Etiology of Cancer PDF

 Etiology of Cancer CARCINOGENIC AGENTS Carcinogenic agents inflict genetic damage, which lies at the heart of carcinogenesis. classes of Radiant Microbial carcinogenic Chemicals...

 Etiology of Cancer CARCINOGENIC AGENTS Carcinogenic agents inflict genetic damage, which lies at the heart of carcinogenesis. classes of Radiant Microbial carcinogenic Chemicals products energy agents Chemical Carcinogens 1-Direct-acting agents require no metabolic 2- The designation indirect-acting refers to chemicals that require metabolic conversion to become carcinogenic. conversion to an ultimate carcinogen They are typically weak carcinogens but Some of the most potent indirect chemical are important because some of them are carcinogens are polycyclic hydrocarbons that are cancer chemotherapy drugs (e.g., alkylating created with burning of fossil fuels, plant, and animal agents) material. For example Can evoke a subsequent second form of -benzo[a]pyrene and other carcinogens formed during cancer usually leukemia. the combustion of tobacco are implicated in the The associated risk for induced cancer is causation of lung cancer low -benzo[a]pyrene created during the burning of coal was likely responsible for the high incidence of scrotal cancer in chimney sweeps. Major 2-Procarcinogens 1-Direct-Acting That Require Chemical Carcinogens Metabolic Carcinogens Activation Polycyclic and Heterocyclic Alkylating Agents Acylating Agents Aromatic Hydrocarbons β-Propiolactone 1-Acetyl-imidazole Benz(a)anthracene Benzo(a)pyrene Dimethyl sulfate Dimethylcarbamyl Dibenz(a,h)anthracene Diepoxybutane chloride 3-Methylcholanthrene Anti-cancer drugs 7,12-Dimethylbenz(a)anthracene (cyclophosphamide, chlorambucil, nitrosoureas, and others)  aromatic amines Polycyclic hydrocarbons benzo[a]pyrene β-naphthylamine and azo dyes may be produced from In the body, It is metabolized to was responsible for a 50- constitute indirect-acting epoxides which form covalent fold increased incidence of animal fats during the carcinogens. adducts (addition products) bladder cancers in heavily process of broiling meats with molecules in the cell, and are present in smoked exposed workers in the principally DNA, but also with meats and fish. aniline dye and rubber RNA and proteins industries. Aflatoxin B1 =Aflatoxin B1 Nitrites Vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, is a naturally occurring A strong correlation has used as food preservatives and polychlorinated agent produced by some been found between the since they cause nitrosylation biphenyls strains of Aspergillus, a dietary level of this food of amines contained in food contaminant and the mold that grows on producing nitrosamines that incidence of hepatocellular are suspected to be improperly stored grains are potential carcinogens in the carcinoma in some parts of carcinogenic and nuts workplace and about the house Africa and the Far East. Mechanisms of Action ofChemical Carcinogens Most chemical carcinogens are mutagenic. All direct carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA, as well as with proteins and RNA. Any gene may be the target of chemical carcinogens as RAS and T53 Aflatoxin B1 produce characteristic mutations in T53 Carcinogenicity of some chemicals is augmented by subsequent administration of promoters (e.g., phorbol esters, hormones, phenols, certain drugs Repeated or sustained exposure to the promoter must follow the application of the mutagenic chemical, or initiator The application of an initiator causes the mutational activation of an oncogene such as RAS Subsequent application of promoters leads to clonal expansion of initiated (mutated) cells Induction of proliferation of the initiated clone of cells causes additional mutations developing eventually into a malignant tumor. Radiation Carcinogenesis Sources of Radiation: Includes UV rays, X-rays, nuclear accidents, and radionuclides, all of which are proven to cause cancer. Examples of Radiation Effects: Miners: Unprotected miners of radioactive materials have a 10-fold increased risk of