1. Neoplasia-2
Etiology and pathogenesis of cancer
S. Parasuraman
Faculty of Pharmacy
AIMST University

2. Cancer incidence
• World wide cancer related death – 20 %
• In US- cancer is second most common cause of death
• Most common cancer in developed countries are
lung, breast, prostate and colorectal
• Most common cancer in developing countries are
liver, cervical and oesophageal.
• Following life-style factor attributing cancer worldwide:
tobacco use, alcohol abuse, obesity, physical
inactivity, low fiber diet, unprotected sex, polluted
air, indoor household smoke and contaminated
injections.

3. Cancer incidence
Five most common primary cancers in the world (descending order)
S.No Men
Women
Children (under 20)
1
Lung
Breast
Acute leukaemia
2
Prostate
Lung
CNS tumour
3
Colorectal
Colorectal
Bone sarcoma
4
Urinary bladder
Endometrial
Endocrine
5
Lymphoma
Lymphoma
Soft tissue sarcoma

4. Epidemiologic factors
1. Predisposing factors
a)
b)
c)
d)
Familial and genetic factors
Racial and geographic factors
Environmental and cultural factors
Age and gender
2. Chronic non-neoplastic (pre-malignant) conditions
a)
b)
c)
Carcinoma in situ
Benign tumour
Miscellaneous conditions
3. Role of hormones in cancer
a)
b)
c)
d)
Oestrogen
Contraceptive hormones
Anabolic steroids
Hormone-dependent tumor

5. Epidemiologic factors
1. Predisposing factors
a)
Familial and genetic factors:
– Risk of developing first degree relatives of cancer patient is 3
times higher as compare to control
– Genetic cancer comprise not greater than 5 % of all cancer. E.g.:
49% of retinoblastoma are inheritance (missing of RB gene in
chromosome 13), 100% of familial Polyposis coli develop cancer
of the colon, neurofibromatosis or von Recklinghausen’s
disease (50% inheritance), cancer of breast (2-6 times higher
risk than normal; inherited breast cancer- 5-10%,; mutant
genes- BRCA-1 and BRCA-2.)

6. Epidemiologic factors
1. Predisposing factors
b)
Racial and geographic factors
White Europeans and
Americans
Lungs, breast and colon;
Breast cancer common in Americans
but uncommon in Japanese
Black Africans
Skin, penis, cervix and liver
Japanese
5 times higher incidence of carcinoma
of the stomach than the Americans
South-East Asians
Chinese- nasopharyngeal cancer
Indians
Higher incidence of carcinoma of the
oral cavity and upper aerodigestive
tract; female- carcinoma of uterine
cervix, breast. Cancer of liver (HBV and
HCV viral hepatitis)

7. Epidemiologic factors
1. Predisposing factors
c) Environmental and cultural factors
–
–
–
–
–
–
Cigarette smock: cancer of oral
cavity, pharynx, larynx, oesophagus, lungs, pancreas and
urinary bladder
Alcohol and tobacco together: risk of developing cancer of the
upper aerodigestive track
Cancer of cervix: age at first coitus, frequency of
coitus, multiplicity of partners and parity
Penile cancer: rare in the Jews and Muslims.
Carcinogenic compound smegma plays a role in etiology of
cancer
Betel nut cancer: common in some part of India due to
habitual of keeping the bolus of pann in particular place of
mouth for a long time

8. Epidemiologic factors
1.
Predisposing factors
d) Age and gender
–
–
–
–
–
–
Age is most significant factor for cancer (two-third of all
cancer occur above 65 yr of age)
Cancer in advanced age may be due to alterations in the cells
of host, longer exposure to the effect of carcinogen, or
decreased ability of the host immunity
Tumours in infancy and childhood:
Neuroblastoma, nephroblastoma, rhabdomyosarcoma, Ewing’
s sarcoma, teratoma and CNS tumours.
Apart form malignant tumours, most tumours are common
for men than in women except cancer of the breast
Breast cancer: throughout the world common for women
Lung cancer: common for men

