Neoplasia V Carcinogenesis

1. Neoplasia VCarcinogenesis Husni Maqboul, M.D

2. Overview of Carcinogenic Agents • Chemical Carcinogens • Physical Agents • Ionizing Radiation • Oncogenic Viruses

3. Impact of Environmental Carcinogens • 80 - 90% of all cancers may be related to environmental agents including diets, lifestyles, and viruses. • Several environmental agents often act together (co-carcinogenesis).

4. Principles of Carcinogenesis • Neoplastic transformation is a progressive process involving multiple “hits” or genetic changes. • Alterations in DNA cause changes in one or both of the following types of genes: • Proto-oncogenes • Tumor suppressor genes • Genes that regulate apoptosis

5. Chemical Carcinogenesis ,Mechanisms • Multi-Step Process Involving: • Initiation • Promotion

9. Initiation • Rapid ,Irreversible, and has “memory” • Results from interaction of chemical with DNA to activate a proto-oncogene or inactivate a tumor suppressor gene by formation of covalent adducts. • Chemicals that can form adducts are usually electrophiles. • Many chemical carcinogens require activation by metabolic pathways (pro-carcinogens or indirect acting carcinogens) • Initiation alone does not result in tumors. • Some initiators can subsequently act as promotors (these are “complete carcinogens”).

10. Initiation • Some procarcinogens (e.g benzopyrene ) are activated by P-450 dependant mono-oxygenases • 10% of whites have highly inducible form of this enzyme are at higher risk to develop smoke related lung cancer • Others are detoxified by glutathione -S-transferase • 50% of whites have deleted locus, and are at higher risk to develop tobacco related lung and bladder cancer

11. Initiation, molecular targets • Vast majority of initiating chemicals are mutagenic ( Ames Test ) • Each class of carcinogenes causes limited DNA damage • Virtually any gene can be targeted, but RAS and TP53 ( aflatoxin B1) mutations are fairly common

13. Chemical Carcinogenesis • Polycyclic hydrocarbons (benzopyrine in cigarette smoke, smoked meet )  epoxides  covalent DNA links • Aromatic amines (β naphthylamine)  urinary bladder Ca • Nitrosamines and nitorsamides ( food amines with preservative nitrites, tobacco smoke)

14. The Initiated Cell • Must “Survive”the insult • Must “Fix” the damage • Damaged DNA template must be replicated • Damaged DNA alone is not cancerous, so they must have other genotypic changes making them autonomous • Initiated cells are susceptible to promoters which induce proliferation, thus immortalizing the defect in a clone of proliferating neoplastic cells.

15. Promotion • Phorbol esters, phenols,hormones, ?bile acids ,and some durgs • Promoters are usually irritants or substances that produce cell activation and proliferation . • Powerful protein kinase C activators Clonal expansion of initiated cells • Effects of promoters are reversible. • Promoters cannot induce neoplasia: i) alone, ii) if applied before initiator, iii) if applied in too small an amount for effect, or iv) if too much time elapses between applications.

17. Radiation Oncogenesis

18. Ultraviolet Light • Strong epidemiologic relationship to squamous cell, basal cell, and melano-carcinoma in fair skinned people. • Causes formation of pyrimidine dimers in the DNA leading to mutations. ( RAS , TP53 ) • Activation of T-suppressor cells facilitates emergence of tumor clones. • Individuals with defects in the enzymes that mediate DNA excision-repair are especially susceptible. • Xeroderma Pigmentosum • Necleotide excision repair mechanism is deficient

22. Ionizing Radiation • Electrogagnetic: X-rays, gamma rays • Particulate : alpha, beta, positrons, protons, neutrons • Primary cosmic radiation • Bone Marrow: Acute leukemia occurs before other radiation-induced neoplasia (Seven year mean latent period in atomic bomb survivors). • Thyroid: Carcinoma occurs in 9 % of those exposed during infancy or childhood. • Lung: Increased frequency of lung cancer in miners exposed to Radon gas (an alpha particle emitter) • Skin, bone and GIT are relatively resistant

23. Mechanisms of Radiation Carcinogenesis • Two theories: Direct interaction with the DNA or indirect damage mediated by free radicals generated from water or oxygen. • Mutation may result by either mechanism. • Mutagenicity of ionizing radiation correlates with: • Radiation quality (High linear energy transfer is most dangerous). • Dose • Dose rate • Efficiency of host DNA repair • Other host factors such as age, immune deficiency

25. Other Radiation and Cancer • Low Level Radiation: Controversial as to whether exposure actually increases the risk of cancer. • Radon: formed from the decay of uranium-radium series of elements. In the U.S.A., 4-5% of homes have 5 times background levels of radon. This may result in 16 excess lung cancer deaths/100,000 persons. • Other: No firm data thatmicrowave radiation, electromagnetic fields, and ultrasound cause cancer.

