carcinogenesis.pptx for preventive health

Education

1. CARCINOGENESIS Dr. Waithera Mbau NEOPLASIA

2. Carcinogenesis OBJECTIVES Introduction Characteristics of benign and malignant tumours Molecular basis of cancer Chemical carcinogenesis Physical carcinogenesis Microbial carcinogenesis

3. Introduction A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change. The persistence of tumors results from genetic alterations that are passed down to the progeny of the tumor cells. These genetic changes allow excessive and unregulated proliferation that becomes autonomous.

4. Characteristics of Benign and Malignant tumours Differentiation and anaplasia Differentiation is to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally; lack of differentiation is called anaplasia. Generally, benign tumors are well differentiated. Malignant neoplasms are characterized by a wide range of parenchymal cell differentiation, from well differentiated to completely undifferentiated. Morphologic changes associated with anaplasia. Pleomorphism Abnormal nuclear changes Loss of polarity Mitotic figures Chromosomal abnormalities

5. Anaplasia

6. Characteristics of Benign and Malignant tumours Rate of growth The rate of growth of a tumor is determined by : the doubling time of tumor cells, the fraction of tumor cells that are in the replicative pool and the rate at which cells are shed or die. The growth rate of tumors correlates with their level of differentiation thus most malignant tumors grow more rapidly than do benign lesions. The growth rate may not be constant over time. Factors such as hormonal stimulation and adequacy of blood supply influence the growth of tumours.

7. Characteristics of Benign and Malignant tumours Invasion Nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and do not have the capacity to infiltrate, invade or metastasize to distant sites, as do malignant tumors. Because they grow and expand slowly, they usually develop a rim of compressed connective tissue, sometimes called a fibrous capsule, which separates them from the host tissue. The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics and body cavities, providing the opportunity for spread.

8. Characteristics of Benign and Malignant tumours Metastasis Benign tumours do not metastasize while all the malignant tumours with a few exceptions like gliomas of the central nervous system and basal cell carcinoma of the skin, can metastasize. Pathways of spread include: Seeding of body cavities and surfaces A malignant neoplasm penetrates into a natural “open field.” Most often involved is the peritoneal cavity but any other cavity may be involved: pleural, pericardial, subarachnoid and joint space.

9. Characteristics of Benign and Malignant tumours Lymphatic spread Most common pathway for the initial dissemination of carcinomas The pattern of lymph node involvement follows the natural routes of lymphatic drainage. The involvement of lymph nodes by malignant cells may be of two forms: Lymphatic permeation. The walls of lymphatics are readily invaded by cancer cells and may form a continuous growth in the lymphatic channels called lymphatic permeation. Lymphatic emboli. The malignant cells may detach to form tumour emboli which are carried along the lymph to the next draining lymph node. The tumour emboli enter the lymph node at its convex surface and are lodged in the subcapsular sinus where they start growing . Later, the whole lymph node may be replaced and enlarged by the metastatic tumour.

10. Characteristics of Benign and Malignant tumours Haematogenous spread Typical of sarcomas. Systemic veins drain blood into vena cavae from limbs, head and neck and pelvis. Therefore, cancers of these sites more often metastasize to the lungs. Portal veins drain blood from the bowel, spleen and pancreas into the liver. Thus, tumours of these organs frequently have secondaries in the liver. Arterial spread of tumours is less likely because they are thick-walled and contain elastic tissue which is resistant to invasion. Arterial spread may occur when tumour cells pass through pulmonary capillary bed or through pulmonary arterial branches which have thin walls. Cancer of the lung may metastasize by pulmonary arterial route to kidneys, adrenals, bones, brain etc. Retrograde spread by blood route may occur at unusual sites due to retrograde spread after venous obstruction.

11. Carcinogenesis Mechanism of induction of tumours ( pathogenesis of cancer); agents which can induce tumours are called carcinogens. A. Molecular pathogenesis of cancer B. Chemical carcinogenesis C. Physical carcinogenesis D. Microbial carcinogenesis

12. Molecular Basis Of Cancer General concept of molecular mechanisms of cancer include: Monoclonality of tumours. Most human cancers arise from a single clone of cells by genetic transformation or mutation e.g. Multiple myeloma, there’s production of a single type of immunoglobulin or its chain as seen by monoclonal spike in serum electrophoresis. Field theory of cancer. In an organ developing cancer, limited number of cells grow in to cancer after undergoing sequence of changes under the influence of etiologic agents. This is termed as ‘field effect’. 3. Multi-step process of cancer growth and progression. Carcinogenesis is a gradual multi-step process involving many generations of cells. The various causes may act on the cell one after another (multi-hit process). The cells formed are genetically and phenotypically transformed cells having phenotypic features of malignancy.

