Cellular And Molecular Mechanisms Of Malignant Tumors

Cell kinetics as a generation time, the time is referred to, which requires a cell to pass through the cell division cycle complete (s. Cell cycle.) To form and two identical daughter cells. Malignant cells, especially those that occur in bone marrow or in the lymphatic system, may have a short generation time; Moreover, this may be a minor proportion of the cells in the G0 phase (quiescent phase). To the initial exponential phase of tumor growth, a plateau in which the cell death corresponds approximately to the rate of cell formation follows. The reduced growth rate may be related to the depleted nutrients and O2 supply the rapidly growing tumor. Small tumors have a higher proportion of actively dividing cells than larger tumors. A subpopulation among numerous tumors that can be identified by surface proteins can have properties of primitive “normal” stem cells, such as those found in early embryos. Therefore, these cells are capable of entering into a proliferative state. They are less sensitive to injury from drugs or radiation. It is believed that they repopulate tumors after surgery, chemotherapy or radiation therapy. The cell kinetics of malignant tumors represents a significant basis for the preparation of chemotherapy protocols and influence the dosage and time intervals of the therapy. Many chemotherapy drugs, such as anti-metabolites, are effective if the cells are actively dividing, and some act only during a specific phase of the cell cycle. They therefore require a longer delivery to achieve the dividing cells in the phase of their maximum sensitivity. Tumor growth and metastasis The necessary for tumor growth nutrients are delivered directly by diffusion from the circulation. The local growth is facilitated by enzymes (eg., Proteases), destroy the adjacent tissue. With increasing tumor size, such as the vascular endothelial growth factor by the tumors tumor angiogenesis factors (VEGF), formed which lead to neovascularization, which is necessary for further tumor growth. Cell cycle. G0 = rest (non-proliferating cells); G1 = variable pre-DNA synthesis phase (12 hours to several days); S = DNA synthesis phase (usually 2-4 hours); (2-4 h, with the DNA content of the cells is now tetraploid) G2 = post-DNA synthesis phase; M1 = mitosis (1-2 h). Already from the beginning of tumor development, tumor cells can be released into the circulation. From animal models it is known that an approximately 1 cm tumor within 24 h> 1 million cells into the venous circulation delivers. Circulating tumor cells are in many patients with advanced cancer before and even for some who have localized disease. Although most circulating tumor cells die in the intravascular space, succeeds isolated cells to bind to the vascular endothelium and invade the surrounding tissue. This leads to the formation of independent tumors (metastases) at distant from the primary tumor sites. Metastatic resulting tumors grow in the same way as the primary tumor and can contribute in the sequence to form new metastases. Experiments suggest that the skills the invasion, migration and successful implantation and stimulating the growth of new blood vessels all are important properties of metastatic cells that are likely to represent a subset of cells in the primary tumor. Molecular changes for the development of malignant tumor cells are genetic mutations responsible, which therefore occur in all cancers. These mutations alter the amount or function of proteins that regulate cell growth, cell division and DNA repair. The two major classes of mutated genes include oncogenes and tumor suppressor genes. Oncogenes Oncogenes are abnormal variants of normal genes (proto-oncogenes) that regulate various aspects of cell growth. Mutations in these genes can lead to the direct and continuous stimulation of signaling pathways that control cell growth and cell division, DNA repair, angiogenesis and other physiological processes (eg., Growth factor receptors on the cell surface, intracellular signal transduction pathways, transcription factors, secreted growth factors). There are known> 100 oncogenes that can lead to neoplastic transformation of human cells. For example, the ras gene encodes the Ras protein, which transmits the signals bound to the membrane receptors along the RAS-MAP kinase pathway to the cell nucleus and thereby regulate cell division. Mutations in this gene result in an excessive activation of the Ras protein, whereby an uncontrolled cell growth can be triggered. In fact, found in about 25% of human tumors abnormalities of the Ras protein. Other oncogenes associated with specific tumor types. These include HER2-NEU (amplified in breast cancer but not mutated) BCR-ABL (a translocation of two genes, the chronic myelogenous leukemia and some of acute lymphoblastic B-cell leukemias are based) C-MYC (Burkitt’s lymphoma) N-MYC (translocation, which activates the ALK tyrosine kinase activity and a particular form of adenocarcinoma of the lung caused) Certain oncogenes can play (small cell lung cancer, neuroblastoma) mutant EGFR (adenocarcinoma of the lung) EML4-ALK an important role in the diagnosis, treatment and prognosis (s. under the individual tumor types). Oncogenes typically (z. B. increasing the copy number of normal genes) are caused by an acquired somatic