Carcinogenesis power point presentation.pptx

Carcinogenesis

1. CARCINOGENS AND CARCINOGENESIS Dr. BUKENYA ALI

2. Definition of Carcinogenesis and Carcinogen. Carcinogenesis / Oncogenesis / Tumorigenesis means mechanism of induction of tumours (pathogenesis of cancer). Agents which can induce tumours are called carcinogens (etiology of cancer).

3. NORMAL CELLS CANCER CELLS CARCINOGENESIS Carcinogenic agent Mutations/ chromosomal translocation

4. Etiology and pathogenesis of cancer can be discussed under following 3 headings: Chemical carcinogens and Chemical Carcinogenesis. Physical carcinogens and Physical Carcinogenesis. Biologic carcinogens and Viral Oncogenesis.

5. CHEMICAL CARCINOGENS AND CARCINOGENESIS:

6. Chemical Carcinogens: Depending upon the mode of action of carcinogenic chemicals, they are divided into 2 broad groups: A. INITIATORS B.PROMOTERS CHEMICAL CARCINOGENS 1. DIRECT-ACTING CARCINOGENS These carcinogens don't require any metabolic conversion to become carcinogenic. They directly damage the DNA causing mutations 2. INDIRECT-ACTING CARCINOGENS These are chemical Substances which require prior metabolic activation before becoming potent ‘ultimate’ carcinogens. Lack the intrinsic carcinogenic potential but their application subsequent to initiator exposure helps the initiated cell to proliferate further.

7. A. INITIATORS I. DIRECT-ACTING CARCINOGENS: i ) Alkylating agents: Anti-cancer drugs (e.g. cyclophosphamide , chlorambucil ) β - propiolactone Epoxides ii) Acylating agents a) Acetyl imidazole b) Dimethyl carbamyl chloride

8. Alkylating agents  are compounds that work by adding an alkyl group to the guanine base of the DNA molecule. This causes breakage of the DNA strands, affecting the ability of the cancer cell to multiply.

9. INDIRECT-ACTING CARCINOGENS (PROCARCINOGENS): Polycyclic Aromatic Hydrocarbons: Eg: Tobacco, smoke, fossil fuel, soot, tar, minerals oil, smoked animal foods, industrial and atmospheric pollutants

10. ii) Azo-dyes: E.g. Butter yellow, Scarlet red.

11. iii. Naturally-occurring products a) Aflatoxin Bl b) Safrole c) Betel nuts

12. Others: Asbestos Arsenical compounds Metals (e.g. Nickel, lead, cobalt, chromium etc) Insecticides, fungicides (e.g. aldrin , dieldrin , chlordane etc) Saccharin.

13. B. PROMOTER CARCINOGENS Dietary fat in cancer of colon. Endogenous or exogenous oestrogen.

14. STAGES IN CHEMICAL CARCINOGENESIS/ PATHOGENESIS OF CHEMICAL CARCINOGENESIS: The induction of cancer by chemical carcinogens occurs after a delay—weeks to months in the case of experimental animals, and often several years in humans . Factors that influence the induction of cancer are the: Dose and Mode of administration of carcinogen. Individual susceptibility. Various predisposing factors.

15. Chemical carcinogenesis occurs by induction of mutation in the Proto-oncogenes and Anti-oncogenes. Chemical carcinogenesis can be learned in three steps: INITIATION OF CARCINOGENESIS PROMOTION OF CARCINOGENESIS PROGRESSION OF CARCINOGENESIS

16. Pathogenesis is different with direct and indirect carcinogens. 1. INITIATION OF CARCINOGENESIS: DIRECT CARCINOGENS (ELECTRONPHILIC) DNA Damage. INDIRECT CARCINOGENS (INACTIVE FORMS) Activation in liver ACTIVE CARCINOGENS DNA Damage. (ELECTRONPHILIC)

17. INDIRECT CARCINOGENS / PROCARCINOGENS METABOLIC ACTIVATION in liver by the mono- oxygenases of the CYTOCHROME P-450 AFTER METABOLISM IN LIVER THEY BECOME ELECTRON-DEFICIENT AND ACT AS ELECTROPHILES REACTIVE ELECTROPHILES BIND TO ELECTRON-RICH PORTIONS OF OTHER MOLECULES OF THE CELL SUCH AS DNA, RNA AND OTHER PROTEINS.