13. Molecular Basis Of Cancer 4. Genetic theory of cancer. Cell growth of normal is under genetic control. In cancer, there are either genetic abnormalities in the cell, or there are normal genes with abnormal expression. The abnormalities in genetic composition may be from inherited or induced mutations The mutated cells transmit their characters to the next progeny of cells and result in cancer. 5. Genetic regulators of normal and abnormal mitosis. In normal cell growth, there are 4 regulatory genes: i )Proto-oncogenes which are growth-promoting genes i.e. they encode for cell proliferation pathway. ii) Anti-oncogenes which are growth-inhibiting or growth suppressor genes. iii) Apoptosis regulatory genes which control the programmed cell death. iv) DNA repair genes are those normal genes which regulate the repair of DNA damage that has occurred during mitosis and also control the damage to proto- oncogenes and antioncogenes .

14. Molecular Basis Of Cancer I n cancer, the transformed cells are produced by abnormal cell growth due to genetic damage to these normal controlling genes. i ) Activation of growth-promoting oncogenes causing transformation of cell. Gene products of oncogenes are called oncoproteins. Oncogenes are considered dominant since they appear in spite of presence of normal proto-oncogenes. ii) Inactivation of cancer-suppressor genes permitting the cellular proliferation of transformed cells. Anti- oncogenes are active in recessive form i.e. they are active only if both alleles are damaged. iii) Abnormal apoptosis regulatory genes which may act as oncogenes or anti-oncogenes. iv) Failure of DNA repair genes and thus inability to repair the DNA damage resulting in mutations.

15. Genetic Characteristics Of Cancer Excessive and autonomous growth: Growth-promoting oncogenes. Mutations convert proto-oncogenes into constitutively active cellular oncogenes that are involved in tumor development because the oncoproteins they encode endow the cell with self-sufficiency in growth. Mechanism of activation of prooncogenes into oncogenes: i ) Point mutations ii ) Chromosomal iii ) Gene amplification

16. Genetic Characteristics Of Cancers Most of the oncogenes encode for components of cell signaling system for promoting cell proliferation. The oncogenes include: Growth factors Receptors for growth factors Cytoplasmic signal transduction proteins Nuclear transcription factors Cell cycle regulatory proteins

17. Genetic Characteristics Of Cancers 2. Refractoriness to growth inhibition: tumour suppressing genes. The products of tumor suppressor genes inhibit cell proliferation. Mutation of tumor suppressing genes results in the removal of the inhibitory effect to cell growth and the abnormal growth continues unchecked.

18. Genetic Characteristics Of Cancers

19. Genetic Characteristics Of Cancers 3. Escaping cell death by apoptosis: Genes regulating apoptosis and cancer. Apoptosis in normal cell is guided by cell death receptor, CD95, resulting in DNA damage . Other pro-apoptotic factors ( BAD, BAX, BID and p53) and apoptosis-inhibitors (BCL2 , BCL-X) also play a role. In cancer cells, the function of apoptosis is interfered due to mutations in the genes which regulate apoptosis in the normal cell.

20. Genetic Characteristics Of Cancers 4. Avoiding cellular aging: Telomeres and telomerase in cancer. After each mitosis there’s progressive shortening of telomeres which are the terminal tips of chromosomes. Telomerase is the RNA enzyme that helps in repair of such damage to DNA and maintains normal telomere length in successive cell divisions. After repetitive mitosis for a maximum of 60 to 70 times, telomeres are lost in normal cells and the cells cease to undergo mitosis. Cancer cells in most malignancies have markedly upregulated telomerase enzyme, and hence telomere length is maintained.

21. Genetic Characteristics Of Cancers 5. Continued perfusion of cancer: Cancer angiogenesis. Cancer cells can stimulate neo-angiogenesis, during which new vessels sprout from previously existing capillaries, or, in some cases, vasculogenesis , in which endothelial cells are recruited from the bone marrow. Tumor vasculature is abnormal. The vessels are leaky and dilated , and have a haphazard pattern of connection. Neovascularization has a dual effect on tumor growth: perfusion supplies needed nutrients and oxygen, and newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors, such as insulin-like growth factors (IGFs), PDGF, and granulocyte-macrophage colony-stimulating factor.

22. Genetic Characteristics Of Cancers 6. Invasion and distant metastasis: Cancer dissemination. As mutations accumulate in genetically unstable cancer cells and the tumor become heterogeneous, a subset of tumor cell subclones develop the right combination of gene products to complete all the steps involved in metastasis. 7. DNA damage and repair system: Mutator genes and cancer. DNA-repair genes abnormalities allow mutations in other genes during the process of normal cell division. Individuals born with such inherited defects in DNA-repair proteins are at a greatly increased risk of developing cancer. Hereditary non- polyposis colon cancer Ataxia telangiectasia Xeroderma pigmentosum Bloom syndrome Hereditary breast cancer

23. Genetic Characteristics Of Cancers 8. Cancer progression and tumour heterogeneity: Clonal aggressiveness. Though cancer cells remain monoclonal in origin, they acquire more mutations which, in turn, produce multiple-mutated subpopulations of more aggressive clones of cancer cells in the growth which have tendency to invade, metastasize and be refractory to hormonal influences. 9. MicroRNAs in cancer: OncomiRs . MicroRNAs ( miRNAs ) are endogenous, noncoding single stranded RNA molecules with a length of 22 nucleotides only. Normally, miRNAs function as the posttranslational gene regulators of cell proliferation, differentiation and survival. oncomiRs can perform various functions: as tumour suppressor, as tumour promoter and as proapoptotic .

