logging in or signing up Molecular_Basis_of_cancer_2 aSGuest131420 Download Post to : URL : Related Presentations : Let's Connect Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Copy embed code: Embed: Flash iPad Dynamic Copy Does not support media & animations Automatically changes to Flash or non-Flash embed WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 128 Category: Entertainment License: All Rights Reserved Like it (0) Dislike it (0) Added: April 04, 2012 This Presentation is Public Favorites: 0 Presentation Description Molecular_Basis_of_cancer Comments Posting comment... Premium member Presentation Transcript MOLECULAR BASIS OF CANCER Assoc.Prof. Işık G. Yuluğ Bilkent University Department of Molecular Biology and Genetics firstname.lastname@example.org: 1 MOLECULAR BASIS OF CANCER Assoc.Prof. Işık G. Yuluğ Bilkent University Department of Molecular Biology and Genetics email@example.comCellular Basis of Cancer: 2 Cellular Basis of Cancer Cancer is a collection of diseases characterized by abnormal and uncontrolled growth Cancer arises from a loss of normal growth control In normal tissues, the rates of new cell growth and old cell death are kept in balance In cancer, this balance is disrupted This disruption can result from 1) uncontrolled cell growth or 2) loss of a cell's ability to undergo apoptosisPowerPoint Presentation: 3 Cancer Cell Do Not Grow Faster Than Normal Cells Rather, Their Growth is Just UncontrolledPowerPoint Presentation: 4 1 fertilized egg 50x10 12 Proliferation Differentiation Death 10 16 cell divisions/lifetimePowerPoint Presentation: 5 Proliferation Differentiation Death Transit Proliferating Exiting Renewing Cellular equilibriumPowerPoint Presentation: 6 Proliferation Differentiation Death Cancer: disruption of cellular equilibriumPowerPoint Presentation: 7 Post mitotic Stem cell Differentiated Normal senescent differentiated cell Benign tumor Grade 2 malignancy Grade 3 or 4 malignancy Stem cells as the target of carcinogensInvasion and Metastasis : 8 Invasion and Metastasis Abnormal cells proliferate and spread (metastasize) to other parts of the body Invasion - direct migration and penetration into neighboring tissues Metastasis - cancer cells penetrate into lymphatic system and blood vesselsPowerPoint Presentation: 9 Benign tumors generally do not spread by invasion or metastasis Malignant tumors are capable of spreading by invasion and metastasis Malignant versus Benign TumorsWhat causes Cancer?: 10 What causes Cancer? Cancer is caused by alterations or mutations in the genetic code Can be induced in somatic cells by: Carcinogenic chemicals Radiation Some viruses Heredity - 5%PowerPoint Presentation: 11 Hanahan and Weinberg, Cell 100: 57, 2000 Apoptosis Oncogenes Tumor Suppressor Inv. and Mets Angiogenesis Cell cyclePowerPoint Presentation: 12 What is the molecular basis of cancer? Cancer is a gene tic disease. Mutations in genes result in altered proteins During cell division External agents Random event Most cancers result from mutations in somatic cells Some cancers are caused by mutations in germline cellsPowerPoint Presentation: 13 Theories of cancer genesis Standard Dogma Proto-oncogenes (Ras – melanoma) Tumor suppressor genes (p53 – various cancers) Modified Dogma Mutation in a DNA repair gene leads to the accumulation of unrepaired mutations (xeroderma pigmentosum) Early-Instability Theory Master genes required for adequate cell reproduction are disabled, resulting in aneuploidy (Philadelphia chromosome)PowerPoint Presentation: 14 CANCER AND GENETICS Cancer: genome disease Causes of genomic changes Effects of genomic changes Revolution in cancer treatment: ‘Smart Bullets Period’PowerPoint Presentation: 15 CANCER: GENOME DISEASE Loss of DNA Gain of DNA Changes in nucleotides Epigenetic effectsPowerPoint Presentation: 16 Signs for Genomic Changes in Cancer Changes in chromosome numbers - Aneuploidy Chromosomal changes Increase in DNA copy number -15 different region - Loss in chromosomal - 200.000 regions Micro changes - Microsatellite changes Mikrosatellite - 100.000 - Nucleotide changesPowerPoint Presentation: 17PowerPoint Presentation: 18 Chromosomal changes in the genome of cancer cells: tip of the iceberg Terminal Deletion http://www.tokyo-med.ac.jp/genet/cai-e.htm Ring Chromosome Robertsonian Translocation Deletion Reciprocal translocation Isochromosomes Insertion Inversion DuplicationPowerPoint Presentation: 19 Nucleotide changes in