CARCINOGENIC AGENTS (Chemical, Radiation & Microbial Agents) 06/10/2023Chemical Carcinogenesis * Carcinogenesis is a multistep process; stages of initiation and promotion. Initiation: . Results from exposure of cells to a sufficient dose of a carcinogenic agent. + It causes permanent DNA damage (mutations). P53, RAS Promotion + Induction of tumors to arise from initiated cells, but they are not tumorigenic by themselves. + Ay tion of promoters leads to proliferation and clonal expansion of initiated (mutated) cells. Pe a+ Promoted sub clones of the initiated cells suffer various additional mutations and eventually a cancerous clone with all the hallmark characteristics emerges. Initiation by Chemical Carcinogens + Are highly reactive electrophiles (have electron-deficient atoms) that can react with nucleophilic (electron-rich) atoms in the cell. ° Their targets are DNA, RNA, and proteins + Initiation inflicts non-lethal damage to the DNA that is repaired in some error-prone fashion. . The mutated cell then passes on the DNA lesions to its daughter cells.real* Chemicals that can cause initiation of carcinogenesis fall into two categories: Y Direct acting ¥ Indirect acting.Direct-acting Carcinogens * Do npt require metabolic conversion to become carcinogenic. * Most are weak carcinogens * Some are cancer chemotherapeutic drugs (e.g., alkylating agents) with potential to evoke a second form of cancer, usually acute myeloid leukemia. * The risk of induced cancer is low, but its existence dictates judicious use of such agents.Indirect-Acting Carcinogens + Require metabolic conversion to become active carcinogens (ultimate carcinogens). & * Most chemical carcinogens are of this type. + Examples: the Polycyclic Hydrocarbons —are present in fossil fuels. + Benzo[a]pyrene (the active component of soot) formed during the high-temperature combustion of tobacco in cigarettes and are implicated in the causation of lung cancer. + Polycyclic hydrocarbons: are also produced from animal fats durin, the process of boiling or grilling meats and are present in smoke meats and fish. + Aromatic amines and Azo dyes widely used in the past in the aniline dye and rubber industries. (bladder cancer)Chromium compounds Ethylene oxide Nickel compounds Radon and its decay Vinyl chloride Angiosarcoma, liver ‘Arsenic and arsenic compounds Beryium and beryllium compounds ‘Cadmium and cadmium+ Exposure to aflatoxin B1 by some strains of the mold Aspergillus. That grows on improperly stored grains and nuts. * There is a strong correlation between the die! level of this food contaminant and the incidence of hepatocellular carcinoma in parts of Africa and the Far East. + Vinyl chloride, Arsenic, Nickel, Chromium, Insecticides, Fungicides and Polychlorinated biphenyls. + Nitrites: used as food preservatives. They react with amines contained in the food to form nitroso-amines which are suspected carcinogens.* Most indirect carcinogens are metabolized by cytochrome P-450-dependent monooxygenases. + The genes that encode these enzymes are polymorphic and the activity and inducibility of these enzymes vary significantly among individuals. * The susceptibi ty to carcinogenesis is related in part to the particular polymorphic variants that an individual inherits. * The metabolism of polycyclic aromatic hydrocarbons eg, benzolalpyrene by the product of the P-450 gene, CYP1A1. Approximately 10% of the white populatic Carry a highly inducible form of this gene. + Light smokers with the susceptible CYP1A1 genotype have a sevenfold higher risk of developing lung cancet compared with smokers without the genotype. + Metabolic pathways also are involved in the inactivation (detoxification) of certain procarcinogens or their derivatives, and variation in these pathways also may influence cancer risk.Radiation Carcinogenesis + Mutagenic and carcinogenic forms of radiant energy are: VUV Rays of Sunlight: ¥ Ionizing Radiation from medical or occupational exposure, nuclear plant accidents, and atomic bomb detonations ¥ Particulate Radiation. + UV Light Exposure:, causes skin cancers . donizing radiation exposure is associated with a variety of cancers e.g, Breast Cancer. They