CANCER, ONCOGENES AND TUMOUR SUPPRESSOR GENES PHL 425 Dr. Mohamed M. Sayed-Ahmed

1. CANCER, ONCOGENES AND TUMOUR SUPPRESSOR GENESPHL 425Dr. Mohamed M. Sayed-Ahmed

2. SOLID TUMOURS • Anal carcinoma • Billary tract carcinoma • Brain tumours (Gliomas) • Breast cancer • Cervical Carcinoma • Colorectal Carcinoma • Endometrial carcinoma • Esophageal carcinoma • Gastric carcinoma • Germ cell carcinomas • Head and neck carcinomaoma • Hepatocellular carcinoma • Lung cancer (SCLC and NSCLC) • Malignant melanoma • Neuroblastoma • Ovarian carcinoma • Pancreatic carcinoma • Prostatic carcinoma • Renal cell carcinoma • Retinoblastoma • Throid carcinoma • Wilms’ tumour (Nephroblastoma)

3. HEMATOLOGIC TUMOURS • Acute lymphoblastic leukemia (ALL) • Acute myeloid leukemia (AML) • Chronic lymphocytic leukemia (CLL) • Chronic myeloid leukemia (CML) • Hairy cell leukemia (HCL) • Hodgkin’s lymphoma (HL) • Non-Hodgkin’s lymphoma (NHL)

4. CANCER • CANCER is the uncontrolled growth of cells due to damage to DNA (mutations). • Cell division (proliferation) is a physiological process that occurs in almost all tissues and under many circumstances. Normally homeostasis, the balance betweenproliferation and programmed cell death (apoptosis) is maintained by tightly regulating both processes to ensure the integrity of organs and tissues. • Mutations in DNA that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes. In fact, a series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell.Only mutations in those certain types of genes which play vital roles in cell division, cell death, and DNA repair will cause a cell to lose control of its proliferation.

5. Characteristics of Cancer Cells 1- They are resistant to apoptosis ("programmed" cell death). 2- They have an uncontrolled ability to divide (or, they are immortal), and they often divide at an increased rate. 3- These cells are self-sufficient with respect to growth factors. 4- They are insensitive to antigrowth factors. 5- They have the ability to invade neighboring tissues, usually through the secretion of metalloproteinases that can digest extracellular matrix material. They can form new tumors (metastases) at distant sites. 6- They secrete chemical signals that stimulate the growth of new blood vessels (angiogenesis).

6. NORMAL CELL Growth factor Growth factor receptor cytoplasm Signal transduction Activation of transcription nucleus

7. NEOPLASTIC CELLS Increased In growth factor receptors Increased in signal transduction Increased In growth factor Increase in activation of transcription

8. Causes of Neoplasia • Environmental causes: (Carcinogens) • Chemicals • Viruses • Radiation • Hereditary causes- Genetic defects. • Combination – common. • All cancer is genetic, not all cancer is hereditary

10. Chemical Carcinogenesis • Initiation • DNA damage eg. DENA (diethylnitrosamine) Benzpyrene • Promotion • Histologic change Ccl4 Turpentine (co-carcinogens) • DENA + Ccl4 (Liver Cancer) • Malignant transformation: • Visible tumor formation

11. INITIATION Initiation is an irreversible genetic alteration which result from the interaction of the ultimate carcinogen with the DNA in the target cell. (1) Is an irreversible process (2) Caused only by carcinogenic compounds (3) Occurs after carcinogen exposure (4) Initiator alone does not result in tumor formation

12. PROMOTION Promotion refers to a phenomenon of gene activation in which the latent altered phenotype of the initiated cellsbecomes expressed through selection and clonal expansion. 1- Is a reversible process 2- Acts only after exposure to an initiator 3- Requires repeated administration 4- Promotor is not carcinogenic in itself 5- promotr alone does not result in tumor formation

13. INITIATION AND PROMOTION

14. Molecular Basis of Carcinogenesis Four classes of regulatory genes. 1- Tumour Promotors:Proto-oncogenes 2- Tumour Inhibitors:Tumour-suppressor genes 3- Genes regulating Apoptosis 4- DNA repair genes.

15. Non-lethal Genetic damage lies at the center of carcinogenesis • Loss/damage to suppressor genes • Overexpression of promotor genes • Loss/damage to Apoptosis genes • Loss/damage of DNA repair genes.

16. PROTO-ONCOGENES are genes which promote cell growth and mitosis (cell division). TUMOUR SUPPRESSOR GENES: discourage cell growth, or temporarily halts cell division from occurring in order to carry out DNA repair. Typically, a series of several mutationsto these genes are required before a normal cell transforms into a cancer cell.

17. Acquired environmental factors chemicals ,radiation ,viruses Pathogenesis Genetic factors Changes in genome of somatic cells Activation of growth promoting oncogenes Inactivation of tumour supressor genes Expression all altered gene products and loss of regular gene products MALIGNANT NEOPLSM

18. Heredity Radiation V-Onc Chemical Other Molecular Basis of Neoplasia Proto-oncogene Oncogene

19. Tumor suppressor genes • A tumor suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. A mutation or deletion of such a gene will increase the probability of the formation of a tumor. • Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis,' which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53.

20. Tumor suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. Examples of tumour suppressor Genes Includes: P53, Rb, BRCA-1 and BRCA-2 The first tumor suppressor protein discovered was the pRB protein in human retinoblastoma; however, recent evidence has also implicated pRb as a tumor survival factor. Another important tumor suppressor is the p53 tumor suppressor protein produced by the TP53 gene. Families in which there is a high breast cancer frequency have mutations affecting the tumor suppressor gene BRCA-1 and BRCA-2.

21. Role of p53 gene 1- p53 senses DNA damage. 2- Induces G1 arrest. 3- Induces DNA repair process. 4- induces apoptosis in cells with un-repairable DNA. 5- “P53 is a guardian of the genome. • Its homozygous loss leads to accumulation of damaged DNA may result in malignancy” • Homozygous loss of p53 is seen in virtually every type of cancer. • Over half of human malignant cells show loss of p53 gene by special tests.

24. proto-Oncogenes * A proto-oncogen is a normal gene that can become an oncogene, either after mutation or increased expression. * Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. *Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. * Upon activation, a proto-oncogene (or its product) becomes a tumor inducing agent, an oncogene.

25. C-MYC C-MYC is a major transcription factor that encodes nuclear DNA binding proteins that regulate cell growth, transformation, angiogenesis, cell-cycle control and apoptosis . This could explain the aggressiveness and poor prognosis associated with tumours over expressing C-MYC proteins.

26. HER-1 HER1 gene, codes for epidermal growth factor receptor (EGFR), which has extracellular ligand binding domain and cytoplasmic domain with high tyrosine kinase activity. It plays an important role in cell proliferation, migration and protection against apoptosis. Poor prognosis of breast tumors over expressing HER1 has been reported. It is well documented that HER1 protein is targeted by inhibiting its extracellular legend binding domain using monoclonal antibodies and/or its tyrosine kinase activity in cytoplasmic domain by tyrosine kinase inhibitors (TKIs).

27. HER2/neu. HER2/neu gene, codes for the human epidermal growth factor receptor 2 (HER2), which has extracellular ligand binding domain and cytoplasmic domain with high tyrosine kinase activity. It plays an important role in cell proliferation, migration and protection against apoptosis. HER2 is overexpressed by many adenocarcinomas, particularly breastadenocarcinomas.Trastuzumab is a monoclonal antibody and must only be administered to female HER-2-positive patients, i.e., in whom the tumours overexpress the HER-2 protein or amplify the HER-2 gene.

28. Cell cycle