1. What is Cancer? Large number of complex diseases Behave differently depending upon cell type from which originate –Age on onset, invasiveness, response to treatment Common general properties –Abnormal cell growth/division (cell proliferation) –Spread to other regions of body (metastasis) Malignant tumors

2. Genetics of Cancer Cancer * mean "crab" * genetic disease * great variety of malignant tumor -uncontrolled cell growth

3. Properties of Cancer Cells Genetic instability –Mutator phenotype –Duplicating, losing and translocating chromosomes or portions of them common Chronic myelogenous leukemia (CML) –Chromosome 9/chromosome 22 translocation –BCR gene fused to ABL (protein kinase) –Mutant signal transduction protein stimulates cells constantly to proliferate

4. Normal and Cancer Karyotypes Chromosome painting (a) is a normal cell, (b) is a “very messed up” cancer cell

5. Tumor arises from a single cell – clonality arise from a single aberrant cell that then proliferate Cancer requires mutation of multiple genes Cancers often develop in progressive steps –From mildly aberrant cells to malignant –Process called tumorigenesis

6. Transformation is a multistep process

7. Tumorigenesis of Cervical Cancer

8. Three types of changes from normal cell to cancer cell  density-dependent inhibition  autocrine growth inhibition  contact inhibition

11. Cancer cell 의 특징 Invasion--collegnase secretion Angiogenesis--cancer cells secrete growth factors that promoter formation of new blood vessels Defective differentiation--fail to differentiate normally (leukemia) Apoptosis failure (damaged DNA death) Metastasis

12. Immortalization and transformation telomerase activity * essential for tumor formations, * critical parameter for immortalization is reactivation of telomerase

13. Two kinds of Cancer genes 1) oncogene ( 종양유발유전자 ) induce cell transformation (cancer cells) 2) tumor suppressor genes ( 종양억제유전자 )) inhibit cell proliferation, negative regulatory inhibit cell proliferation, negative regulatory protein protein *. Types of genes which may mutate to *. Types of genes which may mutate to cause cancer cause cancer DNA repair genes telomerase

14. Oncogenes oncogene is mutated form of normal genes called proto-oncogene proto-oncogene; control of cell proliferation and differentiation oncogenic virus oncogenic DNA virus oncogenic RNA virus (retrovial oncogene) src

15. proto-oncogen activation normal cell genes from which oncogene originated, encoding proteins that function in 1) signal transduction pathway 2) controlling normal cell proliferation

16. Proto-oncogene activation

17. Functions of oncogene products 1) uncotrolled proliferation of cancer cell 2) defective differentiation 3) failure to programmed cell death

18. ras Proto-oncogenes Involved in signal transduction pathway –As are many proto-oncogene products ras family genes mutated in 40% of all cancers Involved in signal transduction pathway from growth factor receptor to nucleus –G protein –Mutant form lacks GTPase activity and remains active

19. Tumour suppressor genes The gene’s normal function is to regulate cell div ision. Both alleles need to be mutated or removed in order to lose the gene activity. The first mutation may be inherited or somatic. The second mutation will often be a gross event leading to loss of heterozygosity in the surrounding area.

20. Tumor suppressor genes block abnormal growth and malignant transformation proto-oncogene; dominant in action tumor-suppressor gene ; recessive ( Rb, p53, INK4, APC, DCC)

21. Functions of tumor suppressor gene products tumor development by eliminating negative regulatory proteins ex) WT1, Rb and INK4, p53 gene product, APC and DCC

22. p53 suppresses progression through the cell cycle in response to DNA damage initiates apoptosis if the damage to the cell is severe acts as a tumour suppressor is a transcription factor and once activated, it represses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control

23. p53 Tumor Suppressor Gene Mutated (inactivated) in more than 50% of all cancers p53 regulates (activates or represses) transcription of more than 50 different genes p53 regulated by Mdm2 (prevents the phosphorylations and acetylations that activate inactive p53) Activated p53 levels rise rapidly if DNA is damaged or repair intermediates accumulate

24. p53 Function Activated p53 acts as transcription factor to turn on genes that –arrest the cell cycle so DNA can be repaired Initiates synthesis of p21, which inhibits CDK4/cyuclinD1 complex, blocking entry into S phase Genes expressed which retard rate of DNA replication Other products block G2/M progression –Initiate apoptosis if DNA cannot be readily repaired Turns on Bax gene, represses Bcl2 gene Bax homodimers activate process of cell destruction Cancer cells lacking p53 do not initiate pathway even if DNA/cellular damage is great

25. pRB Function Tumor suppressor protein that controls the G1/S checkpoint Found in nucleus and activity regulated by level of phosphorylation (by CDK4/cyclinD1 complex) –Nonphosphorylated version binds to TFs such as E2F, inactivating them –Free E2F and the other regulators turn on >30 genes required for transition to S phase

