Principles of carcinogenesis-1&2

1. Principles of carcinogenesis-1&2 Dr D Ponraj Bioscience/SHS/NYP

2. Introduction • Carcinogenesis: • Its the process which results in the transformation of normal cells to neoplastic cells by causing permanent genetic alterations (it strictly applies to malignant tumours). • Oncogenesis: It includes the causation of all tumours, benign and malignant • Carcinogen: Its an agent known or suspected to participate in the causation of tumours (and called carcinogenic agents). • Genetic alterations are absolutely fundamental in carcinogenic process

3. Identification of carcinogens • Epidemiological studies (colorectal cancers, oesophagial Ca) • Assessment of occupational risks (scrotal Ca in chimney sweeps) • Direct accidental exposure (throtrast in angisarcoma of liver, Chernobyl nuclear reactor accident) • Carcinogenic effects on lab animals • Transforming effects on cell cultures • Mutagenicity testing in bacteria

4. Main classes of carcinogens • 1. Chemicals • 2. Viruses [Genetic- oncogenes] • 3. Ionising radiation & non-ionising radiation • 4. Hormones, mycotoxins and parasites • 5. Miscellaneous agents (asbestos & metal like nickel) • Genetic

5. Cellular & molecular events in carcinogenesis • Its a multistep process • May require a initiating (polycyclic hydrocarbon) and promoting (croton oil) agent. If an agent possess both these agents its called “complete carcinogen”, if it has only one action its called incomplete carcinogen” • Growth persists even in the absence of the causative agent. • Genetic alteration of oncogenes and tumour suppressor genes (Ca colon).

7. Chemical carcinogensis • Direct-acting compounds: • which do not require chemical transformation for carcinogenity. • They are highly reactive electrophiles (have electron-deficient atoms) that can react with neuleophilic (electron rich) sites in cell. • Indirect-acting compounds or procarcinogens: which require metabolic conversion in vivo to produce the ultimate carcinogen capable of transforming cells.

8. Chemical carcinogens • 1. Polycyclic hydrocarbons: • the first carcinogen discovered in soot, a tary residue of coal combustion. • Responsible for scrotal ca in chimney sweeps of London. • The most active component is benzo[alpha]pyrene and dibenzanthracene. • Benzopyrene in tobacco smoke is the most important carcinogenic agent.

9. 2. Cigarette smoking: • Including cigar and pipes-is associated with Ca lung, oesophagus, bladder, oropharynx. • Passive smokers also affected • Inhaled polycyclic hydrocarbons (tars) are converted in the liver to an epoxide by a microsomal enzyme, aryl hydrocarbon hydroxylase. • This epoxide (ultimate carcinogen) is an active compound that combines with guanine in DNA, leading to neoplastic transformation. • 10 “pack years”: an increase in 10 times for cancer for some one who smokes a pack of cigarette a day

10. 3. Aromatic amines: • Such as benzidine and naphthylamine is associated with bladder cancers. • They are mostly procarcinogens and enters through skin, lung (leather and dye industries) or intestine. • Cause cancer in animals, but varies in different species of animals tested. Controlled by FDA. • Detected by measuring urine levels.

11. 4. Cyclamates and Saccharin: These are artificial sweeteners used in diabetes. No carcinogenic effect in humans but have carcinogenic effect in animals. • 5. Azo dyes: • These are dyes used for colouring of food (scarlet red & butter yellow). • They were shown to cause liver cancer in animals.

12. 6. Aflatoxins • Its the most potent carcinogen known. • Its a toxic metabolite produced by the fungus Apergillus flavus, known to cause liver cancer in man. In Africa, dietary intake of large amounts of aflatoxins have shown to result in hepatocellular carcinoma. • Ingested aflatoxin is oxidised in the liver to an ultimate carcinogen that binds with guanine in the DNA of hepatic cells. • First the liver goes for acute liver cell necrosis followed by regenerative hyperplasia and possibly cancer.

14. 7. Nitrosamines: • Their ability to react with both nucleic acids and cytoplasmic macromolecules provides a theoretical basis for carcinogenic action. • Nitrosamines are derived mainly by conversion of nitrites in stomach. • Nitrites are ubiquitous in food because of their common use as preservatives, mainly in processed meat, ham, bacon, sausage...

15. Better refrigeration of food for past 20 years has decreased use of preservatives and hence cancer • The high incidence of gastric cancer in Japan is thought to be due to high intake of smoked foods which contain more polycyclic hydrocarbons than to high nitrosamine levels.

