Carcinogenesis PDF

Carcinogenesis AP DR MIE MIE SEIN MBBS BLOCK 1 Learning outcomes 1. Define carcinogenesis and carcinogens.(C2) 2. Correlate the role of chemicals in human carcinogenesis with examples. (C3) 3. Correlate the role of virus in human carcinogenesis with examples. (C3) 4. Correlate the role of radiant en...

Carcinogenesis AP DR MIE MIE SEIN MBBS BLOCK 1 Learning outcomes 1. Define carcinogenesis and carcinogens.(C2) 2. Correlate the role of chemicals in human carcinogenesis with examples. (C3) 3. Correlate the role of virus in human carcinogenesis with examples. (C3) 4. Correlate the role of radiant energy in human carcinogenesis with examples. (C3) 5. State the hormones, mycotoxins, and parasites associated with carcinogenesis. (C1) 6. Explain the role of host factors in carcinogenesis with examples. (C2) Manipal University College Malaysia 2 Carcinogenesis Carcinogenesis is the process that results in the transformation of normal cells to neoplastic cells by causing permanent genetic alterations. Transformed by cumulative mutational events Clonal proliferations Manipal University College Malaysia 3 Carcinogen A carcinogen is an environmental agent participating in the causation of tumours. Carcinogenic Oncogenic Mutagenic The ultimate site of action of all carcinogens is the DNA in which genes are encoded More than one carcinogen is necessary for the complete neoplastic transformation of a cell Manipal University College Malaysia 4 Chemical carcinogenesis Major classes include polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines, azo dyes, alkylating agent Some agents act directly, requiring no metabolic conversion (direct-reacting carcinogens) Indirect-reacting carcinogens (procarcinogens) require metabolic conversion into active ultimate carcinogens. Manipal University College Malaysia 5 1. Chemical carcinogens and associated tumours Chemical Tumour Polycyclic aromatic hydrocarbons Lung cancer Comments Strong link with smoking e.g. 3,4 -benzpyrene Skin cancer Repeated exposure to mineral oils Aromatic amines Bladder cancer Rubber and dye workers e.g. beta-naphthylamine Nitrosamines Azo dyes Gut cancers Bladder and liver cancer Proven in animals Proven in animals e.g. 2-acetylaminofluorene Alkylating agents Leukemia Small risk in humans e.g. cyclophosphamides Other organic chemicals Liver angiosarcoma Used in polyvinyl chloride manufacture e.g. vinyl chloride Manipal University College Malaysia 6 2. Types of carcinogens (a) Direct-reacting carcinogens do not require metabolic conversion to become carcinogenic. Most are weak carcinogens, but some are important because they are cancer chemotherapeutic drugs (e.g., alkylating agents). Tragically, in some instances these agents have cured, controlled, or delayed recurrence of certain types of cancer (e.g., leukemia, lymphoma, or breast carcinoma), only to evoke a second form of cancer, usually acute myeloid leukemia. (b) Indirect-reacting carcinogens require metabolic conversion from procarcinogens to active ultimate carcinogens. e.g, a mucosal glucuronidase in the urinary bladder converts β-naphthylamine glucuronide to the carcinogen β-naphthylamine. Manipal University College Malaysia (MUCM) 7 3. Stages of chemical carcinogenesis (a) Initiation is the first critical carcinogenic event, and it is usually a reaction between a carcinogen and DNA. Two or more agents (e.g., chemicals, viruses, radiation) may act together as cocarcinogens. (b) Promotion is induced by a stimulator of cell proliferation and enhances the carcinogenic process. A promoter is not a carcinogenic in itself but enhances other agents’ carcinogenicity. Manipal University College Malaysia 8 General schema of events in chemical carcinogenesis Promoters cause clonal expansion of the initiated cells → a preneoplastic clone Further proliferation induced by the promoter or other factors causes accumulation of additional mutations and emergence of a malignant tumor. Source: Robbins and cotran pathologic basis of disease Manipal University College Malaysia (MUCM) 9 Viral carcinogenesis Many human tumours are now known to be associated with viruses. Common in young people Immunosuppression favours viral oncogenesis Manipal University College Malaysia 10 Virus types (a) DNA viruses These viruses integrate viral DNA into host genomes, perhaps resulting in host cell expression of viral mRNA coding for specific proteins. Examples include human papillomavirus, Epstein-Barr virus, and hepatitis B virus as prominent