Research Paper on Cancer! Let us make an in-depth study of the cancer. After reading this research paper you will learn about: 1. Introduction to Cancer 2. Classification of Cancers 3. Transformed Cells 4. Properties of Cancer Cells 5. Telomerase Enzyme 6. Oncogenes and Tumor-suppressor Genes 7. Proto-oncogenes & Oncogenes and Others.
Research Paper # Introduction to Cancer:
Cancer is a genetic disease caused by’ malfunctioning of genes. Alterations within the specific genes cause it. Cancer is characterized by unrestrained proliferation of cells. Genes that control the cell division undergo mutation. This leads to unregulated and uncontrolled cell division. The cells divide non-stop and pile up on the top of each other to form malignant tumors.
Cancer may be inherited but mainly it is caused by mutation in the somatic body cells during the life-time of an individual. Both these factors may combine leading to cancer. The most common factors causing cancer are some DNA and RNA viruses, carcinogenic agents and environmental factors like ionizing radiations, chemical pollutants, cigarette smoke, chimney soot, food preservatives, adult-rants and various other chemicals.
These factors cause mutation of (a) gene promoting cell division and (b) genes suppressing cell division. It is an interplay between environmental genetic and hereditary factors.
In 1911 Peyton Ross of Rockefeller Institute of Medical Research discovered that in chickens, a virus which is now named Rous Sarcoma Virus (RSV) causes tumor. Since then many tumor inducing viruses or oncogenic viruses have been discovered. Most of DNA viruses cause cancer.
Among RNA viruses, some retroviruses like RSV, Avian sarcoma virus (ASV) produce tumors. DNA of these viruses integrates with DNA of the host cell. This causes change in the expression of host DNA. Among DNA viruses are polyoma virus, adenovirus and simian virus 40 (SV40) etc. Viruses are associated with a very small number of human cancers. Hepatitis B virus is associated with liver cancer.
Cancer is one of the major killers among human beings and is more prevalent in Europe and USA. It is caused due to failure of the mechanisms that control growth and proliferation of cells.
Cancer is one of the major killers among human beings and is more prevalent in Europe and USA. It is caused due to failure of the mechanisms that control growth and proliferation of cells.
The growth and cell division are subject to a multitude of different types of controls. Cancer results when there occurs breakdown or disruption of these regulatory controls, Cancer is a step-by-step breakdown of cell division controls. Normal genes coding for growth control components are rendered ineffective by mutation.
Two types of genes cause cancer. They are oncogenes and tumor suppressor genes. Proto-oncogenes are normal cellular genes, which are mutated to become oncogenes (cancer genes). The mutations make oncogenes excessively active in cell division. Tumor suppressor genes restrain cell division. Damage to them leads to unrestrained cell division.
Most of the cells are pre-programmed to die after a certain number of cell divisions. This natural death is called apoptosis. The chromatin becomes fragmented and the cells die. Mutations postpone the apoptosis and cells become immortal.
Research Paper # Classification of Cancers:
On the basis of tissues in which they originate, the cancers are named as follows:
1. Carcinomas:
Cancers of epithelial cells. They include cervical, breast, skin and brain cancers. Almost 85% of cancers are of this type.
2. Sarcomas:
These are cancers of connective tissue of mesodermal origin. Cancers of cartilage, bone and muscles are of this type.
3. Lymphomas:
Cancers of lymphocytes, lymph modes, spleen. About 5% of total cancers are of this type.
4. Leukemis:
Caused by proliferation of W.B.C. cells.
Research Paper # Transformed Cells:
Almost all types of cells can become cancerous cells. They lose their ability to control their rate of cell division. Cells exposed to radiations or infected by tumor viruses or treated by chemical carcinogens, they behave very differently. They grow disorderly, irregularly and form jumbled mass which is known as tumor. These cells are called transformed cells.
The most important property of these transformed cells is that if these cells are injected into an animal of the same species, they form tumors in them.
