molecular basis of cancer

molecular basis of cancer
Non lethal genetic damage (mutations) lies at the heart of carcinogenesis. Such mutations may be acquired by the action of environmental agents, such as chemicals, radiation, and viruses, or it may be inherited in the germ line. The alteration of genetic content occur by {point mutation, translocation between two chromosomes, and increase of copy number of particular genes this called (amplification)}.
The genetic hypothesis of cancer implies that a tumor mass results from the clonal expansion of a single precursor (progenitor) cell that has carried the genetic damage.
The targets of genetic damage (mutation) are:
1- Proto-oncogenes cellular genes that promote normal growth and differentiation,.
2- Cancer-suppressor genes (anti-oncogenes) the growth-inhibiting genes.
3- Genes that regulate programmed cell death, or apoptosis.
4- Genes that regulate repair of damaged DNA.
Oncogenes and cancer:
Oncogenes, or cancer-causing genes, are derived from protooncogenes, by retroviral transduction (v-oncs) or by influences that alter their behavior in situ, thereby converting them into cellular oncogenes (c-oncs).
Protein products of oncogenes (onco-proteins):
To aid in the understanding of the nature and functions of oncoproteins, it is necessary to know briefly the sequence of events that characterize normal cell proliferation. Under physiologic conditions, cell proliferation can be readily resolved into the following steps:
1- The binding of a growth factor to its specific receptor on the cell membrane.
2- Transient and limited activation of the growth factor receptor, which, in turn, activates several signal-transducing proteins on the inner leaflet of the plasma membrane
3- Transmission of the signal across the cytosol to the nucleus via second messengers
4- Induction and activation of nuclear regulatory factors that initiate DNA transcription
5- Entry and progression of the cell into the cell cycle, resulting ultimately in cell division
mutant genes affect the normal steps discussed above as following:
1-Mutations of genes that encode growth factors can render them oncogenic, and overexpression of growth factor genes, forcing the cells to secrete large amounts of growth factors.
2-The oncogenic versions of growth factor receptors are associated with persistent dimerization and activation without binding to the growth factor. Hence the mutant receptors deliver continuous mitogenic signals to the cell.
3-Several examples of oncoproteins that mimic the function of normal cytoplasmic signal-transducing proteins have been found. Most such proteins are strategically located on the inner leaflet of the plasma membrane, where they receive signals from outside the cell and transmit them to the cell s nucleus, so mutation in this proteins leading to continuous stimulation of cells without any external trigger.
4-Nuclear Transcription Proteins.
The process of DNA replication and cell division is regulated by a family of genes whose products are localized to the nucleus, where they control the transcription of growth-related genes. The transcription factors contain specific amino acid sequences that allow them to bind DNA or to dimerize for DNA binding. Many of these proteins bind DNA at specific sites from which they can activate or inhibit transcription of adjacent genes. Not surprisingly, therefore, mutations affecting genes that encode nuclear transcription factors are associated with malignant transformation.
Cancer suppressor genes: like P53, and Rb genes.
• In normal cases the Rb gene act as a Brake to DNA replication in cell cycle, so mulation in Rb gene lead to development of specific type of malignancy called Retinoblastoma.
• P53 in normal cell play to important roles, first it prevent replication of damaged DNA, by stopping the cell in the G1 phase of cell cycle, and second role for P53 gene, is directed the cells with damaged DNA (that cannot repair), to undergo apoptosis.
Carcinogenesis:
Carcinogenesis (meaning literally, the creation of cancer) is the process by which normal cells are transformed into cancer cells.
A large number of agents cause genetic damage and induce neoplastic transformation of cells. They fall into the following categories:
(1) chemical carcinogens
(2) radiant energy
(3) oncogenic microbes, chiefly viruses.
1- chemical carcinogens:
Pott astutely who firstly observed the increased incidence of scrotal skin cancer in chimney sweeps to chronic exposure to soot. Over the succeeding two centuries, hundreds of chemicals have been shown to transform cells and lead to neoplastic growth.
Steps involved in chemical carcinogenesis:
cancer induction can be broadly divided into two stages: initiation and promotion.
a- Initiation results from exposure of cells to an appropriate dose of a carcinogenic agent (initiator); an initiated cell is altered, since the initiation causes permanent DNA damage (mutations). It is therefore rapid and irreversible.
b- Promoters are agents that can induce tumors in initiated cells, but they are non tumorigenic by themselves (such as , hormones, phenols, and drugs), so they stimulate clonal proliferation of the initiated (transformed ) cells.
