Pathology

Exploring the Main causes of Cancer



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The word 'Cancer' still has the power to strike fear into all of our hearts. Cancer encompasses a wide variety of diseases, affecting every major tissue of the body, all of which have one thing in common: uncontrolled cellular proliferation.

In essence, the cause of all cancers is simple: cells growing when and where they shouldn't be! Our normal tissues are under strict growth regulation to maintain the desired numbers of cells for the normal, healthy function of our tissues. Any alteration in either the rate of cell division (mitosis) or the rate of cellular death (apoptosis) can lead to the formation of a tumour. Once a tumour starts growing it puts the surrounding tissues at risk, either through starving the normal tissue of resources (such as food and oxygen) or by interfering with their normal function (through damaging the normal tissue architecture, or by pressing on vital tissue structures). Eventually, cells can break away from the primary tumour and form secondary deposits (metastases) throughout the body where they can interfere with other tissues (such as when a tumour spreads to the lungs, which then become blocked by multiple small metastases).

This loss of the normal constraints on cell numbers (and thus the 'cause' of cancer) is almost always genetic. Damage to key genes involved in tissue maintenance, cellular division, and cell death can all lead to cancer. This kind of genetic damage is termed a mutation (a change in the normal DNA sequence found in the nucleus of our cells) and these mutations are caused by numerous different carcinogens which may be either physical (such as radiation which can actually break the chains of DNA) or chemical (such as the carcinogens found in cigarette smoke). When you smoke a cigarette, multiple mutations will occur in the DNA of the cells lining the lungs. However these mutations will only lead to cancer if the DNA damage happens to occur in one of the genes involved in cellular division/death etc. Simple speaking, anything that damages our DNA can cause cancer!

Broadly speaking, these cancer-related genes can be grouped into two main groups: oncogenes and tumour suppressor genes. Oncogenes are genes involved in promoting cell division (so damage to these genes can cause a cell to proliferate excessively) and tumour suppressor genes are involved in preventing cell division, until conditions are favourable for a cell to divide into two daughter cells (damage to these genes removes this protective function and again leads to the growth of more cells). One other important cause' of cancer is viruses. These have been found to be involved in many different cancer types (such as the human papilloma virus which plays an important role in the formation of cervical cancer). A viral infection works in the same way as a mutation in an oncogene: they both lead to an increase in the rate at which a cell divides.

Most human cancers are more common in older people. This reflects the natural aging process of our cells and more importantly indicates that mutations in multiple genes are required, accumulated over a lifetime of exposure to carcinogens. The numbers vary, but for most human cancers mutations in approximately 5-10 genes involved in the growth and proliferation of cells are required for a fully formed mutation. The progression of cancer is a step-wise process: the first mutation results in a relatively normal looking cell, but a cell which has a higher rate of division compared to its neighbours. All the daughter cells from this original cell share the mutation (and the increase in growth rate) which results in a patch' of tissue developing (still essentially normal, but with all cells carrying the first mutation). Over time (often decades) and if the carcinogenic stimulus remains (if you keep on smoking for example), any one of these daughter cells can acquire another mutation. This leads to a further expansion of the population of abnormal cells, and this process continues until any one of the cells has accumulated enough mutations to form a fully blown malignant tumour.

This process doesn't stop, and cancers continue to evolve'. This characteristic is probably the most clinically significant, and is responsible for the eventual failure of many forms of conventional chemotherapy. When we treat a cancer with drugs most of the cells may be killed (the tumour may even disappear from the X-rays), however, if a few cells divide they can gain resistance to the chemotherapy drug used. This resistance is acquired through further genetic mutations. This process is exactly the same mechanism by which drug resistant forms of bacteria arise after prolonged treatment with antibiotics, tumours (and bacterial infections) contain many millions of cells and only a single cell has to gain this resistance-generating' mutation for all the descendant cells to share the drug resistance. This evolving' property of cancer cells continues to frustrate oncologists who inevitably see the rise of resistance to the drugs used to treat a patient.

The battle against cancer has been a long slow journey, since Richard Nixon declared a War on Cancer' in 1971, many billions of dollars and many scientists careers have been devoted to understanding the process by which this disease develops. Over the last few decades process has been unfortunately slow, with little real improvement in survival for many of the major killers such as lung, breast and bowel cancer. However today, in the age of molecular medicine', hopes are high that we know have the understanding and tools to generate new medicines, targeted at the specific molecular defects found in tumours. The sequencing of the human genome has given us a common normal reference' for the DNA in our cells and the vast numbers of mutations catalogued over the last decade have given us a molecular understanding of tumour development in a detail previously only dreamed of.

There is a long way to go, but the future is definitely brighter and we can now dare to hope that the word cancer' won't fill our children with the same fear it has for so long done to our generation.

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