may arise decades later, and long periods observation are necessary to ascertain its full effect. + Radiation may have additive or synergistic effects with other potentially carcinogenic factors.Ultraviolet Rays (from the sun) + Exposure to UV rays particularly in fair-skinned individuals, is associated squamous cell carciriomia, basal cell carcinoma, and melanoma of the skin. + The degree of risk depends on the type of UV rays, the intensity of eyposure, and skin pigmentation (quantity of light absorbing mélanin in the skin) + Locations receiving a great deal of sunlight (e.g., Queensland, Australia, close to the equator) have the highest incidencé of skin cancers in the world. + The UV portion of the solar spectrum can be divided into three wavelength ranges: UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280'nm). * UVB is responsible for the induction of cutaneous cancers. * UVC is also potent mutagen, but is filtered out by the ozone layer surrounding the earth (hence concerns about ozone depletion):Mechanism of Carcinogenesis in UVB Light Exposure + Absorption of the energy in a photon of UV light by DNA produces a chemical reaction that leads to covalent cross-linking of pyrimidine bases. * This distorts the DNA helix and prevents proper pairing of the dimer with bases in the opposite DNA strand. * This overwhelms the capacity of the nucleotide excision repair pathway and error-prone non-templated DNA repair mechanisms become operative. * These allow the cell to survive but also introduce mutations that, lead to cancer.* The importance of the nucleotide excision repair pathway of DNA repair is most graphically illustrated by the high frequency of cancers in In the hereditary disorder xeroderma pigmentosumIonizing Radiation + Electromagnetic (x-rays, y rays) + Particulate (a particles, B particles, protons, neutrons) radiations + X-rays have been associated with ; skin cancers. * Atomic bombs dropped on Hiroshima and Nagasaki; Initially there was a marked increase in the incidence of certain forms of leukemia after an average latent period of about 7 years. * Subsequently the incidence of many solid tumors with longer latent periods (e.g., carcinomas of the breast, colon, thyroid, and Tung) increased. * Children who get two or three CT scans have a threefold higher risk of leukemia, and those who receive five to 10 such scans havea threefold higher risk of brain tumors. + The overall risk in children is very low (roughly one excess leukemia and one excess brain tumor over 10 yéars per 10,000 CT scans).* In humans there is a hierarchy of tissue vulnerability to radiation-induced cancers. * Most frequent: Myeloid leukemias, Cancer of the thyroid follows closely but only in young patients. + Intermediate category: Cancers of the breast, lungs, and salivary glands. + Relatively Resistant Tissues: skin, bone, and the gastrointestinal tract. * However, any cell can be transformed into a cancer cell by sufficient exposure to radiant energy.* lonizing radiation causes chromosome breakage, chromosome rearrangements, and, less frequently, point mutations, any of which may affect cancer genes and thereby drive carcinogenesis.in humans there is a hierarchy of tissue vulnerability to adiation-induced cancers. lost frequent Myeloid leukemias, Cancer of the thyroid follows Hlosely but only in young patients. niterinediate, category: Cancers of the breast, lungs, and salivary ands. elatively Resistant Tissues: skin, bone, and the gastrointestinal ‘act. lowever, any cell can be transformed into a cancer cell by sufficient exposure to radiant energy.Microbial Carcinogenesis Human Oncogenic viruses * Oncogenic human RNA viruses e.g. HTLV-1 * Oncogenic human DNA viruses e.g. polyomavirus, human herpesvirus 8 (HHV8, also called Kaposi sarcoma herpesvirus) Polyomavirus is associated with Merkel cell carcinomas Human Oncogenic bacteria + Helicobacter pylori in gastric cancer.Human T-Cell Leukemia Virus Type 1 (HTLV-1) * HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL) * HTLV-1 has tropism for CD4+ T cells; this subset of T cells is the major target for neoplastic transformation. + Transmission is through transfer infected T cells via sexual intercourse, blood products or breastfeeding. * Leukemia develops in only 3% to 5% of the infected individuals, typically after a long latent period of 40 to 60 years.