26. Asbestos • Asbestos fiber diameter is important • Thick fibers lodge in upper respiratory tract • Thin fibers lodge in terminal alveoli • Malignant mesothelioma of the pleural and peritoneal cavities is the characteristic tumor associated with asbestos. • Association between cancer of the lung and asbestos exposure in smokers.

27. Foreign Body Carcinogenesis • Humans are highly resistant to foreign body carcinogenesis. • Tumors associated with parasitic infections: • Squamous carcinoma of the bladder in persons harboring Schistosoma Haematobium • Cancer of the bile ducts following infection by the liver fluke Clonorchis sinensis

28. Viral Carcinogenesis • DNA oncogenic viruses • Transforming DNA viruses integrate into the host genome, during this process , they loose some genes essential for their complete replication. Early viral genes, however, are transcribed , and expressed in transformed cells.

29. Viral oncogenesis, DN A viruses • Human Papillomavirus • Types 1,2,4, and 7 cause squamous papillomata and linked to SCC of the cervix, anogenital region, oral and laryngeal cancers • Types 16,18 and to a lesser extent 31,33,35 and 51 are found in 85% of invasive SCC of the cervix and its precursors • Types 6 and 11 genital warts with low malignant potential ( Episomal non integrated viral genome)

30. Viral oncogenesis, DN A viruses • Early viral E7 • protein binds to underphosphorylated pRb, releasing E2F transcription factor • Inactivates CDK inhibitors • Activates cyclins • E6 protein • binds to and facilitates degradation of TP53 • Promotes degradation of BAX • Activates telomerase • These viral products bind with high affinity in high risk forms of HPV • Some TP53 alleles are more susceptible to degradation by E6 viral gene product ( arginine -instead of porline form ) • Co-factor role of smoking, infection etc.

33. Viral oncogenesis, DN A viruses • Epstein-Barr Virus • Burkitt lymphoma ( African Form ) • Naso-Pharyngeal Carcinoma • Some cases of H.D • B- Cell NHL • Acts as a polyclonal B-Cell Mitogen

34. Latent infection EBV circularizes into a nuclear “Episome” No viral replication, and no cell death ( Immortalization) Expression of viral proteins Latent Membrane Protein 1 (LMP1): Up regulation of BCL2 preventing apoptosis Activation of growth (mimicking CD40 surface signal) EBNA-2 Activates Cyclin D & src forming genes

36. Viral oncogenesis, DNA viruses • Kaposi Sarcoma Herpesvirus ( KSHV ) • Genomic sequences found in all cases including HIV negative cases • Encodes several genes that participate in cell proliferation ( IL-6, chemokine MIP-1alpha, G protein, Cyclin D and BCL-2 ) • Encodes growth promoting factors such as IL-1, TNF-a that stimulate growth of spindle cells in autocrine and paracrine fashion • HIV infected B cells encode soluble tat ( transactivating proteins )

38. Viral oncogenesis, DN A viruses • Hepatitis B Virus • Hepatocellular Carcinoma • Indirect, possibly multifactorial effect • Injury and regenerative hyperplasia • HBx protein : Activation of growth promoting genes , activation of RAS-MAP kinase , • Rearrangement of chromosomes • Interferes with TP53 activity • Hepatitis C virus • Liver injury and regeneration ( Fertile soil for mutations

39. Slow transforming viruses Don’t have oncogens, replication competent Leukemia in rodents Insertional mutagenesis Acute transforming viruses All except one ( Rous Sarcom Virus ) have lost their replication genes, and placed new set ( V-oncs ) instead V-oncs ( V-SRC, V-ABL, V-MYB) integration into genome  C-oncs Viral oncogenesis, RNA viruses

40. Viral oncogenesis, RNA viruses • Human T-Cell Leukemia Virus 1 (HTLV-1) • Associated with T-cell leukemia\lymphoma in Japan and Caribbean basin • Tropism for CD4 T-Cells • No V-oncs • Contains pX region in the genome, includes tax gene, that activates transcription of c-fos, c-sis that code for cytokine IL-2 and its receptor and GM-CSF • tax also inhibits CDK4 and TP53 normal inhibition • Demyelinating neurologic disorder (Tropical spastic paraparesis )

41. TCLL

43. Helicobacter pylori • Gastric carcinoma in about 3% of infected individuals after decades • Chronic gastritis  atrophy intestinal metaplasia  dysplasia  cancer • Gastric lymphoma • B-cell lymphoma • MALToma • H. pylori  reactive T-cells  polyclonal B-cell activation