24. Genetic Characteristics Of Cancers 10. Cancer a sequential multistep molecular phenomenon: Multistep theory. Malignant tumors arise from a protracted sequence of events. Cancer results from the accumulation of multiple mutations.

25. Genetic Characteristics Of Cancers

26. Chemical Carcinogenesis Cellular transformation by chemical carcinogens is a progressive process involving 3 sequential stages: initiation, promotion and progression. Initiation Results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator); an initiated cell is altered, making it potentially capable of giving rise to a tumor. Initiation alone is not sufficient for tumor formation. It causes permanent DNA damage (mutations), is irreversible and has “memory.” Carcinogens can be directly acting or indirectly acting i.e. require activation. Promotion Promoters can induce tumors in initiated cells, but they are non tumorigenic by themselves. Cellular changes resulting from the application of promoters do not Affect DNA directly and are reversible. Progression Progression of cancer is the stage when mutated proliferated cell shows phenotypic features of malignancy. These features pertain to morphology, biochemical composition and molecular features of malignancy.

27. Chemical Carcinogenesis

28. Physical Carcinogenesis Physical agents in carcinogenesis are divided into 2 groups: 1. Radiation, both ultraviolet light and ionizing radiation. 2. Non-radiation physical agents. RADIATION CARCINOGENESIS Ultra violet light The degree of risk depends on the type of UV rays, the intensity of exposure, and the quantity of the light-absorbing “protective mantle” of melanin in the skin. The carcinogenicity of UV light is due to formation of pyrimidine dimers in DNA. The UV-induced DNA damage in normal individuals is repaired, while in the predisposed persons who are excessively exposed to sunlight such damage remain unrepaired. Ionising radiation These include: x-rays, γ rays, α rays, β rays, protons, neutrons and radioactive isotopes. Mechanism of DNA damage by radiation: a) It may directly alter the cellular DNA. b) It may dislodge ions from water and other molecules of the cell and result in formation of highly reactive free radicals that may bring about the damage.

29. Ionising radiation

30. Physical Carcinogenesis NON RADIATION PHYSICAL AGENTS Mechanical injury to the tissues such as from stones in the gallbladder, stones in the urinary tract, and healed scars following burns or trauma cause of increased risk of carcinoma in those tissues. Others include: asbestos, silicone gel, tobacco smoke, lead.

31. Microbial Carcinogenesis Parasites: Schistosoma haematobium infection of the urinary bladder is associated with high incidence of squamous cell carcinoma of the urinary bladder. Clonorchis sinensis , the liver fluke, lives in the hepatic duct and is implicated in causation of cholangiocarcinoma . Fungus: Aspergillus flavus grows in stored grains and liberates aflatoxin ; its human consumption, especially by those with HBV infection, is associated with development of hepatocellular carcinoma. Bacteria: Helicobacter pylori, a gram-positive spiral-shaped micro-organism, colonises the gastric mucosa and has been found in cases of chronic gastritis and peptic ulcer; its prolonged infection may lead to gastric lymphoma and gastric carcinoma. Viruses: Many RNA and DNA viruses have proved to be oncogenic .

32. Viral oncogenesis Persistence of DNA or RNA viruses may induce mutation in the target host cell causing activation of growth-promoting pathways or inhibition of tumour suppressor products in the infected cells. The virus-infected host cells after having undergone genetic changes enter cell cycle and produce next progeny of transformed cells which have characteristics of autonomous growth and survival completing their role as oncogenic viruses. Mechanism of DNA virus oncogenesis Cell infected by viruses may undergo: i ) Replication. The virus may replicate in the host cell with consequent lysis of the infected cell and release of virions . ii) Integration. The viral DNA may integrate into the host cell DNA. Integration results in inducing mutation and thus neoplastic transformation of the host cell, while replication brings about cell death but no neoplastic transformation.

33. Viral oncogenesis Mechanism of RNA virus oncogenesis RNA viruses or retroviruses contain two identical strands of RNA and the enzyme, reverse transcriptase . i )Reverse transcriptase is RNA-dependent DNA synthetase that acts as a template to synthesise single strand of matching viral DNA i.e. reverse of the normal in which DNA is transcribed into messenger RNA. ii) The single strand of viral DNA is then copied by DNAdependent DNA synthetase to form another strand of complementary DNA resulting in double-stranded viral DNA or provirus. iii) The provirus is then integrated into the DNA of the host cell genome and may induce mutation and thus transform the cell into neoplastic cell. The host cells which allow replication of integrated retrovirus are called permissive cells. Non permissible cells do not permit replication of the integrated retrovirus. v) Viral replication begins after integration of the provirus into host cell genome.

34. Viral carcinogenesis