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CANCER Basic Oncology and viral agents.pdf

  1. Cancer -In young animal, cell multiplication exceeds cell death, so animal increase in size -In adults, the process of cell birth and death are balanced -Sometimes, Control system for cell multiplication break down, and a cell begins to grow and divide in an unregulated fashion Descendant cells inherit this property proliferate without responding to regulation, forming a mass called a tumor A cancer is mainly caused by mutation in somatic cells, number of mutation may vary from 3-20    
  2. ONCOGENES ◼ Normal cells contains highly related but not identical copies of retroviral transforming genes ◼ Proto oncogenes are found in all animals, exert normal cellular function ◼ Components of regulatory pathways to control cell proliferation, division and differentiation. ◼ Incorrect expression of any component might result in uncontrolled growth of cells.
  3. Oncology and Oncogenic Viruses Terminologies ◼ Oncogenes: encode proteins that associated with oncgenesis ◼ Transformation: stable and heritble change in the genes for growth control ◼ Contact inhibition: Stop growing upon contact with neighboring cell ◼ Immortalization: Cell divides for indefinite period ◼ Benign tumor: Composed of cells with abnormal growth but non-invasive ◼ Malignant tumor: Composed of cells with abnormal growth that invade to other organs ◼ Metastasis: Invasion of cancer to other part of the body ◼ Neoplasm: formation of new cells ◼ Hyper plastic: abnormal cell growth
  4. Cancers Originate in Proliferating Cells ◼ Cancers must occur in dividing cells so that mutations are passed on many progeny cells ◼ Mutations in non-dividing cells do not induce cancer ◼ Stem cell present in different organs and tissues divide continuously and generate more stem cells ◼ Oncogenic mutations in theses stem cells DNA can accumulate and eventually transforming them into cancer cells ◼ Cells that have acquired mutations have abnormal proliferation capacity but can not undergo normal process of differentiation
  5. Benign vs. Malignant Tumors Benign Malignant Grow slowly Grow rapidly Well-defined capsule Not encapsulated Not invasive Invasive Well differentiated Poorly differentiated Low mitotic index High mitotic index Do not metastasize Can spread distantly (metastasis)
  6. Classification & Nomenclature ◼ Benign ◼ Named according to the tissue from which they arise, and includes the suffix - “oma” ◼ Lipoma ◼ Glioma ◼ Leiomyoma ◼ Chondroma
  7. Classification & Nomenclature • Malignant tumors Named according to the tissues from which they arise Epithelial tissue – carcinoma Ductal or glandular epithelium – adenocarcinoma Example: mammary adenocarcinoma Connective tissue – sarcoma Example: rhabdomyosarcoma Lymphatic – lymphomas Blood forming cells – leukemia
  8. Classification & Nomenclature ◼ Carcinoma in situ (CIS) ◼ Preinvasive epithelial malignant tumors of glandular or Squamous cell origin that have not broken through the basement membrane or invaded the surround stroma ◼ Cervix, skin, oral cavity, esophagus and bronchus (epithelium) ◼ Stomach, endometrium, breast, large bowel (glandular)
  9. Cancer cells accumulate mutations • Most cancer cells have increased number of mutations then the normal cells • As the cancer progresses, the number of mutation increases • Inactivation of mutator genes decreases the repair damage of DNA, and increase the rate of mutation • The occurrence of different mutations creates an opportunity to select population of cells with particular properties
  10. Cancer arise from a single clone • The occurrence of different mutations creates an opportunity to select the cells with particular properties • In the case of cancer, a mutation that increases the growth potential of a cell will give it a selective advantage • A cell that divides more often, will generate more descendants • At each stage during the progression of a cancer, the cell population is selected for those cells that can grow more aggressively
  11. Tumor cells are immortalized and transformed Three types of changes that occur when a cell becomes tumorigenic -Immortalization -Transformation -Metastasis When cells are placed in culture, -grow for division -enter a senescent stage -go through the crisis -survival of crisis are capable of dividing indefinitely
  12. Properties of a transformed cell Most prominent changes are ◼ Alteration in growth pattern- increased growth rate, anchorage independence ◼ Alteration in cell surface ◼ Alteration in intracellular component and biochemical processes- increase protease and protease activators ◼ Tumorigenecity- forms tumor upon injection in animals
  13. Tumor Cells have altered Morphology Cells cultured from tumors show changes in some or all of these properties. They are said to be transformed • A transformed cell grows in a much less restricted manner • It has reduced serum-dependence, • It does not need to attach to a solid surface • The cells pile up into a focus instead of growing as a surface monolayer. • The cells may form tumors when injected into appropriate test animals.
