Molecular biology

   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 control 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. 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.

Mutations in proto-oncogenes can modify their information 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 appearance 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 altered that the signals for growth become excessive.

Tumor suppressor genes encode information for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally tumor suppressor genes are transcription factors that are activated by cellular stress or DNA damages. The function of such genes is to retain the progression of cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells.

However, a mutation can damage the tumor suppressor gene itself, or the signal which activates it, "switching it off". The invariable consequence of this is that DNA damages accumulate without repairs, inevitably leading to cancer.

 Usually, oncogenes are dominant, while mutated tumor suppressors are recessive. Each cell has two copies of the same gene, one from each parent, and under most cases the transformation of a particular proto-oncogene in onco-gene in one copy is enough initiate the carcinogenesis, while usually the mutation of a particular tumor suppressor gene 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 mutations.

 Mutations of tumor suppressor genes that are passed on to the next generation can cause an increased risk of cancer at the children of patients suffering of these mutations. Members of these families have increased incidence of multiple tumors. The mode of inheritance of mutant tumor suppressors it produces in this way: an affected member inherits a defective copy from one parent, and a normal copy from the other. Because mutations in tumor suppressor genes act in a recessive manner (although there are exceptions), the loss of the normal copy creates the cancer phenotype.

 Cancer pathology is ultimately due to the accumulation of DNA mutations that negatively affect the information of tumor suppressor genes or positively affect the information 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 the appearance of a specific type of cancer.

Tobacco smoking is associated with lung cancer.

 Prolonged exposure to radiation, particularly ultraviolet radiation from the sun, leads to melanoma.

 Breathing asbestos fibers is associated with pleural cancer.

 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.

 Many 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 mitosis. Faster rates of mitosis increasingly leave fewer opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the possibility of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes, which leads to cancer.

 Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers cases worldwide. The main viruses associated with human cancers are human papilloma virus, hepatitis B virus, Epstein-Barr virus, and human T-lymphotropic virus.

The methods in which viruses induce tumors can be divided into two, fast and slow. In acutely transforming viruses, the viral particles carry a gene that encodes the information for an overactive oncogene called viral-oncogene, and the infected cell is transformed as soon as viral-oncogene is formed.

 In contrast, in slowly-transforming viruses, the virus genome is inserted, because viral genome insertion is an obligatory action which retroviruses make, near a proto-oncogene in the host genome. Transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation.

 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.

 Some mutations enable the tumor to grow new blood vessels inside it to provide more nutrients, or to metastasize, spreading to other parts of the body.

Malignant tumor cells have specific properties:

-             evading apoptosis

-             unlimited growth potential

-             insensitivity to anti-growth factors

-             increased cell division rate

-             altered ability to differentiate

-             ability to invade neighbouring tissues

-             ability to spread into the body

-             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 built to obtain 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 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. Cells that divide at a high rate, such as epithelial cells, show a higher risk of becoming tumor cells than those which divide less or don’t divide, for example neurons.