1. 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)

3. Biology of Tumor Growth

4. 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
- ???

5. 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)

6. 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

7. 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

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

9. 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

10. 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

11. Example of human chemical carcinogenesis

12. 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

13. 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

14. 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
- ???

15. 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..

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

17. 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

18. 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

19. Accumulation of mutations during tumor progression

20. 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

21. 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

22. 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