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Toxicology Slide 2 Cancer Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. Slide 3 Tumor or tumour is the name for a swelling or lesion formed by an abnormal growth of cells (termed neoplastic).Tumor is not synonymous with cancer. A tumor can be benign, pre-malignant, malignant, whereas cancer is by definition malignant. Neoplasm Neoplasm is an abnormal mass of tissue as a result of neoplasia. Slide 4 Benign tumor are not cancerous. They can often be removed, and, in most cases, they do not come back. Cells in benign tumors do not spread to other parts of the body. Malignant tumors are cancerous. Cells in these tumors can invade nearby tissues and spread to other parts of the body. The spread of cancer from one part of the body to another is called metastasis. Slide 5 Slide 6 Oncogenes An oncogene is mutated form of proto-oncogene. Proto-oncogenes code for proteins that help to regulate cellular growth and differentiation. Many abnormal cells normally undergo a programmed form of death (apoptosis). Activated oncogenes can cause those cells to survive and proliferate. Most oncogenes require an additional step, such as mutations in another gene, or environmental factors, such as viral infection, to cause cancer. RAS, WNT, MYC, ERK, TRK. HER2/neu Products of oncogenes (Growth factor, Receptors, cytoplasmic kinases, Transcription factors, signal transduction) Slide 7 Tumor suppressor gene A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. The gene codes for Inducer of differentiation Cell adhesion molecules Inhibitor of cellular proliferation Transcription factors Inhibitors of angiogenesis BRCA1, APC, p53 Slide 8 p53 Associated with over 50% of human cancer. DNA repair, apoptosis and regulation of cell division. Coding of enzyme that are imp for DNA repair, apoptosis and regulation of cell division. p53 is guardian of genome. Mutated p53 gene can be inherited. The name p53 is in reference to its apparent molecular mass:(53kDa). The p53 gene can also be damaged in cells by mutagens (chemicals, radiation, or viruses). Slide 9 p53 pathway Slide 10 Characteristics of cancer cell The malignant phenotype refers to structural, functional and behavioral differences in the cells of malignant neoplasm. Loss of contact growth inhibition Autonomy of proliferation Avoidance of apoptosis Aberrant differentiation Induction of angiogenesis Slide 11 Characteristics of cancer cell Tumor can be grade from 1 to 4 that corresponds to its degree of malignancy. Microscopic view of malignant cell Large nucleus Prominent nucleoli Irregularities of chromosomes Production of embryonic proteins (Alpha-fetoprotein and carcinoembryonic antigen). Slide 12 Slide 13 Dysplasia "malformation", is a term used in pathology to refer to an abnormality of development. Slide 14 Definitions Metaplasia: (change in form) is the reversible replacement of one differentiated cell type with another mature differentiated cell type. Anaplasia: Reversion of cells to an immature or a less differentiated form, as occurs in most malignant tumors. Slide 15 Hyperplasia is a general term referring to the proliferation of cells within an organ or tissue beyond that which is ordinarily seen. Slide 16 Benign and Malignant tumors Benign tumor can be life threatening (size, location) Adrenal gland, Islets of langerhans of the pancreas. Carcinoma: epithelial tissue Sarcoma: connective tissue Blastoma: embryonic tissue Melanoma: cancer of melanocyte Leukemia: Sarcoma of blood forming tissue Slide 17 Benign Tumors & Their Tissue of Origin PrefixTissue Benign Tumor Name Adeno-GlandAdenoma Chondro-CartilageChondroma Hemangio- Blood vessels Hemangioma Hepato-LiverHepatoma Lipo-FatLipoma Myo-MuscleMyoma Osteo-BoneOsteoma Fibro- Fibrous CT Fibroma Neuro- Neural tissue Neuroma Slide 18 Malignant tumors & their tissue of origin Adenocarcinoma Glandular epithelium Squamous cell carcinoma Squamous epithelium OsteosarcomaBone ChondrosarcomaCartilage Lymphosarcoma Lymph node Liposarcoma Adipose tissue Retinoblastoma Retinal tissue Neuroblastoma Neural tissue Nephroblastoma Renal tissue Slide 19 Occupational carcinogens CarcinogenOccupation Cancer type AsbestosConstructionLung BenzeneLeatherLeukemia Benzidine Dye, rubber Bladder Chromium Metal worker Lung ArsenicPesticidesLung,skin,liver Slide 20 Tumor angiogenesis, Metastasis &Staging Angiogenic factors Endostatin- Inhibits the angiogenesis process Metastasis (Lung,liver,bone) Common location of metastasis (Lung,liver,bone) TNM The TNM (Tumor, Node and Metastasis) system. It is one way of determining the prognosis of the patient. Slide 21 TNM system for Tumor grading PrimaryTumor (T) TXPrimary tumor can not be evaluated T0No evidence of primary tumor TisCarcinoma in situ T1,T2,T3,T4Size / extent of primary tumor Regionallymph Node (N) NXRegional lymph node can not be evaluated N0No regional lymph node involvement N1,N2,N3Involvement of regional L.N(No./extent of spread) DistantMetastasis (M) MXDistant metastasis can not be evaluated M0No Distant metastasis M1Distant metastasis Slide 22 Carcinogen Any substance at any dose, administered by any route, that increases tumor incidence. A carcinogen is a substance that is capable of causing cancer in humans or animals. Genotoxic Non-genotoxic International Agency for research on cancer (IARC) Group A1: Carcinogenic to humans Group 2A: Probably Carcinogenic to humans Group 2B: Possibly Carcinogenic to humans Group 3: Not classifiable as to its Carcinogenicity to humans Group 4: Probably not Carcinogenic to humans Slide 23 Carcinogen Naturally-occurring microbial carcinogen (Aflatoxin B 1 ) HBV,HPV, Rous sarcoma virus Dioxins and dioxin-like compounds Industrial smoke and tobacco smoke Vinyl chloride Plastic industry Radiation (x-rays, gamma, infrared, ultraviolet radiation) Co-carcinogens: are chemicals that do not necessarily cause cancer on their own, but promote the activity of other carcinogens in causing cancer (sodium arsenite) Biotransformation: Less toxic----- more toxic Slide 24 Carcinogen in food Cooking food at high temperatures, e.g. grilling or barbecuing meats, can lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzo pyrene). Acrylamide is generated in fried or overheated carbohydrate foods (such as French fries and potato chips). Milk protein Casein, found in milk and many prepared foods, is also a carcinogen. However, independent studies report that casein and other milk proteins protect against cancer. Slide 25 Genotoxic Genotoxic carcinogens are DNA reactive or DNA reactive metabolites capable of altering the integrity DNA through direct interaction: Direct acting Carcinogens: Alkylating agents (Methyl chloromethyl ether) Indirect acting Carcinogens: Aflatoxin, polycyclic hydrocarbon benz[a]pyrene. Activation of chemical Transport to Nucleus Formation of a DNA adduct Fixing Mutation Slide 26 NonGenotoxic They do not cause directly mutation of DNA. The mechanism of action is poorly understood. Not all carcinogens are mutagens. Carcinogenesis is often associated with changes in methylation of DNA. Asbestos-related cancer associated with long latency periods,often decades Slide 27 NonGenotoxic Diethylstilbestrol: vaginal and uterine carcinoma Esterogen: breast cancer Slide 28 Slide 29 Chemical induced carcinogenesis Slide 30