Etiology of Cancer

transcript

ETIOLOGY OF CANCER

Dr. Abhilash G

JR-1 Radiotherapy

SRMSIMS

WHAT IS CANCER?

Cancer, known medically as a malignant neoplasm, is a broad group of various diseases, all involving unregulated cell growth.

In cancer, cells divide and grow uncontrollably forming malignant tumors and invade nearby parts of the body.

The cancer may also spread to more distant parts through lymph or blood.

HANAHAN’S SIX HALLMARKS OF CANCER

Self Sufficiency in Growth Signals

Insensitivity to Antigrowth Signals

Tissue Invasion and Metastasis

Limitless Replicative Potential

Sustained Angiogenesis

Evading Apoptosis

Prof. Douglas

Hanahan

Prof. Robert

Weinberg

Indian ICMR Data

ROAD MAP FOR DISCUSSION

A. Tobacco (25-30%)

B. Cancer Susceptibility Syndrome (5-

C. DNA Viruses & RNA Viruses

D. Inflammation (15-

E. Chemical Factors

F. Physical Factors (up to 10%)

G. Dietary Factors

H. Obesity and Physical Activity

(30-35%)

A. TOBACCO

There are about 1.2 billion smokers and

hundreds of millions of smokeless tobacco

users.

Cigarette smoking causes well over 1 million

cancer deaths worldwide.

Lung Cancer is the dominant malignancy.

19 cancers for which evidence is considered

sufficient that they are caused by cigarette

smoking

3 cancers caused by smokeless tobacco

CONSTITUENTS OF CIGARETTE SMOKE CLASSIFIED BY IARC AS

CARCINOGENIC ( UPDATED AND REVISED IN 2010)

72 compounds listed and 15 are carcinogenic to

humans

Polycyclic Aromatic Hydrocarbons

N-Nitrosamines

Aromatic Amines

Aldehydes

Phenolic Compounds

Nitrohydrocarbons

Miscellaneous Organic Compounds

Metals and Inorganic Compounds

MECHANISM OF TOBACCO CARCINOGENESIS

CARCINOGENS AND TOBACCO-INDUCED

CANCERSLung PAH, NNK, Isoprene, Aldehydes,

Benzene

Larynx PAH

Nasal NNK, NNN

Oral Cavity PAH, NNK, NNN

Esophagus NNN, Other Nitrosamines

Liver NNK, Other Nitrosamines

Pancreas NNK, NNAL

Cervix PAH, NNK

Bladder Aromatic Amines

Leukemia Benzene

Colorectal Heterocyclic Aromatic Amines

PAH – Polyaromatic Hydrocarbons ; Nitrosamines - NNN, NNK, NNAL

B. CANCER

SUSCEPTIBILITY

SYNDROMES

Some genetic mutations confer such pro-

tumorigenic power that individuals who harbour

them are at extreme risk for cancer development.

A large number of proteins that regulate genomic

integrity (caretakers) and critical tumour suppressors

are mutated in cancer susceptibility syndromes.

Hereditary tumorigenesis - One mutant allele is inherited from either parent

Sporadic tumorigenesis - One allele is mutated somatically, in which case there is one

predisposed cell.

CANCER SUSCEPTIBILITY GENES &

ASSOCIATED SYNDROMESFunction Gene Associated

Syndrome

Regulation of Translation PTEN

Cowden Syndrome

Peutz-Jeghers

Syndrome

PTCH 1

Nevoid Basal Cell

Syndrome

Regulation of

Proliferation NF 1 Neurofibromatosis 1

APC Familial Adenomatous

Polyposis (AD)

Genomic Integrity and

Apoptosis BLM Bloom’s Syndrome

TP53 Li-Fraumeni Syndrome

PREVALENT SYNDROMES

HNPCC/ Lynch Syndrome – Most common CS

disease; Incidence is 1 in 400; AD with 90%

penetrance; Additional Risk of Endometrial

Cancer.

Hereditary Breast-Ovarian Cancer Syndrome

(HBOC) – BRCA 1 and BRCA 2 mutations; AD

with 85% penetrance.

