Oncogenes Lecture 43

1. OncogenesLecture 43 Dr. Richard D. Howells

2. Normal and Malignant Cell Growth • Multiplication of cells is carefully regulated in humans • In young children, cell division exceeds cell death as a child grows • In adults, cell birth and death are balanced to produce a steady state • Different cells have different lifetimes: intestinal cells exist a few days before they die and are replaced; red blood cells have a 100 d half-life, healthy liver cells rarely die; there is a slow loss of brain cells with little replacement • Some cells lose the fine controls that regulate cell division as a result of accumulated multiple mutations and may lead to tumor formation

3. Changes in cells that cause cancer

4. Tumor Cells and the Onset of Cancer • Tumors arise frequently in aged humans but usually pose little risk: benign tumors remain confined to one area, do not interfere with normal functions, and are easy targets for surgical removal • Malignant tumors invade surrounding tissue and spread to other sites (metastasis). They are difficult to remove surgically • Tumor growth requires formation of new blood vessels (angiogenesis); this has stimulated interest in natural proteins that inhibit angiogenesis, like angiogenin and endostatin, or antagonists of the VEGF receptor, as anti-cancer therapeutic agents

5. DNA from Tumor Cells Can Transform Normal Cultured Cells • This observation established that DNA mutations can result in uncontrolled cell growth • Oncogenes were identified as a result of adding DNA from tumor cells to normal cells and observing cell transformation • Transformed cells have similar properties to malignant tumors, including changes in cell morphology, ability to grow unattached to extracellular matrix, reduced need for growth factors, and secretion of plasminogen activator

6. Development of Cancer Requires Several Mutations: the multi-hit model • The incidence of most types of cancer increase exponentially with age • Animal studies on kinetics of tumor appearance in transgenic mice with overexpressed oncogenes supports the model: there is cooperativity of oncogenic mutations

7. Incidence of Human Cancer Increases with Age

8. Kinetics of Tumor Appearance in Transgenic Mice Expressing Oncogenes

9. Metastasis of human colorectal cancer

10. Oncogenes • An oncogene is any gene that encodes a protein able to transform cells in culture or induce cancer in animals • Most oncogenes are derived from normal cellular genes (i.e. proto-oncogenes) whose products participate in cellular growth-controlling pathways • Activation of a proto-oncogene generally involves a gain-of-function mutation: point mutation leading to constitutively active protein product, gene amplification, or chromosomal translocation that causes inappropriate expression of a growth-regulatory gene

11. Types of Oncogenes

12. Oncogenes were first identified in cancer-causing retroviruses • Peyton Rous observed that if he excised tumors from chickens, ground them up and injected other chickens with the extract, they developed tumors • The transforming agent was later shown to be a virus: Rous sarcoma virus (RSV) • RSV was shown to be a retrovirus that had picked up a mutated v-src gene (oncogene) • In 1977, Bishop and Varmus showed normal cells contain a closely related gene c-src (proto-oncogene): mutation of the proto-oncogene converted it into an oncogene • v-Src protein is a constitutively active mutant of c-Src: a protein tyrosine kinase

13. Oncogenic Mutations Affecting Cell Proliferation • Class I: the sis oncogene encodes a type of aberrant active platelet-derived growth factor (PDGF) • Spleen focus-forming virus (SFFV) is a retrovirus that induces erythroleukemia (a tumor of erythroid progenitors) in mice • SFFV encodes a protein, gp55, that activates Epo receptors on erythroid precursor cells

14. Aberrant Activation of the EPO (erythopoietin) Receptor

15. Type II:Effects of oncogenic mutations in cell-surface receptors

16. Type III: Oncogenic mutation of Src Phosphorylation of Tyr 527 inactivates Src tyrosine kinase activity; v-Src lacks the Tyr 527 and is constitutively active

17. Powerful Anti-Cancer Drug (Gleevec, STI-571) Emerges From Basic Biology The chromosomal translocation causes the fusion of the c-Abl tyrosine kinase from chromosome 9 with the Bcr protein on chromosome 22. Gleevec inhibits the Abl tyrosine kinase and is used to treat chronic myelogenous Leukemia (CML)

18. Ras regulation GDP: guanosinediphosphate GTP: guanosinetriphosphate GEF: guanine nucleotide exchange factor GAP: GTPase activating protein RGS: Regulator of G protein signaling GDI: inhibit GTP hydrolysis

19. Type IV: Transcription Factors v-Fos is a constitutively activated mutant of c-Fos

20. Chromosomal translocation leading to overexpression of c-Myc

21. Types of Oncogenes

22. p53 and induction of apoptosis p53 is a tumor suppressor protein

23. Rb (retinoblastoma) cell cycle control Rb is a tumor suppressor protein

24. Multiple Myeloma • Accounts for 10% of hematologic cancers and 1% of all cancers • Annual incidence in US is 4/100,000 • 13,000 new cases are diagnosed each year in US • Predominantly occurs in 40-80 yr age group • More common in men (1.5x) and African-Americans (2x) • Median survival time with treatment is 24-40 months (12 months if untreated); 5-year survival is 20-35% and 10-year survival is 5-10% • Treatment is not curative and includes chemotherapy with autologous stem cell rescue and allogeneic bone marrow transplantation

25. Additive effects ofnaltrindole with other chemotherapeutic agents on human MM cell proliferation Cell prolif.