16. 8. Asbestos • Crocidolite, the variety of asbestos having the finest diameter fibres (<0.25 mm), presents the greatest hazards • Asbestosis also leads to fibrous proliferation in the pleura, where it results in fibrous plaques that are reliable radiological indicator. • It results in 2 types of cancer • a.Malignant mesothelioma, which involves the pleura, peritonium and pericardium • b. Bronchogenic Carcinoma: this risk is greatly magnified by smoking

17. 9. Betel leaf: • Associated with oral cancers, common in India, srilanka. • The carcinogenic agent is either Areca nut or the crushed limestone or tobacco that is commonly chewed along with betel leaf 10. Anticancer drugs: • Leukaemia is the most common neoplastic disorder associated with alkylating agents, such as cyclophosphamide, busulfan, chlorambucil. • These interfere with nucleic acid synthesis in normal cells and may cause oncogenic mutation

18. 11. Other industrial carcinogens Heavy metals: • nickel, chromium, and cadmium show an increased incidence of lung cancer Arsenic exposure, • in agricultural workers exposed to arsenic -containing pesticide, is associated with skin cancer and to lesser extent, lung cancer Vinyl chloride, • a gas used to manufacture PVC, has been shown to induce malignant vascular neoplasm in liver (angiosarcoma)

19. Viral & Genetic Oncogenesis Dr D Ponraj Bioscience/SHS/NYP

20. Introduction • Cluster of cancer cases in space and time suggest a viral aetiology • Tumours associated with viruses tend to be more common in youth • Immunosuppression favours viral oncogenesis • Viruses implicated in human carcinogenesis include EB virus (Burkitt’s lymphoma) and HPV (cancer cervix)

21. Types of oncogenic virus • Both DNA and RNA viruses can cause neoplasia. • DNA viruses insert their nucleic acid directly into the genome of the host cell. • The replication is sporadic or absent; • However, DNA may persist and produce an oncogene like effect

22. RNA viruses require RNA-directed DNA polymerase (reverse transcriptase), an enzyme that causes production of a DNA copy of the RNA viral genome. • Some RNA viruses contain built-in oncogene that directly activates cell. • Others insert adjacent to an endogenous cellular oncogene that directly activates the cell.

23. RNA viruses • Only few are implicated in human neoplasms • HTLV-I: Japanese T cell leukaemia was first described in Japan. • HIV: associated with B cell lymphoma. (In patients with AIDS Kaposi sarcoma is the commonest malignancy) • All others mostly cause cancer in experimental animals (eg mouse mammary tumour virus MMTV)

24. DNA viruses • HPV: subtypes 16 & 18 are the common cause of malignancy in 85% of in invasive squamous cell ca. • They suppress tumour suppressor gene Rb and P53. • Cotransfection with ras gene results in full malignant transformation. • Normally HPV cause anogenital warts.

25. Epstein-Barr virus • Discovered first in cell cultures from Burkitt’s lymphoma, a B-cell lymphoma endemic in Africa. It also cause infectious mononucleosis. • It also results in nasopharyngeal Ca. • EB virus is not the sole cause of Burkitt’s lymphoma, its one of the multistep factor in development of Burkitt’s lymphoma. • It involves mutation affecting N-ras oncogene and t(8:14) translocation.

26. Others • Hepatitis B virus • liver cancer • Herpes simple virus • Ca cervix

27. Genetic mechanism • Cancer now is increasingly regarded as a genetic disease. • Some times they are consistently associated with chromosomal defect (eg, Philadelphia chromosome in CML) • There are two mechanisms leading to tumour growth: • 1.Loss or inactivation of recessive inhibitory genes- Tumour suppressor genes. • E.g. P53 (guardian of genome), Rb1,APC...

29. 2. Enhanced or abnormal expression of dominant stimulatory genes-Oncogenes. • They govern the neoplastic behaviour of cells. • More than 600 such genes have been identified • Based on their function they are classified into 4 types • eg (ras, myc, sis, erb…) • Both mechanisms operate in most tumours (e.g. Ca colon), but inactivation of tumour suppressor genes explain inherited predisposition of development of tumour (e.g. retinoblastoma). • Note: A 3rd category of genes that control apoptosis are also involved in tumour growth.

30. Mechanisms of genetic mutation Virus

31. # Mutations that "turn on" the oncogenes stimulate growth.# Mutations that result in loss of tumor suppressor genes and their products inhibit growth.

32. Apoptosis (programmed cell death) • It is an energy-dependent process for deletion of unwanted individual cells. It has a role in morphogenesis, organ size. • Individual cell deletion in physiological growth & disease • Reduced apoptosis contributes to cell accumulation in neoplasia • Increased apoptosis results in excessive cell loss (atrophy) • Activated or prevented by several stimuli • Mechanism of cell death is different from necrosis

34. Modes of inheritance • IN MAN: 23 (22+1) PAIRS OF CHROMOSOMES • Autosomal dominant (only one copy of genes need to be inherited, thus both hetero & homozygous are affected) • Autosoaml recessive (both copies of genes must be abnormal, thus homozygous individuals are affected) • Sex chromosome (X)- linked (defective gene is in the X chromosome, males are sufferers, females are carriers)