NF 1 – AD with 100% penetreance.

FAP – AD with high penetrance; Germ line

mutation in APC gene on 5q

CS SYNDROMES DUE TO PROTO-

ONCOGENE ACTIVATION

Costello Syndrome – HRAS Gene

Hereditary Papillary Renal Cancer – MET Gene

Multiple Endocrine Neoplasia Type 2 – RET Gene

Hereditary Gastrointestinal Stromal Tumors – KIT

Familial Melanoma – CDK4 Gene

C. DNA VIRUSES & RNA

VIRUSES

DNA VIRUSES

Hepadnaviruses

Papillomaviruses

Epstein-Barr Virus

Kaposi’s Sarsoma – Associated

Herpesvirus

Human Polyomaviruses

RNA VIRUSES

Retroviruses

HTLV -1

HTLV -2

Human Immunodeficiency Virus

Hepatitis C Virus

HUMAN VIRUSES WITH ONCOGENIC

PROPERTIESVirus Family Type Assoc Tumors Cofactors

Flaviviruses Hepatitis C Hepatocellular Ca -

Hepadnavirus Hepatitis B Hepatocellular Ca Aflatoxin, Alcohol,

Smoking

Herpesviruses EBV Burkitt’s Lymphoma,

Nasopharyngeal

Carcinoma, HL,

Gastric Cancers

Malaria

Nitrosamines

KSHV(HSV8)

Kaposi’s Sarcoma,

Pulmonary Effusion

Lymphoma,

Castleman’s Disease

HIV Infection

Papillomaviruses HPV 16,18 Anogenital Cancers Smoking

Polyomaviruses Merkel Cell

Merkel Cell

Carcinoma

Immunosuppression

Retroviruses HTLV-1 Adult T Cell

Leukemia

Uncertain

D. INFLAMMATION

CANCER AND INFLAMMATION

Chronic inflammation tends to be associated with protumor effects.

Acute inflammation is associated with an antitumor effect.

However, this distinction is not absolute.

CHRONIC INFLAMMATORY CONDITIONS

ASSOCIATED WITH TUMOR FORMATION

Pathological Condition Associated Tumors Etiological Agent

Sjogren Syndrome,

Hashimoto’s Thyroiditis

Mucosa-assoc lymphoid

tissue lymphomas

Reflux esophagitis,

Barrett’s esophagus

Esophageal Carcinoma Gastric acid, Alcoholism,

Smoking

Liver Cirrhosis Hepatocellular Carcinoma Alcoholism

IBD Colorectal carcinoma -

Cystitis, Bladder Bladder Carcinoma Chronic indwelling, urinary

inflammation catheters

Asbestosis, Silicosis Mesothelioma, Lung

Carcinoma

Asbestos fibres, Silica

particles

CANCERS ASSOC WITH INFLAMMATION CAUSED

BY INFECTIOUS AGENTS

Pathological Condition Associated Tumor Pathogens

Hepatitis HCC Hepatitis B, C

Mononucleosis B cell NHL and Burkitt’s EBV

AIDS NHL, SCC, KS HIV, HHV-8

Warts Skin cancer Papillomaviruses

Gastritis/Ulcers Gastric adenocarcinoma H.Pylori

Chronic Cholecystitis Gall bladder Cancer Bacteria, Gallbladder

Stones

Opisthorchiasis, Cholangitis Cholangiosarcoma, Colon Ca Opisthorchis viverrini,

Opisthorcis sinensis

Chronic Cystitis Bladder, Liver, Rectal Ca,

Follicular lymphoma of

Spleen

S.hematobium,

S.japonicum, Irradiation,

Carcinogens

Tissue damage and repair .

Increase in the proliferation rate in the affected tissue.

Increase in the probability of mutation or chromosomal translocation during

mitosis.

