Cancer [2]

For other uses, see Cancer (disambiguation).

When normal cells are damaged beyond repair, they are eliminated by apoptosis. Cancer cells avoid apoptosis and continue to multiply in an unregulated manner.

Cancer is a class of diseases characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue (invasion) or by implantation into distant sites (metastasis). This unregulated growth is caused by damage to DNA, resulting in mutations to genes that control cell division. Several mutations are required to transform a normal cell into a malignant cell. These mutations are often caused by chemicals or physical agents called carcinogens, the best known being tobacco smoke. Some mutations can be inherited.

The word cancer is not used in medicine as it lacks precision, but remains the common name for this group of diseases in most languages. Instead, scientists and physicians use the word neoplasm (Latin neoplasia, new form). Tumor ("swelling" in Latin) is a more general term that describes an abnormal mass. In medicine, tumor is not synonymous with neoplasm; most tumors are not neoplasm, but rather inflammation surrounding an infection. Furthermore, many neoplasms do not cause a tumor, e.g. leukemia and myeloma. In the common language, however, tumor is synonymous with neoplasm. Tumors (and therefore neoplasms) can be malignant or benign. Therefore, cancer is synonymous with malignant tumor or, in medical language, malignant neoplasm.

Cancer can cause many different symptoms, depending on the site and character of the malignancy and whether there is metastasis. Usually, cancer is painless at an early stage. A definitive diagnosis usually requires the histologic examination of tissue by a specialized physician called a pathologist. This tissue is obtained by biopsy or surgery. Once diagnosed, cancer is usually treated with surgery, chemotherapy and/or radiation.

If untreated, most cancers eventually cause death; cancer is one of the leading causes of death in developed countries. Most cancers can be treated and many cured, especially if treatment begins early. Many forms of cancer are associated with environmental factors, which may be avoidable. Cigarette smoking leads to more cancers than any other environmental factor.

History

Hippocrates described several kinds of cancers. He called benign tumours oncos, Greek for swelling, and malignant tumours carcinos, Greek for crab or crayfish. This strange choice of name probably comes from the appearance of the cut surface of a solid malignant tumour, with a roundish hard center surrounded by pointy projections, vaguely resembling the silhouette of a crab. He later added the suffix -oma, Greek for swelling, giving the name carcinoma. Today, carcinoma is the medical term for a malignant tumour derived from epithelial cells. It is Celsus who translated carcinos into the latin cancer, also meaning crab. Galen used "oncos" to describe all tumours, the root for the modern word oncology.^{[Citation needed]}

Classification and nomenclature

Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. The following general categories are usually accepted:

• Carcinoma: malignant tumors derived from epithelial cells. This group represent the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
• Lymphoma and Leukemia: malignant tumors derived from blood and bone marrow cells
• Sarcoma: malignant tumors derived from connective tissue, or mesenchymal cells
• Mesothelioma: tumors derived from the mesothelial cells lining the peritoneum and the pleura.
• Glioma: tumors derived from brain cells
• germ cell tumours: tumors derived from germ cells, normally found in the testicle and ovary
• Choriocarcinoma: malignant tumors derived from the placenta

Malignant tumors are usually named using the Latin or Greek root of the organ as a prefix and the above category name as the suffix. For instance, a malignant tumor of liver cells is called hepatocarcinoma; a malignant tumor of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.

Benign tumors are named using -oma as a suffix. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid)

Adult cancers

In the USA and other developed countries, cancer is presently responsible for about 25% of all deaths^[1]. On a yearly basis, 0.5% of the population is diagnosed with cancer.

For adult males in the United States, the most common cancers are prostate cancer (33% of all cancer cases), lung cancer (13%), colorectal cancer (10%), bladder cancer (7%) and cutaneous melanoma (5%). As a cause of death lung cancer is the most common (31%) cause, followed by prostate cancer (10%), colorectal cancer (10%), pancreatic cancer (5%) and leukemia (4%)^[1].

For adult females in the United States, breast cancer is the most common cancer (32% of all cancer cases) followed by lung cancer (12%), colorectal cancer (11%), endometrial cancer (6%, uterus) and non-Hodgkin's lymphoma (4%). By cause of death, lung cancer is again the most common (27% of all cancer deaths), followed by breast cancer (15%), colorectal cancer (10%), ovarian cancer (6%) and pancreatic cancer (6%)^[1].

These statistics vary substantially in other countries.

Childhood cancers

Cancer can also occur in young children and adolescents. Here, the aberrant genetic processes that fail to safeguard against the clonal proliferation of cells with unregulated growth potential occur early in life and can progress quickly.

The age of peak incidence of cancer in children occurs during the first year of life. Leukemia (usually ALL) is the most common infant malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms' tumor, lymphomas, rhabdomyosarcoma (arising from muscle), retinoblastoma, osteosarcoma and Ewing's sarcoma^[1].

Female infants and male infants have essentially the same overall cancer incidence rates, but white infants have substantially higher cancer rates than black infants for most cancer types. Relative survival for infants is very good for neuroblastoma, Wilms' tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.