Research Paper # Properties of Cancer Cells:
Cancer cells develop property of continued proliferation, failing to sense signals that restrict their cell division. They continue to live when they should die of apoptosis. They become free and divide more rapidly and become immortal. They have high metabolic rate. To obtain nourishment they form new blood vessels.
This process is called angiogenesis. In many cases they depend on anaerobic pathway due to their high metabolic requirement. Tumors become abnormal tissues, cells are undifferentiated and not specialized. There is loss of cell-cell adhesion. The basic lamina is degraded. Cells become rounded.
Most striking feature of cancer cells is the alteration of chromosomes within the nucleus. Chromosome complement becomes highly aberrant. Transformed cells have an abnormal number of chromosomes, they are aneuploid. They may be triploid, tetraploid or have extra copies, of individual chromosomes. These chromosomes also undergo extensive translocations. Cells have large and irregular nucleus.
In cell culture, the cells after some divisions are arrested in Gi stage by density dependent inhibition. But transformed cells are not subject to density dependent inhibition and continue to proliferate and pile upon one another to form tumors, become less adhesive, dissociate from neighbouring cells and infiltrate into other organs.
Normal cells need to attach to a surface to proliferate. When kept in suspension in nutrient medium, they die within a few days. But transformed cells need not attach to a surface and are enchorage independent and continue to proliferate.
Research Paper # Telomerase Enzyme:
With every cell division, the telomere at the end of chromosome is shortened which ultimately cause cell death. Cancer cells produce telomerase enzyme which maintains telomeres at the ends of chromosomes allowing them to continue to divide. Thus they postpone pre-programmed cell death or apoptosis.
Absence of telomerase enzyme from the normal cells is one of body’s major defences that protect against tumor growth.
Research Paper # Oncogenes and Tumor-suppressor Genes:
There are two types of genes associated with cancer. They are oncogenes and tumor suppressor genes. Normal cell genes called proto- oncogenes undergo mutation to become oncogenes. Mutations increase genes activity, become overactive and produce more protein. This is gain-of-function mutation. They are genetically dominant, therefore a single copy of an oncogene is sufficient to make it oncogenic.
On the other hand, tumor suppressor genes become oncogenic (cancerous) as a result of mutation that eliminates their normal activity. Normal un-mutated tumor suppressor gene acts to inhibit the cell from entering into mitosis. Removal of this negative control allows a cell to divide continuously. So this is a loss-of-function mutation. They are recessive, so both alleles of a tumor suppressor gene have to be mutated to make it cancerous.
Research Paper # Proto-oncogenes and Oncogenes:
Normal cell genes, proto-oncogenes undergo mutation to become cancer causing oncogenes.
Oncogenes differ from the proto- oncogenes in following ways:
1. Quantitative difference:
Oncogenes are transcribed at a higher rate. This results in overproduction of the protein which may promote cell division.
2. Qualitative difference:
The protein produced by the oncogene is functionally different from the protein produced by the proto-oncogene and usually more active and often results in cell division signals.
Research Paper # Viral Oncogenes:
Integration of viral DNA into the host DNA causes cell transformation and change in the expression of genes of the host cell. Tumor viruses lack repressors, thus transcription of integrated DNA occurs continuously. A host gene may be separated from its promoter and may come under the influence of viral promoter, thus causing over expression of the proteins produced by the host gene.
Research Paper # The Cellular Counterpart of Viral Oncogene:
A virus can transform a normal cell into a malignant cell as its oncogene encodes a protein that interferes with cell’s normal activities. It was discovered that a gene src (sarcoma producing gene) from Rous sarcoma virus has a similar gene in normal body cells. An identical src like gene is present in DNA of all vertebrates.
To distinguish the two genes, the viral gene is called v-src (viral src) and cellular gene is called c-src. The protein made by both these genes is tyrosine kinase. But the enzymatic activity of c-src is very little as compared to v-src. These kinases bring about transformation of a cell by phosphorylating some proteins. Kinase activity and phosphorylation go together.
The presence of this proto-oncogene in different vertebrates suggests that it is an essential gene of animals. Proto-oncogene is harmless whereas oncogene is cancerous. The c-src sequences are always interrupted whereas v-src never contain introns.
