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Thursday, May 4, 2006

Biological Background

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Carcinogenesis, which means the initiation or generation of cancer, is the process of derangement of the rate of cell division due to damage to DNA. Cancer is, ultimately, a disease of genes. In order for cells to start dividing uncontrollably, genes which regulate cell growth must be damaged. Proto-oncogenes are genes which promote cell growth and mitosis, a process of cell division, and tumor suppressor genes discourage cell growth, or temporarily halt cell division in order to carry out DNA repair. Typically, a series of several mutations to these genes are required before a normal cell transforms into a cancer cell.

Proto-oncogenes promote cell growth through a variety of ways. Many can produce
hormones, a "chemical messenger" between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.
Mutations in proto-oncogenes can modify their
expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and thus cells have a higher chance to divide excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive.

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally tumor suppressors are
transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. Canonical tumor suppressors include the p53 protein, which is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.
In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, which was first
hypothesised as the Knudson hypothesis. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increase as one gets older, because DNA damage forms a feedback loop.

Usually, oncogenes are
dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutation in one copy of a particular proto-oncogene is enough to make that gene a true oncogene, while usually loss of function mutation needs to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one loss of function copy of a tumor suppressor gene can render the other copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their
offspring can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressers act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals who are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and those who are heterozygous for Rb mutations develop retinoblastoma. Similarly, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in colon while young, while mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Cancer pathology is ultimately due to the accumulation of DNA mutations that negatively effect expression of tumour suppressor proteins or positivly effect the expression of proteins that drive the cell cycle. Substances that cause these mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer.
Tobacco smoking is associated with lung cancer. Prolonged exposure to radiation, particularly ultraviolet radiation from the sun, leads to melanoma and other skin malignancies. Breathing asbestos fibers is associated with mesothelioma. In more general terms, chemicals called mutagens and free radicals are known to cause mutations. Other types of mutations can be caused by chronic inflammation, as neutrophil granulocytes secrete free radicals that damage DNA. Chromosomal translocations, such as the Philadelphia chromosome, are a special type of mutation that involve exchanges between different chromosomes.
mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis increasingly leave less opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer.

Furthermore, many cancers originate from a
viral infection; this is especially true in animals such as birds, but less so in humans, as viruses are only responsible for 15% of human cancers. The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming viruses, which already carry the viral-oncogene.
It is impossible to tell the initial cause for any specific cancer. However, with the help of
molecular biological techniques, it is possible to characterize the mutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, some tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body.

Malignant tumors cells have distinct properties:

unlimited growth potential (immortalitization) due to overabundance of
self-sufficiency of
growth factors
insensitivity to anti-growth factors
cell division rate
altered ability to
no ability for
contact inhibition
ability to invade neighbouring
ability to build
metastases at distant sites
ability to promote blood vessel growth (

A cell that degenerates into a tumor cell does not usually acquire all these properties at once, but its descendant cells are
selected to build them. This process is called clonal evolution. A first step in the development of a tumor cell is usually a small change in the DNA, often a point mutation, which leads to a genetic instability of the cell. The instability can increase to a point where the cell loses whole chromosomes, or has multiple copies of several. Also, the DNA methylation pattern of the cell changes, activating and deactivating genes without the usual regulation. Cells that divide at a high rate, such as epithelials, show a higher risk of becoming tumor cells than those which divide less, for example neurons.

Signs and symptoms

Roughly, cancer symptoms can be divided into three groups:

Local symptoms: unusual lumps or swelling (
tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice.

Symptoms of
metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.

Systemic symptoms:
weight loss, poor appetite and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.

Every single item in the above list can be caused by a variety of conditions (a list of which is referred to as the
differential diagnosis). Cancer may be a common or uncommon cause of each item.


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