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Cellular
Kinetics
Generation time is the time required for a quiescent cell to complete a cycle in cell division (see Fig. 1: Overview of Cancer: The cell cycle. ) and give rise to 2 daughter cells. Malignant cells usually have a shorter generation time than nonmalignant cells from the same tissue, and there usually are a smaller percentage of cells in G0 (resting phase). Initial exponential tumor growth is followed by a plateau phase when cell death nearly equals the rate of formation of daughter cells. The slowing in growth rate is likely related to exhaustion of the supply of nutrients and O2 for the rapidly expanding tumor. Small tumors have a greater percentage of actively dividing cells than do large tumors.
Cellular kinetics of particular tumors is an important consideration in the design of antineoplastic drug regimens and may influence the dosing schedules and timing intervals of treatment. Many antineoplastic drugs are effective only if cells are actively dividing, and some drugs work only during a specific phase of the cycle and thus require prolonged administration to catch dividing cells during the phase of maximal sensitivity.
Tumor
Growth and Metastasis
As a tumor grows, nutrients are provided by direct diffusion from the circulation. Local growth is facilitated by enzymes (eg, proteases) that destroy adjacent tissues. As tumor volume increases, tumor angiogenesis factors are produced to promote formation of the vascular supply required for further tumor growth.
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Fig. 1
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The cell cycle.
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G0
= resting phase (nonproliferation of cells); G1
= variable pre-DNA synthetic phase (12 h to a few days); S = DNA synthesis (usually 2 to 4 h); G2
= post-DNA synthesis (2 to 4 h)—a tetraploid quantity of DNA is found within cells; M1
= mitosis (1 to 2 h).
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Almost from inception, a tumor may shed cells into the circulation. From animal models, it is estimated that a 1-cm tumor sheds > 1 million cells/24 h into the venous circulation. Although most circulating tumor cells die as a result of intravascular trauma, an occasional cell may adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites. Metastatic tumors grow in much the same manner as primary tumors and may subsequently give rise to other metastases.
Experiments suggest that through random mutation, a subset of cells in the primary tumor may acquire the ability to invade and migrate to distant sites, resulting in metastasis.
Molecular
Abnormalities
Genetic mutations are responsible for the generation of cancer cells. These mutations alter the quantity or function of protein products that regulate cell growth and division and DNA repair. Two major categories of mutated genes are oncogenes and tumor suppressor genes.
Oncogenes
These are abnormal forms of normal genes (proto-oncogenes) that regulate various aspects of cell growth. Mutation of these genes may result in direct and continuous stimulation of the pathways (eg, intracellular signal transduction pathways, transcription factors, secreted growth factors) that control cellular growth and division, DNA repair, angiogenesis, and other physiologic processes.
There are > 100 known oncogenes that may contribute to human neoplastic transformation. For example, the ras gene encodes the Ras protein, which regulates cell division. Mutations may result in the inappropriate activation of the Ras protein, leading to uncontrolled cell growth and division. In fact, the Ras protein is abnormal in about 25% of human cancers. Other oncogenes have been implicated in specific cancers. These include
Specific oncogenes may have important implications for diagnosis, therapy, and prognosis (see individual discussions under the specific cancer type).
Oncogenes typically result from acquired somatic cell mutations secondary to point mutations (eg, from chemical carcinogens), gene amplification (eg, an increase in the number of copies of a normal gene), or translocations. Occasionally, mutation of genes results in inheritance of a cancer predisposition, as in the inheritance of BRCA1 or BRCA2 in families with a high incidence of breast or ovarian cancer.
Tumor
suppressor genes: Genes such as the p53 gene play a role in normal cell division and DNA repair and are critical for detecting inappropriate growth signals in cells. If these genes, as a result of inherited or acquired mutations, become unable to function, genetic mutations in other genes can proceed unchecked, leading to neoplastic transformation.
