent kinases needed for cell division. Normal suppression the myc gene regulates the level of cyclin in the cell; when myc is mutated, cyclin production is over-stimulated and cells can rapidly divide.


Mutations in growth repressor genes results in abnormal rate of cell division. A second class of tumor-suppressor genes work normally to block cell division when damage has occurred. The p53 tumor suppressor gene, briefly discussed during our section on mitosis, is one such gene.

p53 is a transcription factor that initiates transcription of a protein called p21 that blocks cyclin from binding to the cdk if there is damage to a cell, keeping the cell in the G1 phase so that there is time for DNA repair.

As we learned earlier, p53 can also promote synthesis of transcription factors that initiate transcription of DNA repair enzymes.

If the cell is in bad shape, p53 activates cell suicide genes to prevent the deleterious mutations from being passed on. Such cell death is called apoptosis. When p53 is defective or missing, cancers are more likely.

The p16 and Rb tumor-suppressor genes work in a similar fashion to p53, working collaboratively to block cell growth in G1. Rb is a block that keeps cells in G1. Rb normally gets removed from its blocking position when the cyclin-cdk complex builds to sufficient quantity. p16 can block the cdk from binding to cyclins keeping cells in G1 if there is damage to a cell.

Apoptosis
Destruction of cells by apoptosis is controlled by genes activated by p53. Apoptosis is common in all animals and the regulatory genes are so similar that an apoptosis gene from one organism spliced into a second will function in the second organism. Apoptosis genes are activated by proteins such as p53 when defective DNA is discovered. Apoptosis genes also have opposing oncogenes that repress the activity of the apoptosis gene. For example, the bax gene is an apoptosis gene in humans. Normally the bax gene is active, and can be transcribed to synthesize the bax protein needed for apoptosis. However, bcl-2, an oncogene, can prevent transcription of the bax enzyme leading to growth of defective cells (and subsequently cancer).

How is death programmed by apoptosis?
The bax protein binds to a pore in the mitochondrion membrane that increases permeability. Presumably, that leads to death of the cell by allowing harmful substances into the mitochondria. The bcl-2 protein acts on free radicals – molecules infamous for causing cell damage, thereby preventing the cell from being destroyed. Antioxidants also destroy free radicals – and antioxidants can also block apoptosis.

Note in this example, apoptosis is desirable – we are attempting to destroy a damaged cell that otherwise could divide without restraint to form cancer. Antioxidants are important in normal cells precisely because they can prevent free radical damage.

Cells that are damaged by injury are also destroyed, generally by swelling and bursting, but destruction of injured cells is called necrosis.

Telomerase and Cancer
Normal cells have a tumor-suppressing gene that blocks the synthesis of telomerase. As studied, a cell can divide about 30 times before it reaches the end of its telomeres, and dies. A mutation in the gene that represses synthesis of telomerase permits cells to regenerate telomeres, so that normal control is absent. Cancer cells that have active telomerase can divide "forever".

Being able to synthesize telomerase doesn't cause cancer – but it permits cells that have additional mutations that affect the cell cycle to divide indefinitely so that the tumors can grow.

Who Gets Cancer?
We still cannot answer the question of how one gets cancer or if or why one person will and another will not after exposure to the same potential carcinogens. For example, several mutations are identified in polyp cells that can become colon cancer tumors, including mutations in APC (a gene involved in cell migration and adhesion), Ras and p53.

Two tumor suppressing genes involved in breast cancer were identified in the mid-1990's, BRCA1 and BRCA2. Mutations in either of these two genes increases the risk of breast, ovarian and prostate cancers. Since it appears that most cells need multiple mutations to become malignant, age is often a factor in cancer. Studies have confirmed that mutations occur at a greater rate in cells as one ages. Exposure to a number of carcinogens during one's lifetime can be also crucial as is the intensity of exposure. Ionizing radiation for example is directly dose-related.

More than one-fourth of the cancer deaths in the United States each year are from lung cancer. 90% of those diagnosed with lung cancer are smokers. Combustion products in smoke, which is inhaled into the lung tissue, contain potent carcinogens, including benzo--pyrene. Once benzo--pyrene is absorbed into the epithelial cells of the lungs, a derivative mutates p53. Mutated p53 is found in 70% of all lung cancers.

Some Current Research on Cancer Therapies
The cancer therapies researched today relate directly to the role of gene activation in the cell cycle. Just as researchers have identified target genes (oncogenes and tumor-suppressor genes) where mutations occur, they are now working to counter the effects of those mutations.

Signal Receptors
If the cancer is one that amplifies signal reception, one therapy is to block the receptor with a competitor. For example, 20% of breast cancers overproduce a protein, called HER2, that over-stimulates a signal receptor for a growth factor. Through genetic engineering, protein antibodies have been produced that target HER2 for destruction by the immune system. These specifically targeted antibodies are called monoclonal antibodies.

Monoclonal antibodies have also been used successfully on some melanomas in current cancer trials. They are using cancer cells extracted from the cancer patient to stimulate antibody formation in culture. The cloned antibodies are then injected back into the patient and target the cancer cells.

ras Inactivation Preventing Amplification
Overactive ras protein triggers signal transduction pathways that lead to more frequent cell division.


Blocking src
The src pathway is also a protein-kinase pathway. Since src uses complementary RNA to make copies of itself, a potential cancer treatment would be overwhelming src with anti-sense RNA that would bond to src but not allow replication.

The G1 checkpoint and Rb
The tumor-suppressor Rb blocks cell division by binding to a protein called E2F during G1. E2F promotes cell division. As mentioned, the cyclin-cdk complex phosphorylates Rb removing it from E2F so that cell division can proceed. In the absence of Rb, E2F is always active. 40% of all cancers have defective Rb. Drugs that could inhibit E2F might be a good cancer treatment.

p53
Virus therapy may prove promising for countering mutant p53. Adenoviruses contains a gene that inactivates p53 so that the host cell can be used to synthesize virus DNA. A mutant virus with no p53 inactivator gene could be used to destroy cancer cells that have mutant p53 but could not damage normal cells. (In a normal cell, p53 could not be inactivated to permit the replication of virus DNA.)

Telomerase
Without telomerase cell division is limited. Re-repressing telomerase would have much promise in slowing and halting tumor growth.

Angiogenesis Inhibitors
When tumors grow, they promote formation of new blood vessels to "feed" the tumor cells, a process called angiogenesis. Blocking new blood cell formation can starve a tumor causing it to shrink. No tests have yet been done on humans.

Tumors Spreading
Some cancers metastasize. Once tumors spread, surgical removal becomes far more difficult if not impossible. Chemicals that prevent migration of cells may prove useful in preventing the metastasis of cancers.

These are but a few of the many areas targeted for research today. Even with such promising research, each cancer must be identified, the factors promoting that cancer known and appropriate mix of treatments provided. Although it might seem that great strides are being made (and they are) most of what we have just mentioned is, at best, in testing stages – not available for the public.