Carcinogenesis
Carcinogenesis
refers to the process by which a normal cell is transformed into a malignant cell and repeatedly divides to become a cancer. A chemical which can initiate this process is called a chemical carcinogen. Some chemicals which are noncarcinogenic or only weakly carcinogenic can greatly enhance the effectiveness of carcinogenic chemicals. Such "helpers" are called cocarcinogens. They may act by altering uptake or metabolism of carcinogens by cells.
Carcinogenesis
may take as long as 15-25 years in humans and in several animal models has been shown to involve two stages, initiation and promotion.
-In general, carcinogens are mutagens indicating that they have the potential to interact with DNA.
-Patients with DNA repair defects, such as xeroderma pigmentosum (defect in repair of damage induced by UV and bulky aromatic chemicals), have increased incidence of cancer.
Key words: Carcinogenesis: Pathogenesis of cancer Carcinogen - agent causing cancer. Oncogen - agent causing neoplasm. Mutagen - agent causing mutation. Oncogenes – genes causing cancer p-onc, v-onc – Proto/viral/ - naming of oncogenes.
Factors affecting carcinogenesis These
factors can be divided into three main groups: Environmental
Toxins
chemical physical (e.g. radiation)
Dietary
natural products found in spices, etc. additives (rarely) Lifestyle
hormonally-mediated other
Chemicals Generally Recognized as Carcinogenic in Humans Chemicals Generally Recognized as Carcinogenic in Humans Industrial Exposures Benzidine Vinyl Chloride Certain tars Asbestos
Benzene
Urinary Bladder Liver Skin and Peritoneum (lungs when combined with cigarette smoking) Lymphoid Tissue
Other Exposures Diethylstilbestrol Arsenic Compounds Cigarette Smoke Betal Nut
VaginaI Skin cancer Lungs, urinary tract Buccal Mucosa
Diets play important roles in the development of tumors. The following factors should be considered.
Natural Foods May Contain Carcinogens: Mushrooms»»Hydrazine Betal Nut»»Hydrocarbons
Food contaminants: Aflatoxin B1»»Peanuts Nitrosamines»»Beer, Wine, Pickled Vegetables
Food Processing: Barbecued Meat»»Polycyclic Hydrocarbons Heat Processing of Protein-Rich Foods»»Heterocyclic Aromatic compounds
Dietary Fat: Saturated Fatty Acids Polyunsaturated Fatty Acids: Corn oil, Safflower oil
Natural Foods May Contain Anticarcinogens»»Vitamins, Antioxidants
Carcinogens Chemicals Viruses Radiation Hereditary causes- Genetic defects. Combination – common.
Molecular Basis of Carcinogenesis Genes control cell division by cytokines. Four important classes of regulatory genes (for cell division): 1.
2. 3. 4.
Promotors – Proto-oncogenes Inhibitors – Tumor or Cancer-suppressor genes – p53 Genes regulating Apoptosis. DNA repair genes.
Carcinogenesis Genetic mutations are largely responsible for the generation of malignant cells. Two major categories of mutated genes are oncogenes and tumor suppressor genes. 1-Oncogenes are abnormal forms of normal genes called proto-oncogenes that regulate cell growth. Mutation of these genes may result in direct and continuous stimulation of the molecular biologic pathways that control cellular growth and division. 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.
2-Tumor suppressor genes ,p53, are inherent genes that play a role in 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. Another important regulatory protein, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered apoptotic genes allows cells with abnormal DNA to survive and divide.
p53 Gene p53 senses DNA damage, and induces G1 arrest and induces DNA repair process. Cell with un-repairable DNA is directed to apoptosis by p53 gene. “P53 is a guardian of the genome. Its loss leads to accumulation of damaged DNA may result in malignancy� Loss of p53 is seen in virtually every type of cancer. Over half of human malignant cells show loss of p53 gene by special tests.
Non-lethal Genetic damage lies at the center of carcinogenesis. Loss/damage to suppressor genes, Duplication of promotor genes Loss/damage to Apoptosis genes Loss/damage of DNA repair genes.
Molecular Basis of Neoplasia: Proto-oncogene
Oncogene
Viral Oncogenesis Viruses contribute to the pathogenesis of human malignancies 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. Insertion of viral nucleic acids mutation Alterations in Oncogenes, cancer suppressor genes and genes regulating DNA repair resulting in up-regulation of cell division Carcinogenesis. Human Papilloma Virus Cervical neoplasia – warts, papilloma, ca cx Epstein-Barr virus – Burkitts Lymphoma, Nasopharyngeal ca. Hepatitis B & C virus Hepatocellular carcinoma.
Radiation Carcinogenesis: Ionizing radiation Carcinogenesis can result from ionizing radiation and may develop from 2 different mechanisms; 1. Direct ionization – damages DNA and other molecules can cause direct somatic mutations 2. Secondary effectors such as oxygen radicals can be formed by ionizing radiation. Oxygen free radicals can damage and kill cells and also induce mutations. X Ray workers – Leukemia Radio-isotopes – Thyroid carcinoma Atomic explosion – Skin cancer, Leukemia
Summary DNA damage - loss of control over cell division. Radiation, Chemicals & Viral infections are some known causes of cancers. Cancer evolves in multiple steps by sequentially acquiring different DNA damages. Initiation, Latent stage, Promotion and Malignant transformation are recognizable stages in carcinogenesis. Each character of malignancy depends on unique DNA alteration.
