NEOPLASIA(신생물) Neoplasia: “new growth” – An abnormal mass of tissue, overgrowth of cell, uncordinated with that than of normal tissue A. Growth pattern of neoplastic cells: 1) Autonomous(자율): independent of growth factor and regulatory mechanism 2) Excessive growth(과잉증식) 3) Disorganized(기능상실)

Biology of Tumor Growth

Chemical Carcinogenesis History of Chemical carcinogenesis: - Scrotal cancer in Chimney sweeper, Pott by coal tar or soot, 1775 - Experimental tar Rat ear skin cancer, Yamagiwa & Ichikawa, 1915 - Hepatoma by O-amidazotoluol in Rabbit, Sasaki & Yoshida, 1935 WHAT MAY CAUSE CANCER ? - Hereditary disorders - Chemicals - Viruses - Chronic inflammation - ???

Functions of oncogene 1. Growth Factor (example, Epidermal growth factor EGF , and platelet derived growth factor PDGF) 2. Growth Factor Receptor (Example; PDGFR) 3. Signal transudation (example; Ras) 4. Transcription Factor (example; Jun, Fos, myc)

Proto-Oncogene Oncogene The proto-oncogene become oncogene by 1. Mutation: ex) mutation in Ras gene :Continuous activation of Ras Unregulated cell proliferation: Cell transformation. 2. Abnormal Activity: ex) Removal of the Regulatory domain in the Raf gene and replaced by gag gene : active cell transformation

3. Gene translocation: ex): c-myc gene is translocated from chromosome 8 to the IgH on the chromosome 14 resulting in abnormal c-myc expression - Cell transformation 4. Amplification: ex) Amplification of n-myc : neuroblastoma. Amplification of erbB-2 : Breast & ovarian carcinomas

NORMAL CELL NEOPLASTIC CELLS Growth factor Growth factor receptor cytoplasm Signal transduction Activation of transcription nucleus NEOPLASTIC CELLS

Function of Tumour Suppressor gene 1. Antagonize the action of oncogene 2. Transcription factors - Repressor transcription factors: 3. Regulate cell cycle : - Rb gene: that inhibits the cell cycle in the G1 phase - P53: inhibiting the action of cdk4/cyclin D 4. Induce apoptosis: P53 release will increase Bax form holes in the mitochondria release cytochrom c, which activate apoptosis

Chemical Carcinogenesis IARC (International Agency for Research on Cancer, WHO 1996) - Group 1: Carcinogen to humans: 70 chemicals - Group 2A: Probably carcinogenic to humans: 57 chemicals - Group 2B: Possibly carcinogenic to humans: 224 chemicals Chemical Carcinogenesis in the 21st Century New perceptions of previously known carcinogens: Combined effects of multiple exposures Examples: Alcohol drinking and aflatoxins Alcohol drinking and HBV/HBC Alcohol drinking and tobacco smoking Tobacco smoking and asbestos/arsenic/radon

Example of human chemical carcinogenesis

Classification of Carcinogens According to the Mode of Action GENOTOXIC: DNA-reactive or DNA-reactive metabolites Direct interaction to alter chromosomal number/integrity May be mutagenic or cytotoxic Usually cause mutations in simple systems DNA Adduct Mutation Cancer

Mechanism of Carcinogenesis: Genotoxic Carcinogens 1. Carcinogen activation 2. DNA binding 4. Gene mutation 3. Cell proliferation CYP450s Chemical "Activated“ carcinogen DNA Repair APOPTOSIS “inactivated“ carcinogen

Classification of Carcinogens According to the Mode of Action Non-Genotoxic: Do not directly cause DNA mutation Mechanism of action is not completely understood Difficult to detect - requires rodent carcinogen bioassay Mechanisms of Non-Genotoxic Carcinogenesis - Increased cell proliferation - Decreased apoptosis - Changes in gene expression - Induction of metabolizing enzymes - Activation of receptors (signaling) - Oxidative stress - ???

Chemical Carcinogenesis: Initiation : DNA damage - Benzopyrene Promotion : Cell proliferation: estrogen, androgen, Viral hepatitis, salt Progression: Malignant transformation: Direct Acting Carcinogens: Alkylating Agents: Cyclophosphamide Procarcinogenes (needs activation) Polycyclinc hydrocarbons – Benzopyrene Aromatic amines, dyes - Benzidine Natural products: Aflatoxin Others: Vinyl chloride..

Stages of Carcinogenesis Initiation Initiating Event Cell Proliferation (clonal expansion) Second Mutating Event Promotion Cell Proliferation Progression Mutating Event Cell Proliferation Malignancy

Cellular and Molecular Mechanisms in Multistage Carcinogenesis: INITIATION Initiating event involves cellular genome – MUTATIONS Target genes: - oncogenes/tumor suppressor genes - signal transduction - cell cycle/apoptosis regulators “Simple” genetic changes From http://newscenter.cancer.gov/sciencebehind/

Reversible enhancement/repression of gene expression: Cellular and Molecular Mechanisms in Multistage Carcinogenesis: PROMOTION Reversible enhancement/repression of gene expression: - increased cell proliferation - inhibition of apoptosis No direct structural alteration in DNA by agent or its metabolites From http://newscenter.cancer.gov/sciencebehind/

Accumulation of mutations during tumor progression

Cancer protective and anticancer plants Garlic Organosulfur compounds originating from garlic inhibit carcinogen activation, cause cell cycle arrest mostly in G2/M phase, stimulate the mitochondrial apoptotic pathwayIts Sea curcumber biological effects range from antioxidant, anti-inflammatory to inhibition of angiogenesis

Green tea Cruciferous vegetables (Broccoli and cabbage) Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, appears to be the most biologically active constituent in tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells Cruciferous vegetables (Broccoli and cabbage) Indole-3-carbinol (I3C), a naturally occurring compound found in vegetables of the broccoli and cabbage, is a promising anticancer agent shown to induce a G(1) cell-cycle arrest in the cells Cruciferous vegetables decreased the risk of breast cancer by 40 percent

Tomato Tomatoes are rich sources of lycopene, an antioxidant carotenoid reported to be a more stable and potent singlet oxygen quenching agent compared to other carotenoids: lowers the risk of reactive oxygen species (ROS)-mediated diseases Cell cycle arrest Strawberry Compounds in strawberries have demonstrated anticancer activity in several different experimental systems, blocking initiation of carcinogenesis, and suppressing progression and proliferation of tumors