When the protoncogene and oncogene are exactly identical, the cellular gene is harmless whereas oncogene is dangerous in cancer cells. The reason could be that the amount of cancer causing protein made by a viral oncogene is much greater than the cellular gene as viral gene is regulated in a different way or viral promoter may be stronger. A single copy of proto- oncogene is harmless whereas extra copies provided by integration of viral DNA produce more amount of cancer causing protein.
All the oncogenes formed by the mutation of photo-oncogenes cause extensive cell division and thus ultimately tumor. These mutations are known as gain-of-function mutations.
Research Paper # Cancer and Cell Cycle:
Factors that control the cell cycle can play a prominent role in the development of cancer. Cell cycle consists of G1, S, G2 and M phases. In G1 phase there is a checkpoint. When the cell crosses this checkpoint, it becomes committed to enter into S-phase where DNA synthesis occurs. From here it smoothly sails through the cell cycle. There are proteins that play their role in transition through this checkpoint. They are D-type cyclins, cyclin dependent kinases (CDKs) and RB proteins. These proteins regulate the passage through the checkpoint.
But if anyhow the DNA is damaged, the cyclins or CDK complex prevents the cell from entering into S-phase. It applies brakes at the checkpoint and gives the cell a chance and time to repair the DNA and then enter the S-phase.
In the case of tumor cells, the genes encoding cyclins or CDKs are mutated. Due to these mutations, the cells are pushed into the S-phase even with the damaged DNA. The replication of damaged DNA causes deregulation of the cell cycle and the cell divides freely and ultimately becomes cancerous.
Research Paper # Role of pRB Protein in Cell Cycle:
pRB protein encoded by RB gene is one of the most important constituents of Gi cyclin-CDK complex. In G) phase of cell cycle pRB protein binds to some transcription factors known as E2F family of transcription factors. E2F activates many different genes that encode proteins like DNA polymerase, cyclin and histones etc. The pRB-E2F complex acts as gene represser. This inactivates the chromatin and no DNA synthesis takes place. Thus transition through G1 checkpoint is stopped as pRB protein applies natural brakes. RB gene is a tumor suppressor gene.
Towards end of G1 phase pRB is phosphorylated by cycin-dependent kinases. Once phosphorylated pRB releases its bound E2F transcription factors allowing it to activate genes in S-phase to synthesize DNA.Thus the cell entres S-phase. Later pRB protein is dephosphorylated and is ready for the next round of cell cycle.
If the RB gene undergoes mutation or is deleted, pRB protein loses its activity and therefore is unable to inactivate E2F transcription factors thereby removing restrictions to enter S-phase. Thus the natural control or brakes on the process of cell cycle have been lifted and the unhindered cell is pushed through the cell cycle smoothly. They divide freely even with the damaged DNA which may produce abnormal cells and ultimately may form tumor.
Certain DNA tumor viruses like adenovirus, SV40 etc. are also able to inactivate pRB. They encode a protein that binds to pRB, disabling it, so that it is unable to bind to E2F transcription factors. Therefore negative effect of pRB on cell cycle has been lifted. In this way by blocking pRB, the viruses achieve the same result as the mutation or deletion of RB gene. The pRB protein is a negative regulator of the cell cycle.
Research Paper # RB Protein:
RB protein (pRB) is an essential protein performing many essential functions. RB gene located on chromosome 13th is the retinoblastoma cancer preventing gene, Loss-of-function mutation of RB gene is associated with hereditary eye cancer retinoblastoma. Besides, it is also associated with lung, breast, bladder, cervical and prostrate cancers.
Two tumor suppressor genes have been best studied. They are RB gene and Tp53 gene.
Research Paper # p53 Protein:
This protein is produced by a tumor suppressor gene called Tp53 located on the short arm of chromosome 17th. It is a transcription factor that activates the expression of a large number of genes involved in cell cycle regulation and apoptosis. Genes activated by p53 encode many proteins that inhibit cyclin dependent kinases which drive a cell through G, checkpoint of cell cycle. In the cells with damaged DNA expression of these inhibitor proteins is activated and progression through the cell cycle is arrested. This gives the cell time to repair the genetic damage before it initiates DNA synthesis in S-phase.