18. TARGET OF ELECTROPHILES IS DNA, PRODUCING MUTAGENESIS. IF THE CELL CONTAINING DAMAGED DNA IS NOT REPAIRED AND IT UNDERGOES AT LEAST ONE CYCLE OF PROLIFERATION. Progeny of cells from mother cells will have DNA damage which will be PERMANENT and IRREVERSIBLE

19. DIRECT CARCINOGENS DIRECTLY ACT AS REACTIVE ELECTROPHILES AND BIND TO ELECTRON-RICH PORTIONS OF OTHER MOLECULES OF THE CELL SUCH AS DNA, RNA.

20. NOTE: Any gene may be the target molecule in the DNA for the chemical carcinogen. It has been observed that most frequently affected Genes are RAS gene mutation and p53 gene mutation

21. 2.Promotion of Carcinogenesis Promotion is the next sequential stage in the chemical carcinogenesis. Promoters of carcinogenesis are substances such as Phenols, Hormones, Artificial Sweeteners Drugs like Phenobarbital.

22. They differ from initiators in the following respects: i ) They do not produce sudden change. ii) The change induced may be reversible .

23. iii) They do not damage the DNA per se and are thus not mutagenic but instead enhance the effect of direct-acting carcinogens or indirect carcinogens. iv) Tumour promoters act by further clonal proliferation and expansion of initiated (mutated) cells, and have reduced requirement of growth factor, especially after RAS gene mutation.

24. 3. Progression of Carcinogenesis Progression of cancer is the stage when mutated proliferated cell shows phenotypic features of malignancy. These features pertain to morphology, biochemical composition and molecular features of malignancy The new progeny of cells that develops after such repetitive proliferation inherits genetic and biochemical characteristics of malignancy.

25. NORMAL CELL MUTATED CELL CHEMICAL CARCINOGEN DNA DAMAGE INTIATION PROMOTION PROMOTERS CELL DIVISION MUTATED CELL MUTATED CELL CANCER CELL CANCER CELL PROGRESSION CELL DIVISION CELL DIVISION CHEMICAL CARCINOGENESIS

26. VIRAL ONCOGENESIS: General mode of oncogenesis by DNA and RNA oncogenic viruses is briefly discussed as below 1. Mode of DNA viral oncogenesis 2. Mode of RNA viral oncogenesis

27. 1. Mode of DNA Viral Oncogenesis: Host cells infected by DNA oncogenic viruses may have one of the following 2 results: I) REPLICATION II) INTEGRATION The virus may replicate in the host cell with consequent lysis of the infected cell and release of virions The viral DNA may integrate into the host cell DNA NO NEOPLASTIC TRANSFORMATION & DEATH OF CELL NEOPLASTIC TRANSFORMATION BY INDUCING MUTATION IN DNA

28. 2. Mode of RNA Viral Oncogenesis: All oncogenic RNA viruses are retroviruses . A  retrovirus  is a type of RNA virus that inserts a copy of its genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Retroviruses contain two identical strands of RNA and the enzyme, reverse transcriptase.

29. Retroviruses: Viral RNA Viral RNA  / Reverse transcriptase Viral DNA/ PROVIRUS HOST DNA PROVIRUS Messenger RNA DNA synthetase VIRAL PROTEINS

30. Step 1 . The RNA virus invades the host cell. The viral envelope fuses with the plasma membrane of the host cell; viral RNA genome as well as reverse transcriptase are released into the cytosol . Step 2. Reverse transcriptase acts as template to synthesize single strand of matching viral DNA which is then copied to form complementary DNA resulting in double-stranded viral DNA (provirus).