* The HTLV-1 genome contains the gag, pol, env, and two other additional genes (not in retroviruses) referred to as tax and HBZ. * Mechanisms are unclear but it is thought that protein products of these genes (Tax and HBZ) alter the transcription of host cell genes and also interact with certain host cell signaling proteins. * Characterized by typical latency period of many decades between infection and the development of leukemia, which appears in only a small subset of infected individuals.* The HTLV-1 genome contains the gag, pol, env, and two other additional genes (not in retroviruses) referred to as tax and HBZ. * Mechanisms are unclear but it is thought that protein products of these genes (Tax and HBZ) alter the transcription of host cell genes and also interact with certain host cell signaling proteins. * Characterized by typical latency period of many decades between infection and the development of leukemia, which appears in only a small subset of infected individuals.Human Papillomavirus (HPV) + At least 70 genetically distinct types of HPV have been identified. + Low Risk HPV genotypes e.g., 1, 2, 4, 7, 6 and 11) cause benign neoplasms e.g Squamous papillomas (Warts), genital warts are associated with HPV-6 an -11. * High-risk HPVs (eB. ‘pes 16 and 18): Squamous cell carcinomas of the cervix, Anal, Valvular, agin: enile and Head and Neck (particularly tumors arising in the tonsillar mucosa). * These cancers are sexually transmitted diseases caused by chronic HPV infection. + Ahigh proportion of women infected with HPV clear the infection by immunologic mechanisms, but others do not because of acquired imrnune abnormalities ¢.g, HIV infection, or for unknown reasons. + Women who are coinfected with high-risk HPV types and HIV have an elevated risk of cervical cancer.+ In benign warts, the HPV genome is maintained in a non-integrated episomal form + Incancers the HPV genome is integrated into the host genome. + Integration leads to expression of the HPV E6 and E7 genes, which are responsible for the oncogenic potential of HPV Oncogenic activities of E6. » E6 from high risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types. + The E6 protein binds to degrades p53. + It also stimulates the expression of telomerase reverse transcriptase (TERT) that contributes to the immortalization of cells.Oncogenic activities of E7. + E7 proteins from high-risk HPV types have a higher affinity for RB than do E7 proteins from low-risk HPV types * The E7 protein effects centered on the G1/S cell cycle checkpoint. + E7 protein binds to the RB protein and displaces the E2F transcription factors . This promotes progression through the cell cycle. ¢ E7 also inactivates the CDK inhibitors p21 and p27. + E7 proteins also bind and presumably activate cyclins A and E.Epstein-Barr Virus (EBV) + EBV was the first virus linked to a human tumor, Burkitt lymphoma. + The most common EBV-associated tumors are Lymphomas derived from B cells and Nasopharyngeal Carcinoma. . + Exposure to the virus occurs through saliva. + EBV has surface glycoproteins that recognize and bind to CD21 receptor that allows the virus to attach to and infect B cells. + Viral infection of B cells is latent (there is no viral replication) and the cells are not + EBV proteins are expressed in latently infected B cells that allow the cells to grow indefinitely (immortalization). + Genes involved in the carcinogenesis: Latent Membrane protein-1 (LMP- 1), EBNA-2 gene and vIL-10 gene* Latent Membrane Protein-1 (LMP-1): Behaves like a constitutively active cpap peceptor (a key recipient of helper T-cell signals) that stimulate B-cell growth. + LMP-1 activates the NF-KB and JAK/STAT signaling pathways and promotes B-cell survival and proliferation, + LMP-1 also prevents apoptosis by activating BCL2. + EBNA-2 gene: , encodes a nuclear protein that mimics a constitutively active Notch receptor. + EBNA-2 transactivates several host genes e.g. cyclin D and proto- oncogenes. + DIL-10, gene: Encodes a homologue of IL-10 , It suppresses the activation of T cells by macrophages and contributes to EBV-dependent transformation of B cells.Burkitt Lymphoma + Is a neoplasm of B lymphocytes + Endemic Type: Endemic in central Africa and New Guinea, areas where it is the most common tumor of childhood. * Sporadic Type: A mo hologically identical but occurs sporadicalh throughout fre world. dP Bmeay P cay . There is a strong association between Endemic Burkitt Lymphoma ane . * More than 90% of endemic tumors carry the EBV genome. + All affected patients have elevated antibody titers against viral capsid antigens. + Serum antibody titers against viral capsid antigens are correlated with the risk of developing the tumor+ EBV is not directly ncogenic. It acts as a pelyclonal B-cell mitogen sets the stage for the acquisition of the (8;14) translocation and other mutations that ultimately produce a full-blown cancer. + In most individuals, EBV infection is readily controlled by effective immune responses and lymphomagenesis is rare. + In regions where Burkitt lymphoma is endemic, cofactors such as chronic malaria may favor the acquisition of additional genetic events {e.g,, t(8;14)} that lead to transformation. + Virtually all endemic and sporadic tumors possess the t(8;14) or other translocations that dysregulate MYC. + Although sporadic Burkitt lymphomas are triggered by mechanisms other than EBV, they develop through similar oncogeriic pathways.EXPANSION OP B- me — i (MC translocation) ee INCREASED } mye. ay PROTEIN naNasopharyngeal carcinoma + Also strongly associated with EBV. + All nasopharyngeal carcinomas obtained from all parts of the world contain EBV, and antibody titers to viral capsid antigens are uniformly elevated in affected patients. + LMP-1 is expressed in nasopharyngeal carcinoma cells and (as in B cells) activates the NF-«B pathway, which upregulates the expression of factors such as VECE, FGF-2, MMPS, and COX-2 that may contribute to oncogenesis. . Nasopharyry eal carcinomas typically contain prominent infiltrates composed of T cells, which may be responding to viral antigens such as LMP-1.Hepatitis B and C Viruses. + Worldwide, 70% to 85% of hepatocellular carcinomas are associated with infection with HBV or HCV. + Oncogenes have yet to be identified in HBV or HCV genomes. * The dominant effect seems to be immunologically mediated chronic inflammation and hepatocyte death leading to hepatocyte proliferation during regeneration and, over time, genomic damage. + Chronic viral infection leads to the compensatory proliferation of hepatocytes. * Growth factors, cytokines, chemokines, and other bioactive substances are produced by activated immune cells and promote cell survival, tissue Temodeling, and angiogenesis. + The activated immune cells also produce other mediators, such as reactive oxygen species, that are genotoxic and mutagenic.Helicobacter Pylori + Implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas. + Strains associated with gastric adenocarcinoma contain cytotoxin-associated A (CagA) gene. + CagA protein penetrates into gastric epitieliat cells, where it initiates a signaling cascade that mimics unregulated growth factor stimulation. + The infection initially leads to chronic gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer. * This sequence takes decades to complete and occurs in only 3% of infected patients. oH. pylori is also associated with the development of gastric lymphomas of B-cell origin.+ It is thought that H. py lori.infection leads to the appearance of H, vylori-reactive T cells, which in turn stimulate a polyclonal B-cell proliferation. + These cells grow out into a monoclonal MALToma that remains dependent on T-cell stimulation of B-cell pathways that activate the transcription factor NF-«B. + Eradication of H. pylori by antibiotic therapy “cures” the lymphoma by removing the aritigenic stimulus for T cells. + Additional mutations may be acquired that cause constitutive NF-«B activation. + At this point, the MALToma no longer requires the antigenic stimulus of the bacterium for growth and survival and develops the capacity to spread beyond the stomach to other tissues.