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 non-carcinogenic 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.

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): 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 Heredity Radiation V-Onc Other Chemical 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 Disrupt normal host genes required for control of cell growth and division (Alterations in Oncogenes, cancer suppressor genes and genes regulating DNA repair resulting in up-regulation of cell division  Carcinogenesis). Alternatively, viral infection may result in immune dysfunction, leading to decreased immune surveillance for early tumors. 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.

Summary of Carcinogenesis Initiation DNA damage eg.Benzpyrene Promotion Histological change – eg. Turpentine (co-carcinogens) Malignant transformation: Visible tumor formation

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 [α ] 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- Ni, Cr, Cd, As.

Epigenetic Carcinogen Cytotoxic carcinogens. – Nitrillotriacetate, BHA, BHT. • Tumor promotors. – DDT, Dioxin • Hormones. – Estradiol, DES • Immunosuppressants. – Cyclosporin A • Particulates. – Asbestos.

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 Industrial Exposures Benzidine Urinary Bladder Vinyl Chloride Liver Mesenchyme Certain tars Skin and Asbestos Peritoneum (lungs when combined with cigarette smoking) Benzene Lymphoid Tissue Other Exposures Diethylstilbestrol VaginaI Arsenic Compounds Skin cancer Cigarette Smoke Lungs, urinary tract Betal Nut Buccal Mucosa

Natural Foods May Contain Anticarcinogens»»Vitamins, Antioxidants 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

b- Tomatos : contain lycopene protect against prostate cancer . 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)

eg : fish oil 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…..!