Causes and pathophysiology

Main article: Carcinogenesis

Origins of cancer

Cell division (proliferation) is a physiological process that occurs in almost all tissues and under many circumstances. Normally the balance between proliferation and cell death is tightly regulated to ensure the integrity of organs and tissues. Mutations in DNA that lead to cancer disrupt these orderly processes.

The uncontrolled and often rapid proliferation of cells can lead to either a benign tumor or a malignant tumor (cancer). Benign tumors do not spread to other parts of the body or invade other tissues, and they are rarely a threat to life unless they extrinsically compress vital structures. Malignant tumors can invade other organs, spread to distant locations (metastasize) and become life-threatening.

Molecular biology

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Carcinogenesis (meaning literally, the creation 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 regulate 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 halts cell division from occurring in order to carry out DNA repair. Typically, 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, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and enzymes is responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes will modify their function. If their function is modified so that they become overexpressed and thus produce more proteins of which they are coded for, thus becoming overactive. When this happens, they become oncogenes, and thus cells have a higher chance to divide excessively and uncontrollably. Frustratingly, the chance 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 mutated, that the signals for growth become excessive.

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation fo tumor suppressor geenes. The functions of such genes is to arrest the progression of cell cycle in order to carry out DNA repair, preventing mutations from passed on to daughter cells. Canonical tumor suppressors include the p53 gene, which is a transcription factor activated by many cellular stress including hypoxia and ultraviolet radiation damage.

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, which was first hypothesised by the Knudson hypothesis. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increase as one gets older, because DNA damage forms a feedback loop.

Usually, oncogenes are dominant, as they contain gain of function mutations, while mutated tumor suppressors are recessive, as they contain loss of function mutations. Each cell has two copies of a same gene, one from each parent, and under most cases gain of function mutation in one copy of a particular proto-oncogene is enough to make that gene a true oncogene, while usually loss of function mutation need 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, and this is called dominant negative effect. This is observed in many p53 mutations.

Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressers act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals who are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and those who are heterozygous for Rb mutations develop retinoblastoma. Similarly, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in colon while young, while mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Cancer is ultimately due to accumulation of genetic damage, which are fundamentally mutations in the DNA. Substances that cause these mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer. Prolonged exposure to radiation, particularly ultraviolet radiation from the sun, leads to melanoma and other skin malignancies. Breathing asbestos fibers is associated with mesothelioma. 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. Chromosomal translocations, such as the Philadelphia chromosome, are a special type of mutation that involve exchanges between different chromosomes.

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 rate of cell mitosis. Faster rates of mitosis increasingly leave less oppurtunities for repair enzymes to repair damaged DNA during DNA replication, increasingly the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer.

Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but less so in humans, as viruses only responsible for 15% of human cancers. The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for a overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming virus, which already carries the viral-oncogene.

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, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body.

Malignant tumors cells have distinct properties:

• evading apoptosis
• unlimited growth potential (immortalitization) due to overabundance of telomerase
• self-sufficiency of growth factors
• insensitivity to anti-growth factors
• increased cell division rate
• altered ability to differentiate
• no ability for contact inhibition
• ability to invade neighbouring tissues
• ability to build metastases at distant sites
• ability to promote blood vessel growth (angiogenesis)

A cell that degenerates into a tumor cell does not usually acquire all these properties at once, but its descendant cells are selected to build 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 point 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. Also, the DNA methylation pattern of the cell changes, activating and deactivating genes without the usual regulation. Cells that divide at a high rate, such as epithelials, show a higher risk of becoming tumor cells than those which divide less, for example neurons.

Morphology

Tissue can be organized in a continuous spectrum from normal to cancer.

Cancer tissue has a distinctive appearance under the microscope. Among the distinguishing traits are a large number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, loss of normal tissue organization, and a poorly defined tumor boundary. Immunohistochemistry and other molecular methods may characterise specific markers on tumor cells, which may aid in diagnosis and prognosis.

Biopsy and microscopical examination can also distinguish between malignancy and hyperplasia, which refers to tissue growth based on an excessive rate of cell division, leading to a larger than usual number of cells but with a normal orderly arrangement of cells within the tissue. This process is considered reversible. Hyperplasia can be a normal tissue response to an irritating stimulus, for example callus.

Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure. Often such cells revert back to normal behavior, but occasionally, they gradually become malignant.

The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and shows no propensity to invade other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

Heredity

Most forms of cancer are "sporadic", and have no basis in heredity. There are, however, a number of recognised syndromes of cancer with a hereditary component. Examples are:

• certain inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
• tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
• Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft-tissue sarcoma, brain tumors) due to mutations of p53
• Turcot syndrome (brain tumors and colonic polyposis)
• Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
• Retinoblastoma in young children is an inherited cancer

Environment and diet

The incidence of lung cancer is highly correlated with smoking. Source:NIH.

The most consistent finding, over decades of research, is the strong association between tobacco use and cancers of many sites. Hundreds of epidemiological studies have confirmed this association. Further support comes from the fact that lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men. Up to half of all cancer cases can be attributed to smoking, diet, and environmental pollution.