Cancer

			Chest x-ray showing lung cancer in the left lung.

Cancer is a group of diseases in which cells are aggressive (grow and divide without respect to normal limits), invasive (invade and destroy adjacent tissues), and metastatic (spread to other locations in the body). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited in their growth and don't invade or metastasize (although some benign tumor types are capable of becoming malignant). Cancer may affect people at all ages, even fetuses, but risk for the more common varieties tends to increase with age.Cancer causes about 13% of all deaths. According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007. Apart from humans, forms of cancer may affect other animals and plants.

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

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. Complex interactions between carcinogens and the host genome may explain why only some develop cancer after exposure to a known carcinogen. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly being recognized as important.

Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are often activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are often inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Cancer is usually classified according to the tissue from which the cancerous cells originate, as well as the normal cell type they most resemble. These are location and histology, respectively. A definitive diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.

Classification

Nomenclature
The following closely related terms may be used to designate abnormal growths:

Tumor: originally, it meant any abnormal swelling, lump or mass. In current English, however, the word tumor has become synonymous with neoplasm, specifically solid neoplasm. Note that some neoplasms, such as leukemia, do not form tumors.
Neoplasm: the scientific term to describe an abnormal proliferation of genetically altered cells. Neoplasms can be benign or malignant:
Malignant neoplasm or malignant tumor: synonymous with cancer.
Benign neoplasm or benign tumor: a tumor (solid neoplasm) that stops growing by itself, does not invade other tissues and does not form metastases.
Invasive tumor is another synonym of cancer. The name refers to invasion of surrounding tissues.
Pre-malignancy, pre-cancer or non-invasive tumor: A neoplasm that is not invasive but has the potential to progress to cancer (become invasive) if left untreated. These lesions are, in order of increasing potential for cancer, atypia, dysplasia and carcinoma in situ.
The following terms can be used to describe a cancer:

Screening: a test done on healthy people to detect tumors before they become apparent. A mammogram is a screening test.
Diagnosis: the confirmation of the cancerous nature of a lump. This usually requires a biopsy or removal of the tumor by surgery, followed by examination by a pathologist.
Surgical excision: the removal of a tumor by a surgeon.
Surgical margins: the evaluation by a pathologist of the edges of the tissue removed by the surgeon to determine if the tumor was removed completely ("negative margins") or if tumor was left behind ("positive margins").
Grade: a number (usually on a scale of 3) established by a pathologist to describe the degree of resemblance of the tumor to the surrounding benign tissue.
Stage: a number (usually on a scale of 4) established by the oncologist to describe the degree of invasion of the body by the tumor.
Recurrence: new tumors that appear a the site of the original tumor after surgery.
Metastasis: new tumors that appear far from the original tumor.
Transformation: the concept that a low-grade tumor transforms to a high-grade tumor over time. Example: Richter's transformation.
Chemotherapy: treatment with drugs.
Radiation therapy: treatment with radiations.
Adjuvant therapy: treatment, either chemotherapy or radiation therapy, given after surgery to kill the remaining cancer cells.
Prognosis: the probability of cure after the therapy. It is usually expressed as a probability of survival five years after diagnosis. Alternatively, it can be expressed as the number of years when 50% of the patients are still alive. Both numbers are derived from statistics accumulated with hundreds of similar patients to give a Kaplan-Meier curve.
Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. Examples of general categories include:

Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells
Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).
Blastic tumor: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.
Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ of origin as the root. For instance, a cancer of the liver is called hepatocarcinoma; a cancer 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 with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). Unfortunately, some cancers also use the -oma suffix, examples being melanoma and seminoma.

Adult cancers
In the U.S. and other developed countries, cancer is presently responsible for about 25% of all deaths.On a yearly basis, 0.5% of the population is diagnosed with cancer. The statistics below are for adults in the United States, and may vary substantially in other countries:

Childhood cancers
Cancer can also occur in young children and adolescents, but it is rare (about 150 cases per million yearly in the US). Statistics from the SEER program of the US NCI demonstrate that childhood cancers increased 19% between 1975 and 1990, mainly due to an increased incidence in acute leukemia. Since 1990, incidence rates have decreased

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.Teratoma is the most common tumor in this age group, but most teratomas are surgically removed while still benign, hence not necessarily cancer.

Female 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.