31. Step 3. The provirus is integrated into the host cell genome producing ‘transformed host cell.’ Step 4. Integration of the provirus brings about replication of viral components which are then assembled and released by budding. The provirus integrated into the DNA of the host cell genome and may induce mutation and thus transform the cell into neoplastic cell .

32. PHYSICAL CARCINOGENS & CARCINOGENESIS

33. Physical carcinogens are divided into 2 groups: Radiation physical agents. Non-radiation physical agents.

34. Radiation physical agents. The two main forms of radiation carcinogens which can induce cancer. Ultraviolet (UV) light and Ionising radiation

35. ULTRAVIOLET LIGHT The main source of UV radiation is the sunlight; others are UV lamps and welder’s arcs.

36. Ultraviolet (UV) light Ultraviolet (UV) light

37. Epidemiology: In humans, excessive exposure to UV rays can cause various forms of skin cancers: Squamous Cell Carcinoma, Basal Cell Carcinoma. Malignant Melanoma

38. High incidence of these skin cancers are seen in Fair-skinned Europeans, Albinos who do not tan readily, Inhabitants of Australia and New Zealand Living close to the equator who receive more sunlight, and Farmers and outdoor workers due to the effect of actinic light radiation.

39. Mechanism of Carcinogenesis by UV light: UV light penetrates the skin for a few millimeters only so that its effect is limited to epidermis. The efficiency of UV light as carcinogen depends upon the extent of light-absorbing protective melanin pigmentation of the skin .

40. UV radiation may have various effects on the cells. The most important is Induction of mutation. Others are: Inhibition of cell division. Inactivation of enzymes. Cell death .

41. The most important biochemical effect of UV radiation is the formation of pyrimidine dimers in DNA. Formation of thymine dimer lesion in DNA. The photon causes two consecutive bases on one strand to bind together , destroying the normal base-pairing double-strand structure in that area.

42. Like with other carcinogens, UV radiation also induces mutated forms of oncogenes (in particular RAS gene) and anti- oncogenes (p53 gene).

43. II. IONIZING RADIATION Ionizing radiation  is any type of particle or electromagnetic wave that carries enough energy to ionize or remove electrons from an atom. Examples of IONIZING RADIATION which can ionize atoms: X-rays Alpha rays (emitted by radioactive Uranium, Radium) Beta rays (emitted by decaying nuclear fuel) Gamma-rays (Sun, Nuclear explosions). Protons Neutrons

44. Epidemiology : Most frequently, ionization radiation-induced cancers are All forms of Leukaemias (except CLL); Others are cancers of the thyroid (most commonly papillary carcinoma), skin, breast, ovary, uterus, lung, myeloma, and salivary glands.

45. Mechanism of carcinogenesis by Ionizing Radiation Mechanism Radiation damages the DNA of the cell by one of the 2 possible mechanisms: It may directly alter the cellular DNA. It may dislodge ions from water and other molecules of the cell and result in formation of highly reactive free radicals that may bring about the damage.

46. Damage to the DNA resulting in mutagenesis is the most important action of ionising radiation. It may cause chromosomal breakage, translocation, or point mutation.

47. The effect depends upon a number of factors such as Type of radiation, Dose & Dose-rate, Frequency and Various host factors such as Age, Individual Susceptibility, Immune Competence, Hormonal Influences And Type Of Cells Irradiated

48. B. Non-Radiation Physical Agents. Mechanical injury to the tissues or prolonged contact with certain physical agents has been observed to have higher incidence of certain cancers.

49. Examples (Rare). GALLSTONES: Stones in the gallbladder and in the urinary tract having higher incidence of cancers of these organs.

50. 2. Healed scars: Healed scars following burns or trauma for increased risk of carcinoma of affected skin.

51. 3. ASBESTOSIS : Occupational exposure to asbestos (asbestosis) associated with asbestos-associated tumours of the lung and malignant mesothelioma of the pleura.

52. 4. Workers engaged in hardwood cutting or engraving having high incidence of Adenocarcinoma of paranasal sinuses