26. RB1 Tumor Suppressor Gene Retinoblastoma 1 gene Involved in breast, bone, lung, bladder and retinal cancers (among others) Inheriting one mutated (inactivated) copy of gene increases chances of retinoblastoma formation from 1/14,000-20,000 to 85% (plus increases other cancer rates) –Loss of second copy in a cell eliminates function –Normal cells unlikely to lose both good copies

27. Third category of cancer-causing genes. - excision, mismatch repair - cancer effects are indirect Defective DNA repair = increase rate of failure to repair mutations - mutations accumulate in the genome Significance - have an increased chance of mutation in a proto-oncogene and/or tumor suppressing gene DNA repair genes (Mutator genes)

29. The Main Jobs of the Cell Cycle: 1.To accurately transmit the genetic information! 2.To maintain normal ploidy; i.e. diploidy! Euploidy: additions of whole chromosome sets e.g. n, 2n, 3n, 4n = haploid, diploid, triploid, tetraploid Aneuploidy: additions or subtractions of one or more single chromosomes e.g. 2n + 1, 2n -1, 2n + 2, etc.

30. The cell cycle consists of two major phases: –Interphase, where chromosomes duplicate and cell parts are made –The mitotic phase, when cell division occurs The cell cycle multiplies cells Figure 8.5

31. Defects in Cell Cycle Regulation Cell cycle - G1, S, G2, M phases Progression through cycle is regulated and specific blocks or checkpoints exist Nondividing cell (quiescent) is in an extended G1 phase called G0 –Cancer cells never enter G0

32. Cell Cycle Checkpoints G1/S –Monitors cell size and for DNA damage G2/M –Replication complete, DNA damage? M –Spindle fibers connected, etc.? G0 –Does body require more of my type of cell?

33. Cell Cycle

34. Regulators of Cell Cycle Cyclins and cyclin-dependent kinases (CDKs) Cyclins synthesized and destroyed in a precise pattern –A cyclin bind to a specific CDKs, activating it Other proteins phosphorylated/activated CDK4/cyclinD activate transcription factors for genes such as DNA polymerase delta and DNA ligase CDK1/cyclinB trigger events of early mitosis (chromosome condensation, nuclear membrane breakdown, etc.)

35. Two Types of Cell Cycle Control 1.A Cascade of Protein Phosphorylations Phosphorylation = phosphate groups (PO 4 ) are added onto substrates by enzymes called kinases That guy Kinase asked me out and then told me he wanted give me a phosphate group to turn me on…ugh..men! Oh no he didn’t.

36. Rb P = Hypo-phosphorylated (Under-phosphorylated) Retinoblastoma Protein (Rb) = an important cell cycle regulator and tumor suppressor that is controlled by how much it is phosphorylated. It is a SUBSTRATE for the enzyme cyclin-dependent KINASE (cdk). Rb P P P P P = Hyper-phosphorylated (Over-phosphorylated)

37. E2F Transcription Factor: a protein that helps TRANSCRIBE genes (DNA  RNA) E2F is a transcription factor that is responsible for helping transcription of genes that help cells enter S phase E2F S-phase Gene Pretend this is a gene (piece of DNA) that needs to be transcribed to help push cells into S phase; without the transcription factor, E2F, it is NOT transcribed (no mRNA is made). S-phase Gene When E2F is allowed to “sit” on the gene, it helps the gene to undergo transcription. Copies of mRNA are made Copies of mRNA Transcription

38. E2F Rb and cdk’s Rb P P P P P P Cyclincdk No Transcription; No S-phase genes; No continuation through the cell cycle E2F S-phase Gene Transcription S-phase Gene S-phase genes transcribed! Let’s go start S-phase!

39. Cdk inhibitors E2F Rb P P P P P P Cyclincdk E2F S-phase Gene p16p21 p21 and p16 are proteins that inhibit the function of cdk’s. If you inhibit cdk function, Rb DOES NOT get hyperphosphorylated and E2F is NOT able to transcribe genes; when cdk inhibitors are around, the cell cycle is stopped!

40. Two Types of Cell Cycle Control 2. Checkpoint Control Checkpoints are places in the cell cycle where a cell will be stopped so that it can be checked for mistakes. Hey buddy, I don’t care whatcha say! I am not letting you through unless your DNA is correct!

41. Cell Cycle Checkpoints M G1 G2 S = DNA Damage Checkpoints = Spindle Checkpoints = G1 Checkpoint = G2 Checkpoint

42. Balance E2F Cyclin cdk p16 p21 Rb P P P P P P Checkpoint Proteins CANCER STOP GO

43. Cancer Cells Evade Two “Safety” Mechanisms Built into the Cell Cycle 1. Once p53 is inactivated, cells with DNA damage don’t arrest from G1 and don’t undergo apoptosis. 2. Telomerase enzyme is activated, avoiding the limit to cell divisions imposed by telomere shortening.

44. The Hallmarks of Cancer

45. Summary of Cancer It is a group of diseases caused by loss of cell cycle control. Cancer is associated with abnormal uncontrolled cell growth. Carcinogens are substances which cause cancer by mutating DNA. There are many genes that can mutate to cause loss of control of the cell cycle or genomic stability (DNA repair).