E. CHEMICAL FACTORS

CHEMICAL CARCINOGENS

Lung & Pleura Tobacco, Arsenic,

Asbestos, Silica, Coal tar

Aluminum production, coal

gasification, coke

production, hematite

mining, painters,

Oral Cavity Tobacco, Alcoholic, nickel

compounds

Boot and shoe production,

Furniture manufacturer

Gastric Smoked, salted and

pickled foods

Colon Heterocyclic amines,

Asbestos

Pattern Makers

Liver Aflatoxin, vinyl chloride,

alcoholic beverages -

Bladder Tobacco smoke, Benzidine,

Phenacetin

Magenta manufacture,

auramine manufacture

F. PHYSICAL FACTORS

Ionizing radiation

Ultraviolet Radiation

RF & Microwave Radiation

Electromagnetic Fields

Asbestos

Nanoparticles

Hiroshima and Nagasaki

Bombings

Chernobyl

Accident

It has been estimated that 1 Gy of ionizing radiation

gives rise to about 40 DSBs, 1,000 SSBs, 1,000

base lesions, and 150 DNA-protein cross-links per

RFR and MR do not have sufficient energies to

cause ionizations in target tissues.

Sources - mobile phones, radars, medical devices,

and kitchen appliances.

Mobile phones emit radiofrequency radiation (RFR)

and generate EMFs.

At these intensities, induction of DNA damage has

been detected only in laboratory studies.

G. DIETARY FACTORS

Mutagens in foods, due to heating of

proteins, can cause damage to DNA.

Alcohol - Best established dietary risk factor

Fat – Cancers of breast, colon, prostate, and

endometrium.

Red meat - Increased risk of colorectal

cancer.

Direct damage in the upper GI tract.

Modulation of DNA methylation.

Acetaldehyde - Enhances proliferation of epithelial cells,

forms DNA adducts, and is a recognized carcinogen.

CONTD..

Regular consumption - Increased risk of colorectal cancer.

The association is strongest for processed meat.

Anabolic hormones used in meat production.

Heterocyclic amines and PAH formed during cooking.

High amounts of heme iron, and nitrates and related

compounds convert to carcinogenic nitrosamines in the

colon.

CONTD..

Fruits and vegetables have been hypothesized in

cancer prevention.

Contain antioxidants, minerals, fiber, potassium,

carotenoids, vitamin C, folate, and other vitamins.

Supply less than 5% of total energy intake but

concentration of micronutrients in these foods is

greater than in most others.

CONTD..

Fiber is fermented by the luminal bacteria of the colon.

Bulking effect ; Reduces colonic transit time, and the binding

of potentially carcinogenic luminal chemicals.

May also aid in producing short-chain fatty acids that may

be directly anticarcinogenic, and fiber may induce apoptosis.

H. OBESITY &

PHYSICAL ACTIVITY

Overweight Endogenous Risk of

Endometrial

& Obesity estrogen levels & Breast Cancer

Established risk factor for colon cancer in both men and

women.

Increased physical activity - Protective for colon cancer.

Impact on insulin sensitivity and IGF profiles, and

inflammation, as well as some colon-specific mechanisms

Physical activity stimulates stool transit in the colon,

decreasing the exposure of colonic mucosa to carcinogens in

the stool.

CONTD..

Obese & Gastro esophageal Gastric

High BMI Reflux symptoms

Adenocarcinoma

Obesity, in addition to high blood pressure and diabetes, is

an established risk factor for kidney cancer.

High BMI and Obesity have also been implicated in various

studies of Gall Bladder Cancer, Pancreatic Cancer, Prostate

Cancer and NHL..

TAKE HOME MESSAGE

Most common causes of cancer are Tobacco(25-

30%), Diet and Physical Activity related Factors

(30-35%).

60-65% cancers can be prevented just by Lifestyle

modification.

Vaccines which can prevent malignancies should

be emphasized and counseled to parents.

Genetically related malignancies like Breast and

Colon Cancer should have screening and Genetic

Counseling.

Who is the one

Smoking?

REFERENCES

Devita Hellman and Rosenberg’s Cancer:

Principles and Practice of Oncology, 9th

Edition.

Wikipedia

Google Images

Etiology of Cancer

Health & Medicine