Signs and symptoms
Roughly, cancer symptoms can be divided into three groups:

Local symptoms: unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice (yellowing the eyes and skin).
Symptoms of metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.
Systemic symptoms: weight loss, poor appetite, fatigue and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.
Every symptom in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.

Diagnosis
Most cancers are initially recognized either because signs or symptoms appear or through screening. Neither of these lead to a definitive diagnosis, which usually requires the opinion of a pathologist.

Investigation

Chest x-ray showing lung cancer in the left lung.People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.

Biopsy
A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must be confirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained from a biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctor's office. Biopsies of other organs are performed under anesthesia and require surgery in an operating room.

The tissue diagnosis indicates the type of cell that is proliferating, its histological grade and other features of the tumor. Together, this information is useful to evaluate the prognosis of this patient and choose the best treatment. Cytogenetics and immunohistochemistry may provide information about future behavior of the cancer (prognosis) and best treatment.

Treatment
Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development.

Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.

Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases.

Surgery
In theory, non-hematological cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.

Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.

In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy.

Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.

Radiation therapy
Main article: Radiation therapy
Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.

Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.

Chemotherapy
Main article: Chemotherapy
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.

Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.

The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation. Alternatively, hematopoietic stem cells may be transplanted from a matched unrelated donor (MUD).

Targeted therapies
Main article: Targeted therapy
Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib and gefitinib.

Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.

Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to this peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.

Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors.

Immunotherapy
Main article: Cancer immunotherapy
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells.

Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation" from a genetically non-identical donor) can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.

Hormonal therapy
Main article: Hormonal therapy (oncology)
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.

Angiogenesis inhibitor
Main article: Angiogenesis inhibitor
Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors require to survive. Some, such as bevacizumab, have been approved and are in clinical use. One of the main problems with anti-angiogenesis drugs is that many factors stimulate blood vessel growth, in normal cells and cancer. Anti-angiogenesis drugs only target one factor, so the other factors continue to stimulate blood vessel growth. Other problems include route of administration, maintenance of stability and activity and targeting at the tumor vasculature.

Symptom control
Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. Although doctors generally have the therapeutic skills to reduce pain, nausea, vomiting, diarrhea, hemorrhage and other common problems in cancer patients, the multidisciplinary specialty of palliative care has arisen specifically in response to the symptom control needs of this group of patients.

Pain medication, such as morphine and oxycodone, and antiemetics, drugs to suppress nausea and vomiting, are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.

Chronic pain due to cancer is almost always associated with continuing tissue damage due to the disease process or the treatment (i.e. surgery, radiation, chemotherapy). Although there is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, these are not usually the predominant etiologic factors in patients with cancer pain. Furthermore, many patients with severe pain associated with cancer are nearing the end of their lives and palliative therapies are required. Issues such as social stigma of using opioids, work and functional status, and health care consumption are not likely to be important in the overall case management. Hence, the typical strategy for cancer pain management is to get the patient as comfortable as possible using opioids and other medications, surgery, and physical measures. Doctors have been reluctant to prescribe narcotics for pain in terminal cancer patients, for fear of contributing to addiction or suppressing respiratory function. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients.

Fatigue is a very common problem for cancer patients, and has only recently become important enough for oncologists to suggest treatment, even though it plays a significant role in many patients' quality of life.

Complementary and alternative
Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine. Oncology, the study of human cancer, has a long history of incorporating unconventional or botanical treatments into mainstream cancer therapy. Some examples of this phenomenon include the chemotherapy agent paclitaxel, which is derived from the bark of the Pacific Yew tree, and ATRA, all-trans retinoic acid, a derivative of Vitamin A that induces cures in an aggressive leukemia known as acute promyelocytic leukemia. Many "complementary" and "alternative" medicines for cancer have not been studied using the scientific method, such as in well-designed clinical trials, or they have only been studied in preclinical (animal or in-vitro) laboratory studies. Many times, "complementary" and "alternative" medicines are supported by marketing materials and testimonials from users of the substances. Frequently, when these treatments are subjected to rigorous scientific testing, they are found not to work. A recent example was reported at the 2007 annual meeting of the American Society of Clinical Oncology: a Phase III clinical trial comparing shark cartilage extract to placebo in non-small cell lung cancer demonstrated no benefit of the shark cartilage extract, AE-491.

"Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine. A study of CAM use in patients with cancer in the July 2000 issue of the Journal of Clinical Oncology found that 69% of 453 cancer patients had used at least one CAM therapy as part of their cancer treatment.

Some complementary measures include botanical medicine, such as an NIH trial currently underway testing mistletoe extract combined with chemotherapy for the treatment of solid tumors; acupuncture for managing chemotherapy-associated nausea and vomiting and in controlling pain associated with surgery; and psychological approaches such as "imaging" or meditation to aid in pain relief or improve mood.

A wide range of alternative treatments have been offered for cancer over the last century. The appeal of alternative cures arises from the daunting risks, costs, or potential side effects of many conventional treatments, or in the limited prospect for cure. Some people resort to these so-called "alternative" forms of treatment in desperation or as a last resort. However, no alternative therapies have been shown in any scientific study to effectively treat cancer. Some express the view that the promotion and sale of certain alternative modalities known to be ineffective constitute quackery.

Treatment trials
Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.

A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.

Patients who take part may be helped personally by the treatment(s) they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. Of course, there is no guarantee that a new treatment being tested or a standard treatment will produce good results. New treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit.

Prognosis
Cancer has a reputation for being a deadly disease. While this certainly applies to certain particular types, the truths behind the historical connotations of cancer are increasingly being overturned by advances in medical care. Some types of cancer have a prognosis that is substantially better than nonmalignant diseases such as heart failure and stroke.

Progressive and disseminated malignant disease has a substantial impact on a cancer patient's quality of life, and many cancer treatments (such as chemotherapy) may have severe side-effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care solutions may include permanent or "respite" hospice nursing.

Cancer patients, for the first time in the history of oncology, are visibly returning to the athletic arena and workplace. Patients are living longer with either quiescent persistent disease or even complete, durable remissions. The stories of Lance Armstrong, who won the Tour de France after treatment for metastatic testicular cancer, or Tony Snow, who was working as the White House Press Secretary as of June, 2007 despite relapsed colon cancer, continue to be an inspiration to cancer patients everywhere.

Emotional impact
Many local organizations offer a variety of practical and support services to people with cancer. Support can take the form of support groups, counseling, advice, financial assistance, transportation to and from treatment, films or information about cancer. Neighborhood organizations, local health care providers, or area hospitals may have resources or services available.

While some people are reluctant to seek counseling, studies show that having someone to talk to reduces stress and helps people both mentally and physically. Counseling can also provide emotional support to cancer patients and help them better understand their illness. Different types of counseling include individual, group, family, peer counseling, bereavement, patient-to-patient, and sexuality.

Many governmental and charitable organizations have been established to help patients cope with cancer. These organizations often are involved in cancer prevention, cancer treatment, and cancer research.

Causes

Cancer is a diverse class of diseases which differ widely in their causes and biology. The common thread in all known cancers is the acquisition of abnormalities in the genetic material of the cancer cell and its progeny. Research into the pathogenesis of cancer can be divided into three broad areas of focus. The first area of research focuses on the agents and events which cause or facilitate genetic changes in cells destined to become cancer. Second, it is important to uncover the precise nature of the genetic damage, and the genes which are affected by it. The third focus is on the consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events, leading to further progression of the cancer.

Chemical carcinogens Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA 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 and bladder cancer. Prolonged exposure to asbestos fibers is associated with mesothelioma.

The incidence of lung cancer is highly correlated with smoking

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen. Such chemicals are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes (see aneuploidy above).

The incidence of lung cancer is highly correlated with smoking. Source:NIH.Decades of research have demonstrated the strong association between tobacco use and cancers of many sites, making it perhaps the most important human carcinogen. 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.

Ionizing radiation
Sources of ionizing radiation, such as radon gas, can cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.

Infectious diseases
Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage.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 an 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 an 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 viruses, which already carry the viral oncogene.

Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.

Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the US FDA approved a human papilloma virus vaccine, called Gardasil®. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US CDC Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11-12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.

In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer.

Hormonal imbalances
Some hormones can act in a similar manner to non-mutagenic carcinogens in that they may stimulate excessive cell growth. A well-established example is the role of hyperestrogenic states in promoting endometrial cancer.

Immune system dysfunction
HIV is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer. AIDS-defining illnesses have long included these diagnoses. The increased incidence of malignancies in HIV patients points to the breakdown of immune surveillance as a possible etiology of cancer. Certain other immune deficiency states (e.g. common variable immunodeficiency and IgA deficiency) are also associated with increased risk of malignancy.

