carcinogenesis

2. Individual
Predisposition
* Host factors*
Environmental factors:
( Carcinogens )
1. Physical
2. Chemical
3. Biological
TUMOUR
INDIVIDUAL

3. Molecular Basis of Neoplasia:
Proto-oncogene
Oncogene

5.  Latent period of about 7 years,
 Acute and chronic myeloid leukemias,
 Solid tumors – thyroid gland,
- breast,
-lung;
Radiation carcinogenesis

6.  Sir Percival Pott (1775) …..
Chimney sweeps
Carcinoma Scrotum
2. Chemical Carcinogens:
Soot

7. STEPS:
… 1. Initiation,
… 2. Promotion;
1915 -- Yamagiwa and Ichikawa
Carcinoma of skin
Painting with Coal tar products
Rabbit ears

8. - Initiator ( Polycyclic hydrocarbon )
Group-1 No Tumour
Group-2 Tumour
Group-3 Tumour
Group-4 No Tumour
Group-5 No Tumour
Group-6 No Tumour
- Promoter ( Croton oil ).

9. A. Direct acting carcinogens
1. Alkylating agents
a) Beta - propiolactone
b) Dimethyl sulphate
c) Diepoxybutane
d) Anticancer drugs - Cyclophosphamide
- Chlorambucil,
2. Acylating agents
a) 1 - acetyl - imidazole
b) Dimethyl carbamyl chloride
Major Chemical Carcinogens:

10. 2. Aromatic Amines, Amides, Azo dyes
a) 2 - Naphthylamine ( B - Naphthylamine )
b) Benzidine
c) Acetylaminofluorene
d) Dimethylaminoazobenzene (Butter yellow)
3. Natural plant & microbial products
a) Aflatoxin B1 – Aspergillus flavus
b) Griseofulvin
c) Cycasin
d) Safrole
e) Betel nuts & leaves

11. 4. Others
* Nitrosamines & amides
* Vinyl chloride
* Asbestos
* Nickel & chromium
* Polychlorinated biphenyls;

12. Occupational Carcinogens
Carcinogen Occupational Exposure Cancer Risk
4-aminobiphenyl Chemical & dye workers Bladder
Arsenic Mining, pesticides lung, skin, liver
Asbestos Construction Lung
Auramine Dye workers Bladder
Benzene Leather, petroleum Leukemia
Benzidine Chemical, dye & rubber Bladder
Ether Chemical workers Lung
Chromium metal workers, Lung
electroplaters
Isopropyl alcohol manufacturing by Nasal
strong acid process
Leather dust boot & shoe making Nasal, bladder

13.  3, 4 Benzpyrene
 Affects about 10% Smokers
( Aryl hydrocarbon hydroxylase )
 Other tumours associated with smoking
 Carcinoma of Esophagus,
 Carcinoma of Pancreas,
 Tumours of kidney,
 Urinary bladder tumours;
Cigarette Smoking & Lung Cancer

14. ELECTROPHILIC
INTERMEDIATES
CHEMICAL
CARCINOGEN
BIND TO DNA:
ADDUCT FORMATION
PERMANENT DNA LESION:
(mutation)INITIATED CELL
CELL PROLIFERATION:
ALTERED DIFFERENTIATION
PRENEOPLASTIC CLONE
MALIGNANT NEOPLASM
EXCRETION
DETOXIFICATION
METABOLIC
ACTIVATION
DETOXIFICATION
NORMAL
CELL
CELL
DEATH
PROLIFERATION -
MORE MUTATIONS
DNA repair

16. 1911 - Peyton Rous,
Cell Culture
Sarcoma in chicken;
[ virus ]
Nobel prize in 1968;

17. Viruses: Oncogenic in wide variety of animals;
 In humans:
 Viruses:
- DNA viruses,
- RNA viruses;
 Bacteria:
- Helicobacter pylori
Microbial carcinogenesis

18.  DNA viruses:
- Human papilloma virus (HPV),
- Epstein-Barr virus (EBV),
- Hepatitis B virus (HBV),
- Kaposi sarcoma herpes virus (KSHV),
Microbial carcinogenesis
• RNA VIRUS:
… HTLV – 1,
… Hepatitis C virus;

19.  RNA viruses activate oncogenes
 DNA viruses counteract tumor suppressors

20. 1. Human Papilloma virus ( HPV )
High risk types --
-- 16, 18, 31, 33, 35 & 51,
* Squamous cell carcinoma, cervix,
* Carcinoma anal region,
* Carcinoma larynx,
* Carcinoma oral cavity,
Low risk types - 1, 2, 4, 7 etc.
* Genital warts;

21. Papilloma Viruses
Urogenital cancer
wart malignant squamous cell ca.
Papilloma viruses are found in 91% of women with cervical cancer
Squamous cell carcinoma:
Larynx
Esophagus All histologically similar
Lung
10% of human cancers may be HPV-linked

22.  Burkitt’s Lymphoma ( African form ),
 Nasopharyngeal Carcinoma,
 B - Cell Lymphomas in
Immunosuppressed patients
… HIV Infection,
… Organ transplantation,
 Hodgkin Disease;

23. DNA Tumor Viruses In Human Cancer
Considerable evidence for role in human cancer
• Some very tumorigenic in animals
• Viral DNA found in small proportion of tumor cells: “hit and run”
Epstein-Barr Virus
• Burkitt’s Lymphoma
• Nasopharyngeal cancer
• Infectious mononucleosis
• Transforms human B-lymphocytes in vivo

24.  Enters B-cells - CD21 molecule
 Common in African countries,
 EBV infection worldwide,
 100% Show levels of antibodies
 t (8 : 14) > activation of C - myc,
 Causes infectious mononucleosis,
( self limiting condition )
Burkitt’s Lymphoma:

25. t( 8; 14 )
C - myc
( 8 )
Juxtaposed to
Immunoglobulin
Heavy chain gene
( 14 )
C - myc
activation

26. Burkitt's Lymphoma

27. 3. Hepatitis - B virus:
* Hepatocellular Carcinoma;
* Endemic in far east and Africa,
* 200 fold increases risk,
* Viral DNA integrated form,
* Cofactor - Aflatoxins,
* HBx protein > growth-promoting genes
* " -- binds to p53;
DNA Virus: ( contd …)

28.  Human T-cell Leukemia virus -
Type 1 - ( HTLV - I )
--- Adult T - cell leukemia / lymphoma
* Endemic -- parts of Japan,
-- Caribbean,
* Tropism for CD4+ T - Cells,
* Transmission: .. Sexual intercourse
.. Blood products,
.. Breast feeding;

29. Helicobacter pylori:
- Stomach ---
... Lymphomas,
… Carcinoma,
Chronic infection > H. Pylori
reactive T - cells
B - lymphocyte proliferation;