suspects that play a role in human carcinogenesis. (b) RNA viruses Retroviruses are marked by transcription of viral genomic RNA sequences into DNA by action of viral reverse transcriptase. HTLV-1 (RNA virus) that play a role in Adult T-cell leukemia/lymphoma. Manipal University College Malaysia 11 Viruses implicated in human tumours Virus Human papillomavirus Epstein-Barr virus Tumour Common wart (squamous cell carcinoma) Comments Benign, spontaneously regressing (HPV 6 or 11) Cervical carcinoma Strong association with high-risk HPV types 16 and 18) Requires a cofactor. Probably malaria in Africa Burkitt lymphoma Nasopharyngeal cancer Hepatitis B&C viruses Human herpes virus-8 Hepatocellular carcinoma Kaposi sarcoma Strong association Association between sexually acquired AIDS and Kaposi sarcoma Lymphoma Human T-cell lymphotropic virus-1 Markel cell polyoma virus Manipal University College Malaysia Adult T cell leukemia/lymphoma Merkel cell carcinoma of skin Endemic in Southern Japan and Caribbean basin strong association (80% cases) 12 Radiation carcinogenesis UV rays of sunlight or as ionizing electromagnetic and particulate radiation, is mutagenic and carcinogenic. UV light exposure causes skin cancers Ionizing radiation exposure from medical or occupational exposure, nuclear plant accidents, and atomic bomb detonations is associated with a variety of cancers. Manipal University College Malaysia (MUCM) 13 Ultraviolet rays Exposure to UV rays derived from the sun, particularly in fair-skinned individuals, is associated with an increased incidence of squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin. Manipal University College Malaysia (MUCM) 14 Ionizing radiation Electromagnetic (x-rays, γ rays) and particulate (α particles, β particles, protons, neutrons) radiations are all carcinogenic. follow-up of survivors of the 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 lung) 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 have a threefold higher risk of brain tumors. Manipal University College Malaysia (MUCM) 15 Hormones Exogenous estrogen: mammary and endometrial carcinoma Androgenic and anabolic steroids: Hepatocellular carcinoma Manipal University College Malaysia 16 Bacteria, fungi , parasites and miscellaneous carcinogens Bacteria: Helicobacter pylori – MALT Lymphomas (mucosa- associated lymphoid tissue Lymphomas) and gastric adenocarcinoma Fungi: Mycotoxins are toxic substances produced by fungi. aflatoxins produced by Aspergillus flavus - hepatocellular carcinoma Parasites: Schistosoma haematobium - bladder cancer formation liver flukes Opisthorchis viverrini and Clonorchis sinensis –cholangiocarcinoma Miscellaneous: Asbestos- malignant mesothelioma and carcinoma of the lung Manipal University College Malaysia 17 Host factors in carcinogenesis Race Skin cancer is uncommon in blacks because the melanin in the skin protects them from the carcinogenic effects of ultraviolet sunlight Diet and obesity high dietary fat, red or processed meat - colorectal cancers alcohol - breast and oesophageal cancer smoking – CA lung, liver, bladder, colon and rectum obesity – breast and ovarian cancer Manipal University College Malaysia (MUCM) 18 Inherited predisposition: Increased predisposition to breast cancer occurs in women inheriting mutant BRCA1 (chromosome 17) or BRCA2 (chromosome 13) genes. Adenomatous polyposis coli is an autosomal dominantly inherited predisposition to develop multiple adenomatous polyps of the large bowel due to mutant APC gene (chromosome 5) with an increased risk (almost 100%) of carcinoma of the colon and rectum Age: The incidence of cancer increases with age Sex: Breast cancer is at least 200 times commoner in women than in men Manipal University College Malaysia (MUCM) 19 Premalignant lesions and conditions: -adenomatous polyps of the colon and rectum, and epithelial dysplasia in various sites notably the cervix (CIN) -chronic ulcerative colitis- there is an increased risk of colorectal cancer Transplacental exposure: vaginal clear cell adenocarcinoma (the carcinogen, diethylstilbestrol, was administered to the mother, but the carcinogenic effect was exhibited only in the child resulting from the pregnancy, when she reached young adulthood) Manipal University College Malaysia (MUCM) 20 References: Robbins and Cotran Pathologic Basis of Disease 10th Edition Underwood’s pathology: A clinical approach 7th edition Manipal University College Malaysia 21 Thank you Manipal University College Malaysia 22