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, often a defective tumor suppressor allele. Famous 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.
Hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
Retinoblastoma, when occurring in young children, is due to a hereditary mutation in the retinoblastoma gene.
Down syndrome patients, who have an extra chromosome 21, are known to develop malignancies such as leukemia and testicular cancer, though the reasons for this difference are not well understood.

Other causes
A few types of cancer in non-humans have been found to be caused by the tumor cells themselves. This phenomenon is seen in Sticker's sarcoma, also known as canine transmissible venereal tumor. The closest known analogue to this in humans is individuals who have developed cancer from tumors hiding inside organ transplants.

Pathophysiology Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.

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

There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change which is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Epigenetics
Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell.

Oncogenes
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. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to effect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.

One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.

Tumor suppressor genes
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 of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.

The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.

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.

Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.

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 the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.

Cancer cell biology

Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.

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 has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

Clonal evolution
The process of malignancy can be explained from an evolutionary perspective. Millions of years of biological evolution insure that the cellular metabolic changes that enable cancer to grow occur only very rarely. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. Cancer cells undergo a process analogous to natural selection, in that the few cells with new genetic changes that enhance their survival continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are outcompeted. This process is called clonal evolution. Tumors often continue to evolve in response to chemotherapy treatments, and on occasion aberrant cells may acquire resistance to particular anti-cancer pharmaceuticals.

Biological properties of cancer cells
In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows:

Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
Loss of capacity for senescence, leading to limitless replicative potential (immortality)
Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).
The completion of these multiple steps would be a very rare event without :

Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes.
These biological changes are classical in carcinomas; other malignant tumor may not need all to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of Leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the P53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis.

Prevention
Cancer prevention is defined as active measures to decrease the incidence of cancer. This can be accomplished by avoiding carcinogens or altering their metabolism, pursuing a lifestyle or diet that modifies cancer-causing factors and/or medical intervention (chemoprevention, treatment of pre-malignant lesions). The epidemiological concept of "prevention" is usually defined as either primary prevention, for people who have not been diagnosed with a particular disease, or secondary prevention, aimed at reducing recurrence or complications of a previously diagnosed illness.

Observational epidemiological studies that show associations between risk factors and specific cancers mostly serve to generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials then test whether hypotheses generated by epidemiological trials and laboratory research actually result in reduced cancer incidence and mortality. In many cases, findings from observational epidemiological studies are not confirmed by randomized controlled trials.

About a third of the twelve most common cancers worldwide are due to nine potentially modifiable risk factors. Men with cancer are twice as likely as women to have a modifiable risk factor for their disease. The nine risk factors are tobacco smoking, excessive alcohol use, diet low in fruit and vegetables, limited physical exercise, human papillomavirus infection (unsafe sex), urban air pollution, domestic use of solid fuels, and contaminated injections (hepatitis B and C).

Modifiable ("lifestyle") risk factors
Examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (although 20% of women with lung cancer have never smoked, versus 10% of men[25]), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption may contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexually transmitted diseases, the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures.

Every year, at least 200,000 people die worldwide from cancer related to their workplace. Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces.Currently, most cancer deaths caused by occupational risk factors occur in the developed world. It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.

Diet
The consensus on diet and cancer is that obesity increases the risk of developing cancer. Particular dietary practices often explain differences in cancer incidence in different countries (e.g. gastric cancer is more common in Japan, while colon cancer is more common in the United States). Studies have shown that immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.Whether reducing obesity in a population also reduces cancer incidence is unknown.

Despite frequent reports of particular substances (including foods) having a beneficial or detrimental effect on cancer risk, few of these have an established link to cancer. These reports are often based on studies in cultured cell media or animals. Public health recommendations cannot be made on the basis of these studies until they have been validated in an observational (or occasionally a prospective interventional) trial in humans.

Proposed dietary interventions for primary cancer risk reduction generally gain support from epidemiological association studies. Examples of such studies include reports that reduced meat consumption is associated with decreased risk of colon cancer,and reports that consumption of coffee is associated with a reduced risk of liver cancer.Studies have linked consumption of grilled meat to an increased risk of stomach cancer, colon cancer,breast cancer, and pancreatic cancer, a phenomenon which could be due to the presence of carcinogens such as benzopyrene in foods cooked at high temperatures.