9. Epidemiologic factors
2. Chronic non-neoplastic (pre-malignant) conditions
a)
Carcinoma in situ
–
–
b)
Benign tumour
–
c)
Malignancy are present in epithelium without invasion across the
basement membrane
Common sites for carcinoma in situ are uterine cervix, Bowen’s
disease of the skin, oral leukoplakia, intralobular and intraepithelial
carcinoma of the breast
Benign tumour not become malignant excepts multiple villous
adenomas of the large intestine
(adenocarcinoma), neurofibromatosis (neurofibrosarcoma)
Miscellaneous conditions
–
–
–
–
Patients of long standing ulcerative colitis colorectal cancer
Cirrhosis of liver  hepatocellular carcinoma
Chronic bronchitis in heavy cigarette  cancer of bronchus
Old burn scar (Marjolin’s ulcer)  squamous cell carcinoma

10. Epidemiologic factors
3. Role of hormones in cancer
Hormone sensitive tissues developing tumour are the
breast, endometrium, myometrium, vagina, thyroid, liver, p
rostate and testis.
a)
b)
c)
Oestrogen therapy increase the risk of developing endometrial
carcinoma
Oral contraceptives increase the risk of developing breast cancer
Anabolic steroids increase the risk of developing benign and
malignant tumours

11. Carcinogenesis

12. Causes/ pathogenesis of cancer
Carcinogenesis/ oncogenesis or tumorigenesis : mechanism of
induction of tumours
Three major type of carcinogens
• Chemical carcinogenesis
– Mutagens
– Chemical carcinogenesis and their metabolism
• Physical carcinogenesis (radiation)
– Ultraviolet radiation, Asbestos
• Infectious Pathogens (Viral)
– Human T-cell leukemia viruses, DNA viruses, Human papillomaviruses
– Epstein-Barr virus, Hepatitis B virus

13. Chemical carcinogenesis/ mutagens
• Two-step/ multistep process
– Initiation : causes permanent DNA damage
(Mutation)
– Promotion (Proliferation)
INITIATORS
• Direct acting compounds: Direct acting carcinogens are
bind covalently to cellular macromolecules. E.g. nitrogen
mustard, bis(chloro-methyl) ether, benzyl chloride, Epoxides
• Indirect acting carcinogen (Procarcinogens): Require
metabolic conversion to form ultimate active carcinogen.
PROMOTERS
• Can cause cellular proliferation & induce tumors in
initiated cells, e.g estrogen but they are non tumorigenic
by themselves.
•
Proliferation of a mutated cell may lead to accumulation of
additional mutations.

14. Chemical carcinogenesis/ mutagens
E.g. for indirect-acting chemical carcinogens (procarcinogens)
– Polycyclic aromatic hydrocarbons  cigarette smoke  lung
cancer
– Aflatoxin B1  Fungi Aspergillus flavus (contamination of veg.
food, peanuts)  liver cancer (Africa and Asia regions)
– Aromatic amines and Azo dues  bladder (aniline dye) and liver
tumors.
– Nitrosamines: Nitrosamines (nitrosamine, dimethyl nitrosamine)
are potent carcinogen, produce kidney, liver tumor and
gastrointestinal cancers.
– Metals: Ni2+, Pb2+, Cd2+, Co2+ and Be2+.

15. Test for chemical carcinogenesis
• Experimental induction
– Rodents are used
– Chemical (investigational product) administration  promoting agents
administration  after study period animals are autopsied and results
obtained.
• Test for mutagenicity (AMES’ test)
– Check the mutation ability of a chemical to induce mutation in the
mutant strain of Salmonella typhimurium

16. Factors influencing chemical carcinogenesis
• Metabolism of carcinogens: Most of the chemical carcinogen
required metabolic activation. If carcinogen augmenting the
detoxification pathways, reduce incidence of cancer.
• Sex and hormonal status:
– Pregnancy is associated with a decreased incidence of cancers of the
breast, endometrium and ovary.
– Women who are borne children at an early age are at a lesser risk than
nulliparous woman for cancers of the breast, endometrium and ovary.
– Early menarche, late menopause and later age of first pregnancy all
increase the risk of breast cancer.
• Diet: Low-protein diet reduce the hepatic activity and decreased
sensitivity to hepatocarcinogens. Obesity is associated with an increased
number of tumors.