Initiation carcinogens:
They fall into one of two categories:
(1) direct-acting compounds, which do not require chemical metabolism for their carcinogenicity.
(2) indirect-acting compounds or procarcinogens, which require metabolic conversion in vivo to produce ultimate carcinogens capable of transforming cells.
All direct-acting and ultimate carcinogens have one property in common: They are highly reactive electrophiles (have electron-deficient atoms) that can react with nucleophilic (electron-rich) sites in the cell. The electrophilic reactions may attack several electron-rich sites in the target cells, including DNA, RNA, and proteins, thus sometimes producing lethal damage, in initiated cells, the interaction is obviously nonlethal, and the DNA is the primary target.
few direct-acting alkylating agents that are intrinsically electrophilic, most chemical carcinogens require metabolic activation for conversion into ultimate carcinogens. Age, sex, and nutritional status also determine the internal dose of toxicants and hence determine the affect of chemical carcinogens on the body.
Direct-Acting Alkylating Agents.
they are important because many therapeutic agents (e.g., cyclophosphamide, chlorambucil, busulfan, melphalan, and others) fall into this category. These are used as anticancer drugs but have been documented to induce lymphoid neoplasms, leukemia, and other forms of cancer. Some alkylating agents, such as cyclophosphamide, are also powerful immunosuppressive agents and are therefore used in treatment of immunologic disorders, including rheumatoid arthritis but associated with development of transitional cell carcinoma of the bladder. Although the risk of induced cancer with these agents is low, judicious use of them is indicated. Alkylating agents appear to exert their therapeutic effects by interacting with and damaging DNA, but it is precisely these actions that render them also carcinogenic.
Polycyclic Aromatic Hydrocarbons.
These agents represent some of the most potent carcinogens known. They require metabolic activation and can induce tumors in a wide variety of tissues and species. Painted on the skin, they cause skin cancers; injected subcutaneously, they evoke sarcomas; introduced into a specific organ, they cause cancers locally. The polycyclic hydrocarbons are of particular interest as carcinogens because they are produced in the combustion of tobacco, particularly with cigarette smoking, and may well contribute to the causation of lung cancer and bladder cancer. They are also produced from animal fats in the process of broiling meats and are present in smoked meats and fish.
Aromatic Amines and Azo Dyes.
An agent implicated in human cancers, beta-naphthylamine, in the past, it has been responsible for a 50-fold increased incidence of bladder cancer in heavily exposed workers in aniline dye and rubber industries. After absorption, it is hydroxylated into an active form then detoxified in the liver by conjugation with glucuronic acid. When excreted in the urine, the nontoxic conjugate is split by the urinary enzyme glucuronidase to release the electrophilic reactant again, thus inducing bladder cancer.
Some of the azo dyes were developed to color food may be dangerous to humans.
Naturally Occurring Carcinogens.
Among the several known chemical carcinogens produced by plants and microorganisms, aflatoxin B1 is most important. It is produced by Aspergillus flavus A strong correlation has been found between the dietary level of this hepatocarcinogen and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East. Infection with hepatitis B virus has also been strongly correlated with this cancer, and when exposure to both of these agents occurs, the aflatoxin and the virus collaborate in the production of this form of neoplasia.
Nitrosamines and Amides.
These carcinogens are of interest because of the possibility that they are formed in the gastrointestinal tract of humans and so may contribute to the induction of some forms of cancer, particularly gastric carcinoma. They are derived in the stomach from the reaction of nitrostable amines and nitrate used as a preservative, which is converted to nitrites by bacteria.
Promoters of Chemical Carcinogenesis.
Certain promoters may contribute to cancers in humans. It has been argued that promoters are at least as important as initiating chemicals because cells initiated by exposure to environmental carcinogens are innocuous unless subjected to repeated attach by promoters.
Tumor promotion may occur after exposure to exogenous agents, such as cigarette smoke that cause tissue damage and reactive hyperplasia. Or due to endogenous promoters such as hormones and bile salts. Hormones such as estrogens serve in animals as promoters of liver tumors. The prolonged use of diethylstilbestrol is implicated in the production of postmenopausal endometrial carcinoma. Intake of high levels of dietary fat has been associated with increased risk of colon cancer. This may be related to an increase in synthesis of bile acids, which have been shown to act as promoters in experimental models of colon cancer.