User:Kinkreet/Cancer

Cancer is a group of diseases generally characterised by genomic instability and uncontrolled cell division, eventually leading to invasion of surrounding tissue and eventual dispersal to distant sites.

There are over 200 types (and causes) of cancers, which can arise from mutations (point mutation, deletion, gene amplification, recombination, or transgene) in a few of the tens of thousands of genes in the human genome, or viral infections.

Cancers are named based on the origin of the tumours. Carcinomas are the most common type of cancer and arise from cells originating in the endodermal or ectodermal germ layer; sarcoma originate from mesenchymal cells, myeloma originate from plasma cells, leukaemia originate from the blood or bone marrow, lymphomas originate from the lymphocytes.

Oncogenes
An oncogene is a gene that has the potential to transform healthy cells to become cancerous. In tumor cells, they are often mutated or expressed at high levels.

Oncogenes are constitutively active, and are functionally dominant, requiring only a single mutation for it to cause cancer.

The first oncogene identified is the proto-oncogene tyrosine-protein kinase Src.

Loss of tumour suppressors
Tumour suppressor genes encodes proteins that suppresses tumour formation. These genes are usually suppressed in cancerous cells. In fact, many cancers arise due to the inactivation of these genes, leading to the activation of the oncogenes.

Because tumour suppressor genes are usually present in two copies - one from each copy of the chromosome from the parents - and thus requires for both genes to have loss-of-function mutation before it loses its effect, a feature called functionally recessive. This leads to the Knudson's Two Hit Hypothesis.

Cell Cycle
Before a cell can go go from one phase of the cell cycle to the next, it must pass through transition checkpoints. These checkpoint ensures that the cell is ready to move onto the next phase, and that it is beneficial to the organism for it to progress. Cancer cells ignore these checkpoints and replicate anyways, leading to a mass of cells - the tumour.

The signal for cell-cycle progression has been shown to be diffusible, as when cells synchronized in G1 and S phase are fused together, the cell in G1 phase was able to enter S phase, because some diffusible element(s) was able to pass from the S phase cell to the G1 phase cell.

Retinoblastoma
E2 binding factor (E2F) is a heterodimeric transcription factor that promotes G1 to S phase transition.

The retinablastoma protein is usually hypophosphorylated in G0/G1 states, but becomes hyperphosphorylated when it needs to progress through the cell cycle. It allows this because it normally binds to E2F, and prevent it from signalling cell cycle progression; but when it is hyperphosphorylated, it releases E2F and allows for cell cycle progression. E7 can also bind to Rb and blocks its phosphorylation, and this has likewise been shown to drive G1 to S phase transition.

Signalling
A whole host of signalling pathways mediates cell-cycle progression, including, EGF signalling, mediated by PI3K, Ras, Akt, mTOR pathways. When some of the genes (proto-oncogenes) in these pathways are over-expressed, they can lead to cancer. Viruses often introduce viral copies of these genes and cause tumorigenesis.

DNA damage
Exposure to mutagens, oxidative damage and radiation can generate generic lesions such as double/single strand breaks, single nucleotide mutations etc., generating genomic instability. These damages may not only cause senescence, but can also lead to mutations that induces tumorigenesis.

Cells have mechanisms of DNA repair which aims to return the cell back to normal or induce apoptosis if the damage is too vast.

Viral cancer
The first oncogene identified, the proto-oncogene tyrosine-protein kinase Src, can be introduced into a cell via a virus. It was discovered by Peyton Rous in 1911. He identified a large lump in the breast of a chicken as sarcoma, he then transplanted this lump into another closely-related chicken and saw that the cancer becomes more aggressive. Rous then attempted to identify the element which conferred this tumour property. He minced the tumour in a solution of saline and passed it through a filter to eliminate bacteria and tumor cells. He then injected the extract into healthy chicken and saw tumour develop in these chickens too. The element in the extract which conferred the tumour properties was the retrovirus Rous Sarcoma Virus (RSV), which contained a v-src gene that gets reverse transcribed and incorporated into the genome, and is then constitutively-transcribed.

Retrovirus
Rous sarcoma (src), rat sarcoma (ras), FBJ murine osteosarcoma (fos) and Simian sarcoma (sis) are examples of retrovirus containing an oncogene.

There are three sets of genes encoded into every retrovirus - Group Antigens (Gag), reverse transcriptase (Pol), and envelope protein (Env).

There can also be additional elements such as oncogenes, which allow viruses such as RSV to induce cancers in healthy cells.

DNA virus
Adenovirus, simian virus 40 (SV40) and human papilloma virus (HPV) are examples of DNA viruses.

Small DNA tumour viruses have genome size of between 5 and 50 kilbases. They do not incorporate into the genome, but rather induce the transcription of oncoproteins. For example, E2 binding factor (E2F) is a heterodimeric transcription factor that promotes G1 to S phase transition. E2F binds to the E2 promoter in adenovirus to produce E1A and E1B, which are analogous to E7. E1A and E1B binds to Rb and displaces E2F to induce G1 to S phase transition.

Molecular abnormalities

Effects on cell function

Therapy

Activating invasion and metastasis
When a tumour grows, its cell mass will increase until it has enough force to break through the basal lamina and invade capillaries, the cancer cell will then travel through the bloodstream to a distant site, where it will adhere to blood vessel walls and extravasate into the tissue to form a new tumour (metastases) there.

The cancer cells in the bloodstream are mostly cleared, with less than 1 in 1000 surviving to form metastases.