Cancer as a genetic disease

It is known that cancer is linked to harmful genetic alterations of cells and many genes have been linked to various forms of cancer, but the genetics of cancer is very complicated and less well understood than classic genetics. No single cancer-causing gene has ever been discovered that is mutated in all cancers, and even in specific tumour types there can be several possible genetic mechanisms and genes involved in the formation of the tumour. In some families an inherited disposition has been shown to play a role in cancer formation, but these familial cancers make up only a small proportion of cancer cases.

Cancer is a collection of disorders sharing the common feature of uncontrolled cell growth, leading to the formation of a mass of cells known as a 'neoplasm' or 'tumour'. Malignant neoplasms have the ability to invade adjacent tissues and often metastasize to more distant parts of the body, a process that is the cause of 90% of cancer deaths (Sporn, 1996). There are more than 200 types of cancer, and each is classified according to the tissue type in which they arise.

Cancers are almost always derived from a single ancestral somatic cell. The cells in an emerging neoplasm accumulate a series of genetic changes that lead to changes in gene activity and phenotype (Ponder, 2001). From studies on the incidence of cancer, it is thought that up to six or seven events are needed to turn a normal cell into a fully fledged invasive carcinoma. This is initially very confusing, because the probability of a single cell undergoing six independent mutations is virtually nil. There are mechanisms that can explain how this process can happen. These altered cells are subject to selection, and eventually a cell population evolves that can escape the controls of proliferation and territory. Initially mutations increase proliferation (growth), and this gives an increased target population of cells for the next mutation. At the same time some mutations will alter the stability of the whole genome, at either the DNA or chromosome level, and increase the overall mutation rate. This is a multi-step process, which explains why tumours always develop in stages, from benign growths to malignant tumour cells, at each step developing new mutations (Kinzler and Vogelstein, 1996) (Figure 6.2).

Mutation 1 Mutation 2 Mutation 3 Malignant

Mutation 1 Mutation 2 Mutation 3 Malignant

of mutant cell of mutant cells

Figure 6.2 The multistage evolution of a cancer, with successive mutations giving cells a growth advantage; expanded populations of cells thus present a larger target for the next mutation. Cells are shaded progressively darker after each mutation.

of mutant cell of mutant cells

Figure 6.2 The multistage evolution of a cancer, with successive mutations giving cells a growth advantage; expanded populations of cells thus present a larger target for the next mutation. Cells are shaded progressively darker after each mutation.

Cancer-causing mutations generally affect genes that regulate cellular growth (the cell cycle) or death (apoptosis). It is thought that this process involves up to six essential alterations in cell physiology, including: self-sufficiency in the production of positive growth signals; disregard of inhibitory growth signals; an acquired capability for sustained growth (immortality of the cell); angiogene-sis (blood vessel development); and finally metastasis (invasion and spread). Each of these changes represents the breaching of one of the body's anti-cancer mechanisms. These are predominantly somatic events, although in many of the inherited cancer syndromes one of these events may be inherited. Mutagenic environmental factors such as diet, radiation and exposure to carcinogenic compounds (e.g. cigarette smoke) can also affect the probability of these mutational events (Jorde et al., 2000).

The regulatory components that give the signals for cellular growth or inhibition of growth are usually external growth factors that act via complex signalling pathways affecting cellular growth (the cell cycle). It is various members of these pathways, and cell-cycle components, that are inactivated or down- or upregulated in many of the tumorigenic alterations to cell physiology. Growth signals include various cellular growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF) a. These growth factors have signalling pathways that are also altered by many cancers to allow self-sufficiency in growth. Anti-growth signals can include growth factors such as TGFp, and these need to be inactivated to allow cancer progression. These growth-inhibitory signals are also received by receptor molecules of the cell surface and coupled to other complicated networks of signalling pathways. Many of these signals are associated with the cell cycle, and can force cells out of the active proliferative cycle into a dormant state, where they remain until signalled at some future point. There are other complicated pathways governing apoptosis, senescence and angiogenesis which all have to be overcome in the development of a cancer (Hanahan and Weinberg, 2000). Once the cell has become hyperproliferative and cancerous, metastasis is a further multistep process, where the tumour cells have to detach from the primary tumour site and then reattach (via specific adhesion molecules) to the vascular tissues or other tissue sites to be invaded. Extracellular matrix proteins have to be degraded by enzymes released from the tumour or the surrounding cells.

Cancer genes can be divided into three main groups, according to whether they activate cellular proliferation (oncogenes), inhibit proliferation (tumour suppressors) or participate in DNA repair.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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