lung cancer. Hiroshima & Nagasaki Survivors: Increased leukemia incidence after 7 years and higher rates of thyroid, breast, colon, and lung cancers. Chernobyl Accident: Long-term increase in cancer incidence in surrounding areas due to nuclear power accident Therapeutic Irradiation: Head and neck radiation can lead to papillary thyroid cancer years later. Mechanisms of Cancer Induction by Radiation : Causes DNA damage (e.g., chromosome breaks, rearrangements, and point mutations). Double-stranded DNA breaks are the most critical type of damage. UV Radiation from the sun: Nonmelanoma Skin Cancer: (such as squamous cell carcinomas, and basal cell carcinomasAssociated with cumulative UV exposure. Melanoma: Linked to intermittent intense UV exposure (e.g., sunbathing). UV radiation forms pyrimidine dimers, repaired by the nucleotide excision repair pathway. Overwhelming exposure overwhelms repair mechanisms, leading to skin cancer. Genetic Conditions: Xeroderma Pigmentosum: A defect in the nucleotide excision repair pathway, significantly increasing the risk of UV-induced skin cancers. Viral and Microbial Oncogenesis 1- Oncogenic RNA Viruses Human T-cell leukemia virus type 1 (HTLV-1): Causes adult T-cell leukemia/lymphoma (ATLL), endemic in Japan, the Caribbean, South America, and Africa. Approximately 15-20 million people worldwide are infected, but only 3-5% develop leukemia, often after a long latency period (40-60 years). Targets CD4+ T cells and spreads via sexual contact, blood products, or breastfeeding. Unique Features of HTLV-1: HTLV-1 lacks an oncogene, but viral integration shows a clonal pattern, indicating its involvement in transformation. Contains the tax gene, encoding the Tax protein, which is crucial for viral replication and transformation Although the site of viral integration in host chromosomes is random the site The HTLV-1 genome contains the gag, of integration is identical within all cells of a given cancer. pol, env, and longterminal-repeat This would not occur if HTLV-1 were merely a passenger that infects cells after regions typical of all retroviruses transformation In contrast to other leukemia viruses It means that HTLV-1 must have been present at the moment of it also contains another genereferred transformation placing it at the “scene of the crime.” to as tax Mechanisms of Tax-Induced Transformation: 4. Induces genomic 1. Promotes survival and 2. Drives cell cycle 3. Activates the instability: growth: progression: transcription factor NF-κB: Interferes with DNA repair and Interacts with PI3 kinase, Upregulates the expression Promotes lymphocyte inhibits cell cycle checkpoints, stimulating pathways that cyclin D and represses CDK survival. activated by DNA damage enhance cell survival and inhibitors. leading to highly aneuploid metabolism. leukemias. 2. Oncogenic DNA Viruses 1-Human papilloma virus (HPV) 1. Human papilloma virus (HPV) HPV has been associated with: 1- Benign squamous papilloma (warts) 2. Epstein-Barr virus (EBV) (HPV 1,2,4,7) Kaposi sarcoma herpesvirus (KSHV, 2- Genital warts (HPV 6,11) 3. also called human herpesvirus-8 [HHV-8]) 2- Cervical cancer (HPV 16 & 18). 4. Polyoma virus called Merkel cell virus 3- Oropharyngeal cancer. 5. Hepatitis B virus (HBV) Depends on two viral oncoproteins, E6 and E7, particularly from high-risk HPV types. E6 Protein: E7 Protein: 1. Binds to and degrades p53. 1. Binds to RB, and displaces E2F 2. Activates telomerase, transcription factors and contributing to cellular promoting the cell cycle. immortalization. 2. Inhibits CDK inhibitors (p21 3. E6 from high-risk HPV has a and p27) and activates cyclins E stronger affinity for p53 than and A. low-risk HPV. 3. E7 from high-risk HPV has a stronger affinity for RB than low- risk HPV. Outcome of HPV Infection: High-risk HPVs inactivate RB and p53, drive cell cycle progression, and prevent senescence. Infection alone is insufficient for cancer; additional mutations in host genes (e.g., RAS) are required. The effectiveness of HPV vaccines confirms the role of HPV in cervical cancer prevention.