the genome of cancer cells: unseen site of the iceberg Nucleotide Deletions Nucleotide Insertions Nucleotide Substitutions http://www.tokyo-med.ac.jp/genet/cai-e.htmPowerPoint Presentation: 20 DNA Loss in cancer cellsPowerPoint Presentation: 21 Early Brain Tumor ( Astrocytoma Stage II ) Advance Brain Tumor Gl i oblastoma Multiform ( Stage IV) DNA Loss in cancer cells : beyond coincidence . ..PowerPoint Presentation: 22 p53 locus Chromosomal loss: Mostly, it is a sign for the loss of a tumor suppressor gene PTEN locus CDKN2 locus RB1 locus ??? locusPowerPoint Presentation: 23 Cancer: Genome Disease Epigenetic effectsPowerPoint Presentation: 24 Genetic and Epigenetic Silencing of Tumor Suppressor Genes Plass - 2002PowerPoint Presentation: 25 Carcinogenic chemicals UV Replication Errors Radiation Viruses Rearrangements (translocation, deletions, amplifications) Point mutations Alters DNA of genes controlling cell proliferation. (Proliferation becomes abnormal) Cancer cell Normal cell Damaged DNA THE CAUSES OF GENOMIC CHANGES IN CANCERPowerPoint Presentation: 26 Hasar Etken T ü r ü Hasar Etkeni Kanser Riski İşareti Fiziksel Mor ö tesi Işınlar Deri Ka., Melanoma P53 (CC-TT) Radyasyon Tiroid Ka., L ö semi Translokasyon Kimyasal Benzopren Akciğer Ka. p53 (G-T) Aflatoksin Karaciğer Ka. p53 (249 G-T) Oksidatif Stres Yaşlılık Kanserleri P53 (C-T) Biyolojik HBV Karaciğer Ka. Virus DNA İntegrasyonu THE CAUSES OF GENOMIC CHANGES IN CANCER: Somatic ChangesPowerPoint Presentation: 27 Genes Disease Function Inheretance Cancer Risk FA Genes F-A DNA Damage respose ? OR L ö semi XP Genes X-P NER Type DNA Repair OR Skin Ca. BLM Bloom DNA Helicase ? OR Various cancers WRN Werner DNA Helicase ? OR Sarcoma RECQ4 Rothmund-Thomson DNA Helicase OR Sarcoma MLH1, MSH2, PMS1, PMS2 MMR DNA Repair OD Colon, Endometrium Ca. OR L ö semi, NF1 BRCA1, BRCA2 DNA Repair OD Breast, Ovary, Prostate, Pancreas Ca ATM A-T DNA Damage sense ? OR Lymphoma, Leukemia OD Breast Ca. ? p53 Li-Fraumeni DNA Damage sense OD Various cancers THE CAUSES OF GENOMIC CHANGES IN CANCER: Hereditary PredispositionPowerPoint Presentation: 28 Approximately 90-95% of all cancers are sporadic. 5-10% are inherited. CANCER AND GENETICSPowerPoint Presentation: 29 • Oncogenes • Tumor suppressor genes • DNA repair genes GENES PLAYING ROLE IN CANCER DEVELOPMENTPowerPoint Presentation: 30 What are the genes responsible for tumorigenic cell growth? Normal Cancer Proto-oncogenes Cell growth and proliferation Tumor suppressor genes + - Mutated or “activated” oncogenes Malignant transformation Loss or mutation of Tumor suppressor genes ++ONCOGENES: 31 ONCOGENES Oncogenes are mutated forms of cellular proto-oncogenes. Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation.PowerPoint Presentation: 32 Class I: Growth Factors Class II: Receptors for Growth Factors and Hormones Class III: Intracellular Signal Transducers Class IV: Nuclear Transcription Factors Class V: Cell-Cycle Control Proteins Five types of proteins encoded by proto-oncogenes participate in control of cell growth:PowerPoint Presentation: 33 4. Nuclear Proteins: Transcription Factors 5. Cell Growth Genes 3. Cytoplasmic Signal Transduction Proteins 1. Secreted Growth Factors 2. Growth Factor Receptors Functions of Cellular Proto-OncogenesPowerPoint Presentation: 34 A generic signalling pathwayOncogenes: 35 Oncogenes proto-oncogene = ras Oncogene = mutated ras Always activated Always stimulating proliferationPowerPoint Presentation: 36 amino acid position Ras gene 12 59 61 Tumor c-ras (H, K, N) Gly Ala Gln normal cells H-ras Gly Ala Leu lung carcinoma Val Ala Gln bladder carcinoma K-ras Cys Ala Gln lung carcinoma Arg Ala Gln lung carcinoma Val Ala Gln colon carcinoma N-ras Gly Ala Lys neuroblastoma Gly Ala Arg lung carcinoma Murine sarcoma virus H-ras Arg Thr Gln Harvey strain K-ras Ser Thr Gln Kirsten strain Amino acid substitutions in Ras family proteins (inactivates GTPase)Activation mechanisms of proto-oncogenes: 37 Activation mechanisms of proto-oncogenes proto-oncogene --> oncogenePowerPoint Presentation: 38 CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8;14) 80% of cases c-myc 1 t(8;22) 15% of cases t(2;8) 5% of cases Chronic myelogenous t(9;22) 90-95% of cases bcr-abl 2 leukemia Acute lymphocytic t(9;22) 10-15% of cases bcr-abl 2 Leukemia 1 c-myc is translocated to the IgG locus, which results in its activated expression 2 bcr-abl fusion protein is produced, which results in a constitutively