When both copies of TP53 gene in a cell are mutated, cells can no longer produce inhibitor proteins that prevent it from entering S-phase. Failure to repair DNA damage leads to the production of abnormal cells that have potential to proliferate and form tumor.
TP53 gene mutations are involved in a number of human cancers. About half of the human cancers carry mutation of TP53. In response to DNA damage, p53 protein leads the cell either through cell arrest and applies brakes on cell cycle or leads it to apoptosis, In the apoptosis cell is driven to natural death. Most common apoptotic protein in human beings in p53.
It activates several genes which encode pro-apptotic proteins such as BAX whose encoded protein Bax initiates apoptosis.Pro-apoptotic proteins cause death of cells with damaged DNA. When TP53 is mutated or eliminated, apoptosis cannot be enforced and cells proliferate forming tumors. Apoptosis is one of the body’s primary mechanisms of ridding itself of potential tumor cells.
TP53 gene deletion causes more types of cancer in humans than any other gene. TP53 is a tumor suppressor gene. When it is mutated or eliminated, human beings, become highly susceptible to cancer including breast cancer, brain cancer and leukemia. More than fifty percent of all human cancers result from mutation in both alleles of TP53. This gene is responsible for a rare inherited disorder called Li-Fraumeni syndrome. This TP53 is an antitumor gene and is considered to be defence of the genome.
Research Paper # Knudson’s Two-hit Hypothesis:
Retinoblastoma is a cancer of the retina of the eye in children. The gene responsible for this disorder is RB which is a tumor suppressor gene.
There are two types of retinoblastoma cancers, inherited and sporadic. In hereditary retinoblastoma, a single defective allele of RB gene is inherited, where a deletion of small portion of one chromosome of 13th pair took place. The deletion was present in all cells both retinal and body cells. In order to develop retinoblastoma, the second allele also needs to be mutated, giving no functional RB protein. This is known as loss-of heterogygosity.
In sporadic retinoblastoma cases, both normal RB alleles are inherited but both of them undergo loss-of-function somatic mutations in a single cell.
According to Alferd- Knudson of University of Texas, development of retinoblastoma requires that both alleles of the RB gene of a retinal cell be mutated or deleted. Thus cancer arises as a result of two independent mutations or hits in a single cell. Mutations of of RB alleles are common in breast and lung cancers. The women who inherit one mutant allele of BRCAI which is a tumor suppressor gene may develop breast cancer later in life if the second BRCAI allele is also mutated.
Research Paper # Multi-hit Model of Cancer:
Multiple mutations are usually required to convert a normal cell into a mal’gnant one. Series of successive mutations in one cell’s descendents give it growth advantage in successive generations which add up to ultimately make them malignant. Moreover different mutations are generally required for the cancer to develop. All these mutations add up to form a full blown cancer.
Best example of multi-hit model is colon cancer. Different successive stages of colon cancer can be seen which proves that series of mutations have caused colon cancer. Successive stages like polyps, benign pre-cancerous tumor, adenomas and malignant cancer can be observed.
It is caused by mutation of ACP gene, TP53 gene and K-ras genes. These multiple mutations co-ordinate leading to cancer. This is the reason, the risk of cancer increases with the age as it takes years for multiple mutations to occur. This multiple mutation model is known as multi-hit model of cancer.
Moreover, cancer cells generally lack DNA repair systems, which explains large number of mutations that they accumulate.
Research Paper # Environmental Carcinogens:
Of the numerous causes of cancer, a few are known are radiations, chemicals and viruses. Human chromatin is very sensitive to radiations and various chemicals as they are Mutagenic. X-rays and other radiations increase the incidence of cancer. Uranium miners have high rate of lung cancer.
Survivors of atomic bomb attack in Japan in second world war had high rate of cancer. Similarly, radioactive radiations from Chernobyl nuclear reactor disaster in USSR had caused cancer to numerous people. Over exposure to ultraviolet rays causes skin cancer mostly in Africa. Radiations are being extensively used in medical treatment and industry.