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Table 1
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Human Cancers Associated
With Chromosomal Abnormalities
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Category
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Examples
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Leukemias
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Lymphocytic
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Acute lymphocytic leukemia
Chronic lymphocytic leukemia
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Myeloid
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Acute monocytic leukemia
Acute myelogenous leukemia with maturation
Acute myelomonocytic leukemia with eosinophilia
Acute nonlymphocytic leukemia with increased basophils
Acute promyelocytic leukemia
Chronic myelocytic leukemia
Therapy-related acute myelogenous leukemia
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Lymphomas
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–
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Burkitt's
Non-Hodgkin
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Solid tumors
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Benign
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Colonic adenomas
Meningioma
Mixed tumors of salivary gland
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Adenocarcinomas
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Bladder
Colon
Kidney
Ovary
Prostate
Small cell lung cancer
Uterus
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Sarcomas
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Ewing's tumor
Extraskeletal myxoid chondrosarcoma
Liposarcoma, myxoid
Peripheral neuroepithelioma
Rhabdomyosarcoma (alveolar)
Synovial sarcoma
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Other
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Malignant melanoma
Mesothelioma
Neuroblastoma
Retinoblastoma
Testicular and ovarian dysgerminoma
Wilms' tumor
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As with most genes, 2 alleles are present that encode for each tumor suppressor gene. A defective copy of one gene may be inherited, leaving only one functional allele for the individual tumor suppressor gene. If a mutation is acquired in the other allele, the normal protective mechanisms of the tumor suppressor gene are lost, and dysfunction of other protein products or DNA damage may escape unregulated, leading to cancer. For example, the retinoblastoma (RB) gene encodes for the protein Rb, which regulates the cell cycle by stopping DNA replication. Mutations in the RB gene family occur in many human cancers, allowing affected cells to divide continuously.
Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal DNA to survive and divide. Mutations are passed to daughter cells, conferring a high probability of neoplastic transformation. The p53 gene is defective in many human cancers. As with oncogenes, mutation of tumor suppressor genes such as p53 or RB in germ cell lines may result in vertical transmission and a higher incidence of cancer in offspring.
Chromosomal
abnormalities
Gross chromosomal abnormalities (see Chromosomal Anomalies: Introduction) can occur through deletion, translocation, or duplication. If these alterations activate or inactivate genes that result in a proliferative advantage over normal cells, then a tumor may develop. Chromosomal abnormalities occur in certain human cancers (see Table 1: Overview of Cancer: Human Cancers Associated With Chromosomal Abnormalities ). In some congenital diseases (Bloom syndrome, Fanconi anemia, Down syndrome), DNA repair processes are defective and chromosomes break easily, putting children at high risk of developing acute leukemia and lymphomas.
Other influences
Most cancers likely involve several of the mechanisms described above that lead to neoplastic conversion. For example, the development of tumor in familial polyposis takes place through a sequence of genetic events: epithelium hyperproliferation (loss of a suppressor gene on chromosome 5), early adenoma (change in DNA methylation), intermediate adenoma (overactivity of the ras oncogene), late adenoma (loss of a suppressor gene on chromosome 18), and finally, cancer (loss of a gene on chromosome 17). Further genetic changes may be required for metastasis.
Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integrity. In normal tissue, telomere shortening (with aging) results in a finite limit in cell division. The enzyme telomerase provides for telomere synthesis and maintenance; thus telomerase may potentially allow for cellular immortality. Activation of telomerase in tumors allows continuous proliferation of tumors.
Environmental
Factors
Infections
Viruses contribute to the pathogenesis of human cancers (see Table 2: Overview of Cancer: Cancer-Associated Viruses). Pathogenesis may occur through the integration of viral genetic elements into the host DNA. These new genes are expressed by the host; they may affect cell growth or division or disrupt normal host genes required for control of cell growth and division. Alternatively, viral infection may result in immune dysfunction, leading to decreased immune surveillance for early tumors.
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Table 2
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Cancer-Associated Viruses
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Virus
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Associated Cancer
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Epstein-Barr virus
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Burkitt's lymphoma
Nasopharyngeal carcinoma
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Hepatitis B or hepatitis C virus
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Hepatocellular carcinoma
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Herpesvirus 8
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Kaposi's sarcoma
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Human papillomaviruses
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Anal carcinoma
Cervical carcinoma
Head and neck carcinoma
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Human T-lymphotrophic virus
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T-cell lymphomas
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Bacteria may also cause cancer. Helicobacter pylori infection increases the risk of several kinds of cancer (gastric adenocarcinoma, gastric lymphoma, mucosa-associated lymphoid tissue [MALT] lymphoma).
Parasites of some types can lead to cancer. Schistosoma haematobium causes chronic inflammation and fibrosis of the bladder, which may lead to cancer. Opisthorchis sinensis has been linked to carcinoma of the pancreas and bile ducts.
Radiation
Ultraviolet radiation may induce skin cancer (eg, basal and squamous cell carcinoma, melanoma) by damaging DNA. This DNA damage consists of formation of thymidine dimers, which may escape repair due to inherent defects in DNA repair (eg, xeroderma pigmentosum) or through rare, random events.