  14. Seven types of protein control cell growth ◼ Cancers can result from expression of mutant from proteins like:  Growth factors (I)  Growth factor receptors (II)  Signal transduction Proteins (III)  Transcription factors (IV)  Pro- or anti- apoptotic proteins (V)  Cell cycle control proteins (VI)  DNA repair proteins (VII)
  15. . Growth factor (I) Growth factor receptor (II) Intracellular transducer (III) Intracellular effector region (PTK) Second messenger (phosphorylated proteins) Transcription factors (IV) DNA Transcription DNA repair Proteins (VII) RNA Cell cycle control proteins (VI) mRNA Proteins Anti-apoptosis proteins (V) Intracellular receptors (II) Virus encoded activators of growth –factor receptors (Ia)
  16. Mechanisms of oncogenic activation ◼ Mechanisms of activation of proto oncogene and converting to a cancer gene vary - over expression - constituently active - express in wrong time - express in wrong place Interaction of proto-oncogene product with other proteins altered
  17. Mechanisms of activations ◼ Transduction by retroviruses ◼ Insertional mutagenesis ◼ Translocation ◼ Gene amplification ◼ mutation
  18. Transduction ◼ Cellular proto oncogenes may transduced into retroviral genome ◼ Transduced gene replicated and transmitted like viral genes ◼ Upon infection the transduced gene expressed abundantly under viral signal
  19. Insertion ◼ Insertion of a retroviral promoter adjacent to cellular oncogene ◼ First occurred in avian leucosis virus Host gene 5’LTR 3’ LTR C- myc
  20. Translocation ◼ Translocation of a proto-oncogene near a strong regulatory sequence ◼ Translocation may affect the expression of proto-oncogene or gene product Translocation in Burkitt’s lymphoma H pro. H-gene C-myc pro. C-myc gene H pro. C-myc gene C-myc pro. H-gene Chromosome 14 8 Chromosome 14 8
  21. Gene Amplification ◼ Increase in copy number of a potential gene resulting in excess production of the encoded protein ◼ Amplification of oncogene HER-2/neu occur in breast cancer ◼ Gene amplification mostly occur at the late stage of tumor progression
  22. Mutation ◼ Point mutation or deletion might change the function of a protein, ◼ Substrate specificity, ◼ cell binding property, ◼ Binding specificity of a transcription factors etc. ◼ Altered protein may lead to oncogenic activation, eg. C-ras gene
  23. Oncogenic Viruses ◼ DNA Viruses - Human papilomaviruses (HPV) - Epstein Barr Virus (EBV) - Hepatitis B Virus (HBV) ◼ RNA Viruses -Retroviruses -Hepatitis C Virus ◼ RNA tumor viruses introduce a transforming gene into the cell (??HCV) ◼ DNA tumor viruses induce or alter the expression of a pre existing cellular gene/s (proto-oncogene)
  24. Transformation by DNA and RNA Viruses ◼ DNA tumor Viruses do not carry any transduced oncogene but, most of the RNA tumor viruses do ◼ DNA tumor Viruses do not produce tumor in their natural host cells, but replicate there. ◼ RNA tumor viruses cause cancer in their natural host ◼ Both kind of tumor viruses integrate their genome into host DNA; at least a few copies of gene
  25. Transformation ……… Viruses (cont) • Permissive cells are productively infected. The virus proceeds through a lytic cycle that is divided into the usual early and late stages. The cycle ends with release of progeny viruses and (ultimately) cell death. • Nonpermissive cells cannot be productively infected, and viral replication is abortive. Some of the infected cells are transformed; in this case, the phenotype of the individual cell changes and the culture is perpetuated in an unrestrained manner.
  26. Transformation ……… Viruses (cont) • The oncogenes of DNA transforming viruses carry out early viral functions. • The oncogene becomes integrated into the host cell genome and is expressed constitutively. • The oncogenes of polyomaviruses are T antigens, which are expressed by alternative splicing from a single locus. • Adenoviruses express several E1A and E1B proteins from two genes.
  27. Retroviruses activate or incorporate cellular genes ◼ Retroviruses can transfer genetic information both horizontally and vertically. ◼ Horizontal transfer is accomplished by the normal process of viral infection, in which increasing numbers of cells become infected in the same host. ◼ Vertical transfer results whenever a virus becomes integrated in the germ line of an organism as an endogenous provirus; like a lysogenic Bacteriophage.
  28. • Nondefective viruses follow the usual retroviral life cycle. They provide infectious agents that have a long latent period, and often are associated with the induction of leukemias. Two classic models are FeLV (feline leukemia virus) and MMTV (mouse mammary tumor virus). • Tumorigenicity does not rely upon an individual viral oncogene, but upon the ability of the virus to activate a cellular proto-oncogene (s). ⚫ Acute transforming viruses have gained new genetic information in the form of an oncogene. This gene is not present in the ancestral (nontransforming virus); it originated as a cellular gene that was captured by the virus by means of a transduction event during an infective cycle. These viruses usually induce tumor formation in vivo rather rapidly, and they can transform cultured cells in vitro. Reflecting the fact that each acute transforming virus has specificity toward a particular type of target cell, these viruses are divided into classes. • Acute transforming retroviruses have oncogenes that are derived from cellular genes.
  29. ◼ When a retrovirus captures a cellular gene by exchanging part of its own sequence for a cellular sequence, some of the original retro - viral sequences are replaced by a cellular sequence, creates a transducing virus that has two important properties, -Usually these viruses are replication-defective, cannot replicate by itself, but they can propagate with a wild-type "helper" virus -During an infection, their expression may alter the phenotype of the infected cell