mutation as a result of point mutations (eg., By chemical carcinogens), gene amplification or by translocations (in which parts of different genes merge into a single sequence). These changes can either increase the activity of the gene production (protein) or change its function. Occasionally cause gene mutations in a familial predisposition to the development of malignant tumors, as in the inherited cancer syndrome that play with a mutation or a loss of function of BRCA1, BRCA2 or p53 associated ist.Tumorsuppressorgene genes such as the p53 gene in normal cell division and DNA repair a role and are critical to the discovery of inappropriate growth signals or DNA damage in cells. If these genes lose their function due to a congenital or acquired mutation, the monitoring mechanism of DNA integration is inefficient, while cells persist with spontaneous genetic mutations and multiply, resulting in tumors result. There are two alleles as with most genes even when tumor suppressor genes. A defect in a gene can be congenital, so that the person concerned has only one functional allele of a single tumor suppressor gene. If now an acquired mutation in the other allele of the normal protective mechanism of the second normal tumor suppressor gene is lost. For example, the retinoblastoma gene (RB) encoding the protein Rb, which regulates the cell cycle by the disruption of DNA replication. Mutations in the RB gene family lead to a continued division of the affected cells and occur in many human tumors. Another important regulatory protein is p53, which prevents the replication of damaged DNA in normal cells and cell death (apoptosis) promotes in cells with abnormal DNA. Inactive or altered p53 leads to survival and division of the cells with abnormal DNA. Mutations are passed on to daughter cells, increase the likelihood of replication error-prone DNA and neoplastic transformation results. In many human tumors a defective p53 gene is present. As with the oncogenes, mutations in tumor suppressor genes such as the p53 or RB gene in germ line cells for vertical transmission and a higher incidence of tumor diseases in the Nachkommen.Chromosomenveränderungen Serious chromosome damage (chromosomal abnormalities at a Glance) can occur by deletion, translocation or duplication. If these changes to the activation or inactivation of genes perform and there is thereby a growth advantage in proliferation compared to normal cells, can develop tumors. Chromosomal changes occur in most human tumor types. For some hereditary diseases (eg. As Bloom syndrome, Fanconi anemia, Down’s syndrome) is the DNA repair mechanism is defective and chromosome breaks occur frequently, reducing the risk in children increases of developing acute leukemia or other lymphomas. other influences most epithelial cancers likely result from a sequence of mutations that lead to a neoplastic conversion. For example, tumors in familial polyposis develop a sequence of genetic events. Via steps epithelial hyperproliferation (loss of suppressor gene on chromosome 5), early adenoma (changes in the DNA methylation), intermediate adenoma (overactivity of the RAS oncogene) and late adenoma (loss of suppressor gene on chromosome 18) is produced, ultimately, a carcinoma (loss a gene on chromosome 17). The development of metastases may require further genetic modification. Telomeres are nucleoprotein complexes which are supported at the ends of chromosomes and maintain its integrity. In normal tissue the shortening of telomeres leads (which is associated with the aging process) in a finite number of possible cell divisions. When the enzyme telomerase is activated in tumor cells, allowing a new telomere synthesis and continuous growth of tumors. Environmental influences infections Viruses can also the development of human malignant tumors (s. Virus Associated tumors) promoting. The pathogenesis may be through the integration of viral genes into the host DNA. These new genes are expressed by the host and can influence cell growth or cell division or destroy properties necessary for the regulation of cell growth and cell division genes. In addition, a viral infection can lead to immunological dysfunction, which is associated with decreased immune response and immune surveillance against tumors early. Associated Virus Tumor Virus Associated diseases tumor Epstein-Barr virus Burkitt’s lymphoma nasopharyngeal carcinoma, Hepatitis B or Hepatitis C virus hepatocellular carcinoma human herpesvirus 8 Kaposi’s sarcoma, human papillomavirus cervical anal carcinoma of head and neck carcinoma Human T-cell lymphotropic virus T-cell lymphomas bacteria can also cause malignant tumors. Infection with Helicobacter pylori increases the risk of various malignant tumors (adenocarcinoma of the stomach, gastric lymphoma, MALT [mucosa-associated lymphoid tissue] lymphoma). Also some parasitic infections can lead to malignancy. Schistosoma haematobium causes chronic inflammation and fibrosis of the bladder. As a result, a bladder cancer can develop. Opisthorchis sinensis is associated with the development of carcinoma of the pancreas and Gallengangs.Strahlung Ultraviolet radiation, the development of skin tumors through DNA damage (eg. As basal cell and squamous cell carcinomas, malignant melanoma) trigger. These DNA damage is the formation of thymidine dimers that