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Cancer Cell Development

Our bodies are made up of many tiny units called cells, which are arranged into tissues and organs. Tissue and organ growth (in children) and repair (in adults) are generally the result of cells growing in size and dividing into 2 cells in a controlled manner. Chemical signals tell the cells to divide or stop dividing. Normally, the orders for cell growth are clear and our cells obey.

When cells divide, they reproduce themselves exactly. One cell divides into 2 identical cells, then 2 cells divide into 4, and so on. In adults, cells normally grow and divide to produce more cells only when the body needs them to replace aging or damaged cells. Many cells live for a given amount of time and then are programmed to die by a process called apoptosis. This turnover of cells helps keep the body healthy. Cells of different tissues and organs divide at different rates. For example, skin cells divide relatively quickly, whereas nerve cells divide very slowly or not at all once they mature.

Cell Division_E

Cancer can start in any cell in the body. The cell starts out normal, but then changes. It is thought that a normal cell needs several injuries (mutations) before it will change into a cancer cell. These injuries to the cell affect how it grows, works, reproduces and dies. They may cause the cell to continue to grow and divide out of control instead of dying when it should. Although there are many different types of cancer, they all start because of uncontrolled, abnormal growth of cells.

Cancer cells behave differently from normal cells because they don’t:

  • stop dividing
  • obey signals from other normal cells
  • stick together very well and can spread to other parts of the body
  • specialize into mature cells but stay immature

Chromosomes and genes

The DNADNAThe molecules inside the cell that program genetic information. DNA determines the structure, function and behaviour of a cell. in our cells is packed into rod-shaped structures called chromosomeschromosomesThe part of a cell that contains DNA (genetic information).. There are 46 chromosomes (arranged in 23 different pairs) in most cells of a person's body. Chromosome pairs 1 through 22 are called "autosomes" and look the same in males and females. Chromosome pair 23 are the sex chromosomes and are different for males and females. Females have 2 X chromosomes, and males have an X and a Y chromosome. Chromosomes are located in the nucleus of the cell. A copy of each chromosome is inherited from each parent (a person receives 23 chromosomes from their mother and 23 chromosomes from their father).

GenesGenesThe basic biological unit of heredity passed from parents to a child. Genes are pieces of DNA and determine a particular characteristic of an individual. are the basic units of heredity that code for and transfer traits from cell to cell and from parents to children. They direct much of what happens in the body and determine characteristics like a person's eye and hair colour and their blood type. There are about 25,000 different human genes. There are 2 copies of each gene, called alleles, that differ slightly from each other. A person inherits one gene from their mother and the other from their father. A gene that controls eye colour will have 2 copies – one that may be for blue eyes and one that may be for brown eyes.

Genes are made of DNA and are located on chromosomes. Two strands of DNA join and twist together to form a DNA double helix. Chemicals, called bases or nucleotides, keep the 2 strands of DNA joined together. There are 4 different bases: adenine (A), thymine (T), cytosine (C) and guanine (G). The bases can be arranged in any order. The order of the bases in a gene determines the message the gene contains.

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Cell division

Before a cell divides, it must duplicate all of its contents. It makes exact copies of its 46 chromosomes so that each of the 2 daughter cells will have exactly the same genes as the parent cell. This involves a complex process in which the DNA strands in each chromosome untwist so that they can be copied. The cell forms 2 identical double helices, one of which will be transferred to each of the 2 daughter cells when division occurs. Because this process is so complex, errors (mutations) frequently occur. The cell recognizes most of these errors and automatically repairs them. However, some errors are missed and may be passed on to the daughter cells.

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Gene mutations

Most cancers are caused by a change in or damage to genes. A change in a gene is called a gene mutationgene mutationA permanent change or alteration in a gene.. One might think of gene mutations as spelling errors that have not been corrected by gene repair mechanisms, which are like spell checkers that look for and fix mistakes. Mutations can affect the structure of the gene and stop it from working properly.