A 2005 secondary prevention study showed that consumption of a plant-based diet and lifestyle changes resulted in a reduction in cancer markers in a group of men with prostate cancer who were using no conventional treatments at the time. These results were amplified by a 2006 study in which over 2,400 women were studied, half randomly assigned to a normal diet, the other half assigned to a diet containing less than 20% calories from fat. The women on the low fat diet were found to have a markedly lower risk of breast cancer recurrence, in the interim report of December, 2006.

Vitamins
There is a concept that cancer can be prevented through vitamin supplementation stems from early observations correlating human disease with vitamin deficiency, such as pernicious anemia with vitamin B12 deficiency, and scurvy with Vitamin C deficiency. This has largely not been proven to be the case with cancer, and vitamin supplementation is largely not proving effective in preventing cancer. The cancer-fighting components of food are also proving to be more numerous and varied than previously understood, so patients are increasingly being advised to consume fresh, unprocessed fruits and vegetables for maximal health benefits.

The Canadian Cancer Society has advised Canadians that the intake of vitamin D has shown a reduction of cancers by close to 60%,[38] and at least one study has shown a specific benefit for this vitamin in preventing colon cancer.

Vitamin D and its protective effect against cancer has been contrasted with the risk of malignancy from sun exposure. Since exposure to the sun enhances natural human production of vitamin D, some cancer researchers have argued that the potential deleterious malignant effects of sun exposure are far outweighed by the cancer-preventing effects of extra vitamin D synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that 23,800 premature cancer deaths occur in the US annually due to insufficient UVB exposure (apparently via vitamin D deficiency).This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun exposure might be beneficial. Another research group estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.

The case of beta-carotene provides an example of the importance of randomized clinical trials. Epidemiologists studying both diet and serum levels observed that high levels of beta-carotene, a precursor to vitamin A, were associated with a protective effect, reducing the risk of cancer. This effect was particularly strong in lung cancer. This hypothesis led to a series of large randomized clinical trials conducted in both Finland and the United States (CARET study) during the 1980s and 1990s. This study provided about 80,000 smokers or former smokers with daily supplements of beta-carotene or placebos. Contrary to expectation, these tests found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality. In fact, the risk of lung cancer was slightly, but not significantly, increased by beta-carotene, leading to an early termination of the study.

Results reported in the Journal of the American Medical Association (JAMA) in 2007 indicate that folic acid supplementation is not effective in preventing colon cancer, and folate consumers may be more likely to form colon polyps.

Chemoprevention
The concept that medications could be used to prevent cancer is an attractive one, and many high-quality clinical trials support the use of such chemoprevention in defined circumstances.

Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. A recent study reported that the selective estrogen receptor modulator raloxifene has similar benefits to tamoxifen in preventing breast cancer in high-risk women, with a more favorable side effect profile.

Raloxifene is a SERM like tamoxifen; it has been shown (in the STAR trial) to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. In this trial, which studied almost 20,000 women, raloxifene had fewer side effects than tamoxifen, though it did permit more DCIS to form.

Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors. The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients and in the general population. In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.

Genetic testing
Genetic testing for high-risk individuals is already available for certain cancer-related genetic mutations. Carriers of genetic mutations that increase risk for cancer incidence can undergo enhanced surveillance, chemoprevention, or risk-reducing surgery. Early identification of inherited genetic risk for cancer, along with cancer-preventing interventions such as surgery or enhanced surveillance, can be lifesaving for high-risk individuals.

Gene Cancer types Availability
BRCA1, BRCA2 Breast, ovarian, pancreatic Commercially available for clinical specimens
MLH1, MSH2, MSH6, PMS1, PMS2 Colon, uterine, small bowel, stomach, urinary tract Commercially available for clinical specimens

Vaccination
Considerable research effort is now devoted to the development of vaccines to prevent infection by oncogenic infectious agents, as well as to mount an immune response against cancer-specific epitopes) and to potential venues for gene therapy for individuals with genetic mutations or polymorphisms that put them at high risk of cancer.

As reported above, a preventive human papillomavirus vaccine exists that targets certain sexually transmitted strains of human papillomavirus that are associated with the development of cervical cancer and genital warts. The only two HPV vaccines on the market as of October 2007 are Gardasil and Cervarix.