Ionizing radiation is also carcinogenic. For example, survivors of the atomic bomb explosions in Hiroshima and Nagasaki have a higher-than-expected incidence of leukemia and other cancers. Similarly, the previous use of x-rays to treat nonmalignant disease (acne, thymic or adenoid enlargement, and ankylosing spondylitis) resulted in higher rates of acute and chronic leukemias, Hodgkin and non-Hodgkin lymphomas, multiple myeloma, aplastic anemia terminating in acute nonlymphocytic leukemia, myelofibrosis, melanoma, and thyroid cancer. Use of x-rays in diagnostic imaging studies is thought to increase risk of cancer (see Principles of Radiologic Imaging). Industrial exposure (eg, to uranium by mine workers) is linked to development of lung cancer after a 15- to 20-yr latency. Long-term exposure to occupational irradiation or to internally deposited thorium dioxide predisposes people to angiosarcomas and acute nonlymphocytic leukemia.
Exposure to the radioactive gas radon, which is released from soil, increases the risk of lung cancer. Normally, radon disperses rapidly into the atmosphere and produces no harm. However, when a building is placed on soil with high radon content, radon can accumulate within the building, sometimes producing sufficiently high levels in the air to cause harm. In exposed people who also smoke, the risk of lung cancer is further increased.
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Table 3
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Common Chemical Carcinogens
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Carcinogens
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Type of Cancer
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Environmental and industrial
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Aromatic amines
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Bladder cancer
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Arsenic
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Lung cancer
Skin cancer
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Asbestos
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Lung cancer
Mesothelioma
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Benzene
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Leukemia
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Chromates
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Lung cancer
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Diesel exhaust
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Lung cancer
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Formaldehyde
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Nasal cancer
Nasopharyngeal cancer
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Hair dyes
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Bladder cancer
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Ionizing radiation
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Leukemia
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Manufactured mineral fibers
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Lung cancer
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Nickel
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Lung cancer
Nasal sinus cancer
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Painting materials
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Lung cancer
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Pesticides, nonarsenic
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Lung cancer
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Radon
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Lung cancer
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Radiation therapy
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Leukemia
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Ultraviolet radiation
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Skin cancer
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Vinyl chloride
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Hepatic angiosarcoma
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Lifestyle
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Betel nuts
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Oropharyngeal cancer
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Tobacco
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Bladder cancer
Cervical cancer
Esophageal cancer
Head and neck cancer
Kidney cancer
Lung cancer
Pancreatic cancer
Stomach cancer
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Drugs*
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Alkylating drugs
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Leukemia
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Diethylstilbestrol (DES)
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Cervicovaginal cancer in women exposed in utero
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Oxymetholone
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Liver cancer
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*Health care practitioners exposed to antineoplastic drugs are also at risk of adverse effects on reproduction.
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Drugs
and chemicals
Estrogens in oral contraceptives may slightly increase the risk of breast cancer, but this risk decreases over time. Estrogen and progestin used for hormone replacement therapy also increase the risk of breast cancer. Diethylstilbestrol (DES) increases the risk of breast cancer in women who took the drug and increases the risk of vaginal carcinoma in daughters of these women who were exposed before birth. Long-term use of anabolic steroids may increase the risk of liver cancer. Treatment of cancer with chemotherapy drugs and with radiation therapy increases the risk of developing a second cancer.
Chemical carcinogens can induce gene mutations and result in uncontrolled growth and tumor formation (see Table 3: Overview of Cancer: Common Chemical Carcinogens). Other substances, called co-carcinogens, have little or no inherent carcinogenic potency but enhance the carcinogenic effect of another agent when exposed simultaneously.
Dietary substances
Certain substances consumed in the diet can increase the risk of cancer. For instance, a diet high in fat has been linked to an increased risk of colon, breast, and possibly prostate cancer. People who drink large amounts of alcohol are at much higher risk of developing esophageal cancer. A diet high in smoked and pickled foods or in barbecued meats increases the risk of developing stomach cancer. People who are overweight or obese have a higher risk of cancer of the breast, endometrium, colon, kidneys, and esophagus.
Physical factors
Chronic skin irritation leads to chronic dermatitis and, in rare cases, to squamous cell carcinoma. This occurrence is presumably due to random mutations that occur more frequently because of the increased cell turnover.
Immunologic
Disorders
Immune system dysfunction as a result of inherited genetic mutation, acquired disorders, aging, or immunosuppressants interferes with normal immune surveillance of early tumors and results in higher rates of cancer. Known cancer-associated immune disorders include
Last full review/revision August 2008 by Bruce A. Chabner, MD; Elizabeth Chabner Thompson, MD, MPH
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