Genes can become mutated for various reasons, and mutations can occur in several different ways. The simplest type of mutation is a substitution of a different DNA base. For example, thymine (T) may replace adenine (A), which could change the message of the gene. Other types of simple mutations include deletion or duplication of one or more bases (nucleotides). Some mutations do not affect critical areas of a gene and may not cause a problem, but other mutations will.

Over the past few years, scientists have learned a great deal about how abnormal changes in our genes can influence our health and increase the risk of cancer.

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The body's repair system

Each cell has the ability to spot changes in the DNA and fix them before they are passed on to new cells. But sometimes a cell’s ability to make these repairs fails. As the mutations build up over time, the damaged cell is more likely to become cancerous. Cells are often destroyed by several mechanisms if DNA damage cannot be repaired. However, these "cell death triggering systems" may also become defective in cancer cells. If a cell with mutations is not destroyed, it has the potential to turn into cancer. Cancer usually requires at least 6 mutations to occur before the normal growth control checks are removed and the healthy cell changes into a malignant one. It usually takes many years for these mutations to build up and transform a normal cell into a malignant (cancerous) cell.

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Causes of gene mutations

There are 2 basic causes of gene mutations. They can occur by chance or be inherited.

Sporadic mutations

Most cancers occur because of genetic changes in the cells that happen mostly by chance and build upthroughout a person's lifetime. They are called sporadic (spontaneous) or acquired mutations. Sometimes these changes are errors that occur while a cell is dividing. They can also be caused by something that damages the cell's DNA, such as risk factors like smoking, certain chemicals (toxins) and viruses, and radiation.

Most sporadic mutations occur in cells other than egg and sperm cells. These other cells are called somatic cells, while the egg and sperm cells are called germ cells. Mutations in somatic cells are not passed on from a parent to a child.

Inherited mutations

Sometimes damaged genes that make a person more susceptible to cancer are inherited, or passed on from a parent to a child. Inherited mutations are called germline mutations because they are present in a parent's reproductive cells (germ cells), either the father's sperm cell or the mother's egg cell. Because the mutation is present in one of the germ cells, it can be passed on at the time of conception and will be present in every cell of the child's body. Men and women who carry a germline mutation have a 50% chance (or 1 in 2 chance) of passing it on to their children. Germline mutations can be passed on from generation to generation. However, only about 5%–10% of cancers are caused by inherited gene mutations.

Inherited mutations have to start somewhere. All germline mutations start as a de novo mutation – a new mutation in a germ cell. This mutation may have occurred in some ancestor many generations ago, and is then passed down through the family. De novo mutations can also occur in a parent’s sperm or egg and be passed on to their children. De novo mutations may explain a genetic mutation in a child when there is no family history of a disorder. However, most people who pass inherited mutations on to their children received the mutation from one of their parents.

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Types of cancer genes

Scientists have found 3 main classes of genes that are important in controlling cell growth and play a role in cancer cell development. People may inherit a mutated form of one of these genes, which may make them more likely to develop a particular type of cancer.

Oncogenes

Oncogenes cause cells to grow out of control. They promote cancer cell growth. Oncogenes are damaged versions of normal genes called proto-oncogenesproto-oncogenesA normal gene involved in the control of cell growth and division that can mutate (change) and become an oncogene. Mutations can be inherited or caused by exposure to a carcinogen (a substance that causes cancer) in the environment.. Proto-oncogenes control a variety of cell functions related to cell growth and reproduction.

Every person has 2 copies of each gene (one inherited from each parent). Oncogene mutations are dominant, which means that an inherited defect in one copy of a proto-oncogene can lead to cancer even if the second copy of the gene is normal.

Tumour suppressor genes

Tumour suppressor genes are genes that normally protect against cancer. They act as brakes and help stop cell growth and control cell death. If tumour suppressor genes are damaged, missing or otherwise don't work properly, cell growth, cell division and cell death (apoptosis) may not be controlled. Nearly 50% of all cancers are thought to involve a damaged or missing tumour suppressor gene.