may go undetected by the excision and resynthesis normal DNA strands. This is a result of congenital defects of DNA repair mechanisms (eg. As xeroderma pigmentosum) or rare random events. In addition, ionizing radiation can have a carcinogenic effect. Thus, for shows. As in survivors of the atomic bombings in Hiroshima and Nagasaki have a higher incidence of leukemia and other cancers. Similarly, the exposure to a therapeutic irradiation years later may lead to leukemia, breast cancer and other solid tumors. Also, it is assumed that the X-rays in diagnostic imaging increase the risk of malignant tumors (Broad radiological imaging). The industrial radiation exposure (eg. As compared to uranium at miners to asbestos) can develop lung cancer after 15-20 years. A long-term exposure to radiation due to the employment or by Thoriumdioxiddepots in the body is a predisposing factor for the development of angiosarcomas or acute leukemias nichtlymphatischen. The exposure to the discharged from the bottom of radioactive radon gas increases the risk of lung cancer. Normally, radon rapidly distributed in the atmosphere and causes no harm. When a building, however, is on a substrate with high radon levels, radon can accumulate in buildings; the concentration in the air is then sometimes so high that there will be damage. Exposed Persons who smoke also have a further increased risk of lung cancer. Common chemical carcinogens carcinogen tumor environment and the workplace Aromatic amines bladder cancer Arsenic lung carcinoma skin cancer asbestos lung cancer mesothelioma benzene leukemia Chromates lung carcinoma diesel exhaust lung carcinoma formaldehyde nose carcinoma nasopharyngeal carcinoma bladder carcinoma hair dye Ionizing Radiation Leukemia Artificial mineral fibers lung carcinoma Nickel lung carcinoma carcinoma of the paranasal sinuses coatings lung carcinoma pesticides, not arsenic lung carcinoma Radon lung cancer radiation therapy leukemia UV radiation skin tumor Vinylch dichloride Hepatic angiosarcoma lifestyle betel nuts Oropharyngeal cancer tobacco bladder carcinoma cervical carcinoma esophageal carcinoma of head and neck tumors, renal cell carcinoma lung carcinoma pancreatic cancer stomach cancer drug Alkylating drugs (cyclophosphamide, platinum analogs) leukemia Diethylstilbestrol (DES) Zervikovaginales carcinoma in exposure of the female fetus Oxymetholon liver cancer topoisomerase inhibitors (anthracyclines, etoposide) leukemia * In health care, persons working with exposure to antineoplastic drugs are exposed to the risk of adverse effects on reproduction. Drugs and chemicals estrogen in oral contraceptives may slightly increase the risk of breast cancer, but which decreases the risk over time. increase estrogen and progestin in hormone replacement therapy also breast cancer risk. Diethylstilbestrol (DES) increases the risk of breast cancer in women who took the Arneimittel, and increases the risk of vaginal carcinoma their daughters who were exposed to drugs before birth. A long-term use of anabolic steroids can increase the risk of hepatocellular carcinoma. The treatment of malignant tumors with chemotherapy alone or with radiation increases the risk of developing a second tumor. Chemical carcinogens can induce genetic mutations and lead to uncontrolled growth and the formation of tumors (s. Common chemical carcinogens). Other substances, called Cokarzinogene, have little or no carcinogenic potential, but may increase the carcinogenic effect of other substances if exposure concurrently herewith auftritt.Ernährung Certain substances in the diet can increase the risk of cancer. For example, a high-fat diet and obesity were taken even with an increased risk for the development of colon, breast and possibly prostate cancer in combination. Persons with high alcohol consumption have a higher risk for developing head and neck cancer, as well as of esophageal carcinoma. Is there a diet to a high portion of smoked and pickled foods or meat that is cooked at high temperatures, there is an increased risk of gastric cancer. Overweight or obese individuals are at higher risk for cancers of the breast, endometrium, colon, kidney and Speiseröhre.Physikalische factors Chronic skin, lung, gastrointestinal or thyroid inflammation may increase the risk of cancer development. For example, patients with long-standing inflammatory bowel disease (ulcerative colitis) an increased risk of colon cancer. Sunlight and tanning lamps increase the risk of skin cancer and melanoma. Immune diseases dysfunction of the immune system as a result of inherited genetic mutations, acquired diseases, immunosuppressive drugs or diseases of old age affect the physiological monitoring functions with respect to early tumors and lead to increased tumor rate. Among the known tumor-associated immune disorders include ataxia telangiectasia (acute lymphoblastic leukemia [ALL], brain tumors, gastric tumors) Wiskott-Aldrich syndrome (lymphoma, ALL) X-linked agammaglobulinemia (lymphoma, ALL) immune deficiency syndromes due to immunosuppressants or HIV infection (large cell lymphoma, cervical cancer, head and neck cancer, Kaposi’s sarcoma) rheumatic diseases such as SLE, rheumatoid arthritis and Sjogren’s syndrome (B cell lymphoma) Fanconi anemia (AML)

Health Life Media Team

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