17. Physical carcinogenesis
Physical
carcinogenesis
radiation
Physical
Carcinogenesis
Non-radiation
Physical
Carcinogenesis
Radiation
Ultraviolet
light
Ionising
radiation

18. Physical carcinogenesis
• Radiation- Ultraviolet light
– Causes: mutation, inhibits cell division and cell death
– MOA: formation of pyrimidine dimer
– Main source of UV light is sunlight, UV lamp and welder’s arcs
– Penetration of UV light protected by melanin pigmentation of
the skin.
• Sun light  white race  basal cell carcinoma, squamous
carcinoma and malignantmelanoma
• Sun light  darker races  protected by melanin
pigment, which absorbs UV radiation
• Lifetime risk of 1 rad of whole-body x-ray or gamma-ray
radiation is one excess cancer death per 10,000 person

19. Physical carcinogenesis
• Radiation- Ionising radiation
• X-rays, α-, β- and γrays, radioactive
isotopes, protons and
neutrons can cause cancer
Image form ‘Essential Pathology for Dental Students’ by Harsh Mohan and Sugandha Mohan, 4th ed. India

20. Physical carcinogenesis
• Non-radiation Physical Carcinogenesis
– Asbestos: A fibrous amphibole; used for making
fireproof articles
– Inhaling asbestos can cause lung cancer
– Source of inhalation:
•
•
•
•
•
mining and manufacturing of asbestos
installation of asbestos insulation
air in the vicinity of asbestos plants
contaminated air in buildings undergoing repair or demolition
clothing of asbestos workers

21. Infectious Pathogens
• Virus
Viral infection is responsible for 20% of human cancer
worldwide
– RNA retrovirus HTLV-I  T-cell leukemia/ lymphoma (endemic in
Japan, Africa, the Caribbean basin and southeastern United
States)
– Human papillomavirus (DNA)  squamous carcinoma of the
cervix
– Hepatitis B and C viruses  primary hepatocellular carcinoma
– Epstein-Barr virus (EBV)  lymphoma and nasopharyngeal
carcinoma
– Human herpesvirus 8  kaposi sarcoma

22. Infectious Pathogens
Bacteria
• Helicobacter Pylori (Gastric lymphoma, Mucosal Associated
Lymphoid Tumor (MALT) & Gastric carcinoma)
Fungi
• aflatoxins produced by Aspergillus flavus - hepatocellular
carcinoma
Parasites
• Schistosoma and Clonorchis sinensis
Cancer inheritance
•
Cancer inheritance: Genetic basis. E.g., Breast cancer
(associated genes are BRCA-1 and BRCA-2)

23. Thank you

24. Tobacco-Related Cancers
• Lung cancer estimates for 2013 (Source: Cancer Facts & Figures
2013):
– New cases of lung cancer: 228,190
Males: 118,080
Females: 110,110
– Deaths from lung cancer: 159,480
Males: 87,260
Females: 72,220
• Tobacco use also increases the risk for cancers of the mouth, lips, nasal
cavity (nose) and sinuses, larynx (voice box), pharynx (throat), esophagus
(swallowing tube), stomach, pancreas, kidney, bladder, uterus, cervix,
colon/rectum, ovary (mucinous), and acute myeloid leukemia.
• Tobacco use is responsible for nearly 1 in 5 deaths in US
• Tobacco use accounts for at least 30% of all cancer deaths and 87% of lung
cancer deaths
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25. Cancer induced by alcohol abuse:
•
•
•
•
•
•
•
Mouth cancer
Pharyngeal cancer (upper throat)
Oesophageal cancer (food pipe)
Laryngeal cancer (voice box)
Breast cancer
Bowel cancer
Liver cancer
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26. Cancer induced by obesity:
• 49 % of endometrial cancers are caused by excess body fat.
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–
–
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–
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esophageal cancer
pancreatic cancer
kidney cancer
gallbladder cancer cases
breast cancer cases
colorectal cancer cases
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27. Cancer induced by unprotected sex :
• HPV is a virus that's transmitted through sexual
contact -- genital or oral
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