TP53 is a tumour suppressor gene that triggers cell death. It is commonly damaged or missing in many types of cancer.

Tumour suppressor gene mutations are recessive, which means that both copies of the gene need to have a defect for the person to be at risk of developing cancer.

DNA repair genes

DNA repair genes are responsible for repairing damaged genes. They fix mistakes (mutations) that commonly occur when DNA is being copied. If these genes themselves are damaged, mutations may not be repaired and will build up. DNA repair genes may also be considered a type of tumour suppressor gene. DNA repair gene mutations are also recessive, so both copies of the gene need to have a defect for the person to be at risk of developing cancer.

Scientists don't know all the mutations that may be involved in allowing cancers to grow and progress. Although oncogenes, tumour suppressor genes and DNA repair genes are the main causes of cancer-related mutations, mutations in other types of genes involved in cell growth may also play a part. These include genes involved with cell aging or cell death. Additional gene mutations may occur that allow cancer cells to spread into nearby tissues, avoid the immune system’s defences, make new blood vessels and travel to new sites. Many cancers cannot be linked to a specific gene.

Genes may also interact with each other or with other factors to cause cancer.

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Steps of cancer development

Generally, cancer develops in 3 main steps. It can take a long time for cancer to develop because several steps and several genetic mutations are usually required. Usually many years pass between exposure to a cancer-causing agent or event and cancer actually developing. This time frame is called the latency period, or lag time. The chance of cancer developing increases as a person gets older because there has been more time for exposures and mutations to build up.

Initiation

Experts believe that many cancers are caused by gene mutations. Other cancers may be caused by additional mechanisms, such as translocations (where pieces of chromosomes break away from their normal location and join a completely different chromosome) or when a specific gene’s function is changed because of changes to that gene’s messages. Each cell has the ability to spot these mutations and can either destroy itself (by apoptosis) or fix the mutations before they are passed on to new cells. If the cell's ability to make these repairs fails and more mutations occur, the damaged cell is more likely to become cancerous.

This initial change may be caused by carcinogens, such as chemicals, smoking or exposure to radiation, but often the cause is unknown and may be a random. Changes caused by carcinogens are called initiators. The cell starts to become abnormal at this stage.

Promotion

Further and repeated damage needs to occur before cancer develops. Agents, such as hormones or some drugs, cause this further damage and are called promoters. Unlike carcinogens, promoters do not cause cancer by themselves, but allow a cell that has undergone initiation to become cancerous.

Some carcinogens, such as exposure to large doses of radiation, are powerful enough to cause cancer without the help of promoters.

Progression

The change (transformation) in a normal cell causes it to behave, grow and function quite differently and turn into a cancer cell. The cell’s growth instructions get mixed up. This causes the cell to go on growing and reproducing itself. The time it takes a cell to double in number is called the doubling time. A fast-growing cancer cell may double over 1–4 weeks, a slower growing one over 2–6 months. The doubling time varies with the type of cancer cell and how aggressive it is.

In adults, there is usually a long developmental (latency) period after initiation during which promotion and progression are occurring, which means it takes a long time before a cell becomes cancerous. In children, this latency period is much shorter.

As cancer cells grow, they can group together to form a lump (tumour). It can take several months or even years (up to 30 years) for cancer cells to form a lump that is big enough to be felt or detected by an imaging test. By this time, the cancer cell has undergone about 30 or more doublings, and even though the lump is very small, it can contain about a billion cells. In children, the time is much less for a lump to become noticeable.

Cancer Development

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Metastasis

As cancer cells divide, they can invade surrounding tissue. They can also break away from the original (primary) tumour and enter the bloodstream or lymphatic system. If the cancer cells  escape detection by the immune system, they can be carried by the blood and lymph to distant parts of the body. This is how cancer can spread (metastasize).

Childhood cancers tend to metastasize earlier than adult cancers. About 80% of childhood cancers have metastasized when they are diagnosed.

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