Carcinogenesis Lecture 7 PDF

Carcinogenesis Lecture 7 22/3/2020 by Dr. Ghada Samy  Carcinogenesis Carcinogenesis: Is the process through which cancer develops. Chemical carcinogenesis: Study of the mechanisms through which chemical carcinogens induce cancer, & con...

Carcinogenesis Lecture 7 22/3/2020 by Dr. Ghada Samy  Carcinogenesis Carcinogenesis: Is the process through which cancer develops. Chemical carcinogenesis: Study of the mechanisms through which chemical carcinogens induce cancer, & conducting experiments to identify a potential human carcinogen. Is only a tissue swelling, the term is now used as a synonym Tumor for a neoplasm A new or autonomous ↑ growth of abnormal tissue Neoplasm or uncoordinated with normal tissue, & persists after cessation tumor of the stimuli that evoked it. There are 2 types of neoplasms: benign & malignant Lesions characterized by general slow growth, don’t invade i) Benign surrounding tissues & no metastases Lesions characterized by slow to rapid invasive growth, ii) Malignant infiltrating into surrounding tissues & metastases Metastases 2ry growths derived from a 1ry malignant neoplasm Is a type of a neoplasm or tumor, it is used as the general Cancer name for a malignant neoplasm Physical or chemical agent that causes or induces neoplasm. Carcinogen It has 2 classes: i) Genotoxic Carcinogens that interact with DNA resulting in mutation Carcinogens that modify gene expression, but don’t damage ii) Nongenotoxic DNA 2  Cancer Cancer is one of the leading causes of death in the world Cancer is characterized by: 1. Uncontrolled growth of an abnormal cell 2. Tissue invasion & metastasis 3. Mutation & proliferation 4. Incidence of most cancers ↑ with age Terminology of Cancer Suffix for tissue of origin + type of neoplasm Tissue of origin benign malignant Suffix √ “oma” + “oma” Epithelial cells Adenoma Carcinoma Example 1 Liver cell Hepatocellular Liver adenoma carcinoma Mesenchymal cells oma Sarcoma Example 2 Bone Osteoma Ostoesarcoma Example 3 Melanocytes Melanoma Blood - forming cells: Leukemia Example 4  Hematopoietic  Lymphoid Lymphomas Stem cells Blastoma Example 5  Retina Retinoblastoma  Glia Glioblastoma  Neurons Neuroblastoma Example 6 Mesothelium Mesothelioma 3 Incidence of human cancer Causes of Cancer 4  Carcinogens 1. DNA-damaging agents (genotoxic) Types of Carcinogens - Chemicals: e.g: Benzene , Asbestos, Cigarette Smoke, Arsenic compounds - Viruses: e.g: Hepatitis B & C, HIV type I - Radiation: e.g: UV & X-ray radiations & Radioisotopes: (Radium-containing paints & Radioactive I2) Classes of carcinogens associated with carcinogenesis, according to their mutagenicity: 1. DNA damaging agents (genotoxic) Carcinogens that produce permanent alterations to DNA of the host, resulting in mutation 2. Epigenetic agents (nongenotoxic) Carcinogens that are not mutagenic & don't damage DNA. They alter or modify expression of certain genes, or interact with signal pathways that affect cellular events related to proliferation, differentiation, or apoptosis 5  1. DNA-damaging agents (genotoxic) 1. Direct-acting carcinogens: Agents that can directly bind to DNA without metabolic change to be activated. They are highly reactive electrophilic molecules that can interact with & bind to nucleophiles Example: Mustard gases, arsenic, benzene 2. Indirect-acting carcinogens: Procarcinogen require metabolic activation → ultimate carcinogen at target tissue that covalently binds to DNA Procarcinogen: The parent compound Proximate carcinogen: Intermediate metabolite Ultimate carcinogen: Final metabolite that reacts with DNA Examples: Dimethylnitrosamine, Benzo[a]pyrene, Aflatoxin B1, Azo dyes 2. Epigenetic agents (nongenotoxic) Epigenetic agents can be divided into four major categories: Hormones: e.g: Estrogens Immunosuppressive xenobiotics: e.g: Azathioprine & Cyclosporin A Solid state agents: e.g: Plastic implants & Asbestos Tumor promoters in rodent models: e.g: Peroxisome proliferators (ex: fenofibrate), TCDD & Phenobarbital 6  Co-carcinogenesis A co-carcinogen is an agent that enhances effects of genotoxic carcinogens when given simultaneously & results in significantly higher tumor yields than with carcinogen alone. They may act by: a) ↑ concentration of initiator or genotoxic carcinogen b) May inhibit rate of DNA repair, or may enhance conversion of DNA lesions to permanent alterations c) ↑ concentration of reactive metabolite. This can be achieved either by: i) ↑ absorption or bioactivation of carcinogen, via GIT or skin. ii) ↓ elimination of initiator either by inhibiting detoxification enzymes or by depleting endogenous substrates involved in metabolism, such as glutathione. Examples: Silicon dioxide dust in combination with benzo(a)pyrene is cocarcinogenic for carcinoma of larynx, trachea, & lungs in experimental animals Catechols in tobacco smoke (which contains ↓ amount of genotoxic carcinogens), may cause its marked carcinogenicity Uranium dust exposure has a synergistic effect on formation of lung tumors among cigarette smokers Asbestos exposure in workers, who are also smokers, causes Lung carcinoma 7 General aspects of chemically-induced carcinogenesis 8  Stages of Carcinogenesis (The initiation/promotion model of chemical carcinogenesis in experiments) 1. Initiation ↓ 2. Promotion ↓ 3. Progression 9  Characteristics of the Stages of Carcinogenesis Initiation Promotion Progression Modification is not sufficient for neoplastic formation Conversion of preneoplastic Clonal expansion of initiated cells to lesions into neoplastic Requires cell division for produce preneoplastic lesion (benign → malignant) “fixation” Genotoxic Non genotoxic Genotoxic DNA modification No direct DNA modification DNA modification Mutation No direct mutation Mutation Single exposure to initiating agent can Require prolonged exposure to May require single or more induce mutation promoters treatment Irreversible Reversible Irreversible Promoters aren’t usually electrophiles, do not bind to DNA & aren’t carcinogenic Initiating agents are electrophiles Must be given repetitively after or are metabolically activated to initiating agent to ↑ cancer incidence electrophiles, which bind to DNA Examples of promoters: Reactive Oxygen Species (ROS) Must be before promoters Polycyclic aromatics (e.g. Dioxin) Estrogens Phenobarbital DDT 10