Most of human cancers are caused by chemicals. Some carcinogens arc acridine dyes, mustard gas, benzopyrene, azodyes etc. Workers of coal mines, dyes, coal tar industries are more susceptible to skin cancer. Inhaling of asbestos dust, coal tar fumes are carcinogen. Active chemical of coaltar is 3-4 benzapyrine which is carcinogenic.
Cigarette smokers suffer high risk of lung, throat, esophageal, bladder, kidney cancers etc. Benzo-a-pyrene found in cigarette smoke causes mutation of p53 gene, causative agent of -lung cancer. Chewing tobacco is equally harmful. Intake of alcohol is also suspect.
All carcinogens are mutagenic and alter nucleotides in DNA. This leads to decreased production of tumor suppressor proteins and increased production of oncogenic proteins. Most cancer cells lack DNA repair systems. Most cancer cells produce telomerase which causes immortalization of cancer cells.
Research Paper # Treatment of Cancer:
By the time cancer is detected, tumor consists of billions of cells and have often spread to other areas by metastasis. For any treatment to succeed, distinguishing cancer cells from the normal cells is necessary. It is necessary to eliminate all cancer cells from the body. To identify and locate tumors. X-rays, isotop scans, CT scans and MR1 are used. Biopsy of tumor lump is done.Tumor grading is done to determine degree and stage of cancer.
Cancer is mainly treated by using surgery, radiations and chemotherapy. All these treatments are partially effective as they kill normal cells also along with cancer cells. Techniques to target only cancer cells are being perfected.
Immune system of the body plays major role in natural defence of the body against cancer. Administering antibodies that recognize, bind to and kill cancer cells are being extensively used. Radioactive atoms or a toxic compound attached to antibodies that kill the target cells have been developed.
Antibodies specifically deliver cytotoxic substances to cancer cells. Immune cells from patient’s own body are grown in culture and re-introduced into the patient’s body. Two of radioactive antibodies being used are zevatin and Bexxar.
Among various drugs which are in use are methotrexate, fluorouracial and hydroxyurea. All these treatments sometimes kill the cancer patients also. About 75 percent of all cancer patients ultimately die.
Summary:
Cancer is a genetic disease. Alterations within the specific genes cause it. It is characterized by unrestrained proliferation of cells. Genes that control cell division undergo mutation which leads to uncontrolled cell division, which leads to formation of tumors. Mainly it is caused by mutations in the somatic body cells during life time of an individual. In 1911 Peyton Ross discovered tumor in chickens caused by Rous sarcoma virus.
Loss of cell division regulation due to mutations of proto-oncogenes and tumor suppressor genes cause uncontrolled cell division. In cell culture, cells grow in a single confluent monolayer. But when exposed to radiations or infected by tumor viruses they become transformed cells. They grow irregularly to form tumor; when these transformed cells are injected into an animal of the same species, they form tumors in them.
They develop properties of continued proliferation. Cancer cells produce telomerase enzyme, which prevents shortening of chromosomes, thus postpone programmed cell death or apoptosis and cells become immortal. Two types of genes are associated with cancer, tumor suppressor genes and oncogenes. Proto-oncogenes are normal cellular genes, which have the potential to become oncogenes.
Many viral oncogenes have cellular counterparts. Cancer cells influence the cell cycle and allow even the cells with damaged DNA to go through unrestricted cell cycle. The protein, pRB also influences cell cycle and as a result of RB gene mutation pRB protein also loses its activity and cell is pushed through the cell cycle. Another protein P53 produced by a gene TP53 is also involved in cell cycle control.
According to Knudson’ two-hit hypothesis, both alleles of a gene be mutated or inactivated for the cancer to manifest. According to multi-hit model series of successive mutations lead to cancer e.g. Colon cancer. Cancer is an interplay between genetics and environmental factors. By the time tumor is detected it already consists of billions of cells. It is necessary to eliminate all cancer cells from the body. Cancer is mainly treated by using surgery, radiations and chemotherapy.