Carcinogenesis Initiation DNA damage eg.Benzpyrene
Promotion Histologic change – eg. Turpentine (co-carcinogens)
Malignant transformation: Visible tumor formation – further DNA damage.
Initiation - point at which an irreversible alteration, usually genetic, is introduced into a target cell. (genotoxicity)=Interaction with DNA
May involve conversion of proto-oncogen to oncogen Initiation:
(1) is essentially irreversible (2) caused only by carcinogenic compounds (3) occurs rapidly after carcinogen exposure (4) alone does not result in tumor formation Several exposures to an initiator may result in tumor without presence of a promoter.
Promotion is the process whereby an initiated tissue or organ develop focal proliferations and it requires the presence of continuous stimulation. A promotor: is a substance which doesn't damage DNA but enhance growth of tumor induced by genotoxic carcinogens e.g.: skin cancer in mice can be induced by application of benzo [Îą ] pyrene ( initiator) followed by phorbol ester from cotton oil ( promoter). Promotion
(1) reversible (2) acts only after exposure to an initiating agent (3) requires repeated administration of a promoter (4) is not carcinogenic in itself
Etiology and Pathogenesis of Neoplasia Initiation and Promotion
Chemical Carcinogenesis In general, chemical carcinogens are electrophiles or can be metabolically converted to electrophiles. (by metabolic activation). These electrophiles can react with nucleophilic centers (predominantly N and O and to some extent S) in cellular macromolecules such as DNA, RNA and protein.
Classification of Carcinogens Genotoxic – Act directly on DNA or expression of DNA during translation. • DNA replication errors. • Point mutations. • Chromosomal aberration.
Epigenetic – Non-DNA reactive. – Potentiators. – Ex.: hormone, immune function modifiers
Genotoxic Carcinogen Chemical capable of producing cancer by directly altering the genetic material of target cells. 1- Direct carcinogens (no metabolic activation). – Alkylating agents. 2-Indirect carcinogens (metabolic activation). – Polycyclic aromatic hydrocarbons. – Aromatic amines. – Nitrosamines. – Natural substances. 3– Inorganic carcinogens. 4- Heavy metals (Ni, Cr, Cd, As).
Epigenetic Carcinogen • Cytotoxic carcinogens. – Nitrillotriacetate, BHA, BHT. • Tumor promotors. – DDT, Dioxin • Hormones. – Estradiol, DES • Immunosuppressants. – Cyclosporin A • Particulates. – Asbestos.
Chemicals Generally Recognized as Carcinogenic in Humans Chemicals Generally Recognized as Carcinogenic in Humans Industrial Exposures Benzidine Vinyl Chloride Certain tars Asbestos
Benzene
Urinary Bladder Liver Skin and Peritoneum (lungs when combined with cigarette smoking) Lymphoid Tissue
Other Exposures Diethylstilbestrol Arsenic Compounds Cigarette Smoke Betal Nut
VaginaI Skin cancer Lungs, urinary tract Buccal Mucosa
Diet & nutrients protecting from cancer : Fruits & vegetables * High level of fibers * Antioxidants which decrease damaging effects caused by free radicals and reactive oxygen species on DNA Examples: a- Tocopherol & β- carotene ( carotenoids), vit C : decrease tumor incidence. b- Tomatos : contain lycopene protect against prostate cancer . c- Green tea : contain polyphenols which act as antioxidants. d- Red grapes : contain resveratrol which acts an antioxidant.
Garlic & onions ( allylsulphide + diallylsulphide) : * They inhibit Cyt P450 ( Phase I) which converts percarcinogents to carcinogens * They activate glutathione-s- transferase ( GSTs ) which help conjugation of carcinogens with cellular GSH ( Phase II)
Cruciferous vegetables : * Eg: Cabbage - broccoli. • They contain dithiol thiones & isothiocyanates which activate phase II enzymes that help eliminating the carcinogen.
Omega 3 fatty acids:
eg : fish oil They crowd other fats replacing them inside the cells , thus preventing their promoter action.
Soy products: * Contain weakly estrogenic isoflavonoids * These isoflavonoids compete with estrogen for its peripheral receptors on breast blocking them , ttt of estrogen – dependant breast cancer ( as tamoxifen ).
Red grapes : * Red grapes contain resveratrol & tumeric contains curcumin. * tumor cells secrete factor that promotes the development of new blood vessels which are necessary for tumor growth ; this process is know as angiogenesis. Resveratrol & curcumin suppress the release of growth factors by the tumor inhibit angiogenesis.
Principle of Treatment Surgical therapy – early stage/debulk Chemotherapy Radiotherapy
Immunotherapy
It is easy to kill cancer cells, but the challenge is keeping the patient alive at the same time‌..!