active abl kinasePowerPoint Presentation: 39 GENE AMPLIFICATION Oncogene Amplification Source of tumor c-myc ~20-fold leukemia and lung carcinoma N-myc 5-1,000-fold neuroblastoma retinoblastoma L-myc 10-20-fold small-cell lung cancer c-abl ~5-fold chronic myoloid leukemia c-myb 5-10-fold acute myeloid leukemia colon carcinoma c-erbB ~30-fold epidermoid carcinoma K-ras 4-20-fold colon carcinoma 30-60-fold adrenocortical carcinomaPowerPoint Presentation: 40 Oncogenes are usually dominant (gain of function) cellular proto-oncogenes that have been mutated (and “activated”) cellular proto-oncogenes that have been captured by retroviruses and have been mutated in the process (and “activated”) virus-specific genes that behave like cellular proto-oncogenes that have been mutated to oncogenes (i.e., “activated”)The result:: 41 The result : Overproduction of growth factors Flooding of the cell with replication signals Uncontrolled stimulation in the intermediary pathways Cell growth by elevated levels of transcription factorsTumor suppressor genes: 42 Tumor suppressor genes Normal function - inhibit cell proliferation Absence/inactivation of inhibitor --> cancer Both gene copies must be defectivePowerPoint Presentation: 43 KNUDSON TWO HIT HYPOTHESIS IN FAMILIAL CASES RB rb rb rb RB Familial RB (%30) Tumor cells Normal cells Normal cells Inactivation of a tumor suppressor gene requires two mutations, inherited mutation and somatic mutation. RB LOHPowerPoint Presentation: 44 RB RB RB LOH RB Mutation Normal Cells Tumor cells KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES RB RB Inactivation of a tumor suppressor gene requires two somatic mutations.PowerPoint Presentation: 45 TUMOR SUPPRESSOR GENES Disorders in which gene is affected Gene (locus) Function Familial Sporadic DCC (18q) cell surface unknown colorectal interactions cancer WT1 (11p) transcription Wilm’s tumor lung cancer Rb1 (13q) transcription retinoblastoma small-cell lung carcinoma p53 (17p) transcription Li-Fraumeni breast, colon, syndrome & lung cancer BRCA1(17q) transcriptional breast cancer breast/ovarian tumors BRCA2 (13q) regulator/DNA repairPowerPoint Presentation: 46 CELL CYCLE Daugther cell Mitosis DNA replication Control Point Gateway Growth Factors Cell cycle inhibitors CELL CYCLE SRb gene: 47 Rb gene Rb protein controls cell cycle moving past G1 checkpoint Rb protein binds regulatory transcription factor E2F E2F required for synthesis of replication enzymes E2F - Rb bound = no transcription/replication Growth factor --> Ras pathway --> G1Cdk-cyclin synthesized Active G1 Cdk-cyclin kinase phosphorylates Rb Phosphorylated Rb cannot bind E2F --> S phase Disruption/deletion of Rb gene Inactivation of Rb protein --> uncontrolled cell proliferation --> cancerp53: 48 p53 Phosphyorylated p53 activates transcription of p21 gene p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase activity) Cell cycle arrested to allow DNA to be repaired If damage cannot be repaired --> cell death (apoptosis) Disruption/deletion of p53 gene Inactivation of p53 protein --> uncorrected DNA damage --> uncontrolled cell proliferation --> cancerPowerPoint Presentation: 49 These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle. Mutations in DNA repair genes lead to an increase in the frequency of mutations in other genes, such as proto-oncogenes and tumor suppressor genes. i.e. Breast cancer susceptibility genes (BRCA1 and BRCA2) Hereditary non-polyposis colon cancer susceptibility genes (MSH2, MLH1, PMS1, PMS2) have DNA repair functions. Their mutation will cause tumorigenesis. DNA REPAIR GENESPowerPoint Presentation: 50 Van Gent et al, 2001 Molecular mechanisms of DNA double strand break repair BRCA1/2PowerPoint Presentation: 51 IMPORTANCE OF DNA REPAIRMultiple mutations lead to colon cancer Genetic changes --> tumor changes: 52 Multiple mutations lead to colon cancer Genetic changes --> tumor changes Cellular Tumor ProgressionPowerPoint Presentation: 53 Revolution in cancer treatment: ‘ Smart Bullets Period ’PowerPoint Presentation: 54 Hanahan & Weinberg 2000 Summary of 30 years of research (1971-2001)PowerPoint Presentation: 55 Bilimsel Araştırmaların Kanserle Savaşa Katkısı HERCEPTİN HERCEPTIN STI-571PowerPoint Presentation: 56 Translocation and Bcr-Abl fusion in CMLPowerPoint Presentation: 57 STI-571 against Bcr-AblPowerPoint Presentation: 58 Smart bullet STI-571 lockes itself to the target molecule STI-571PowerPoint Presentation: 59 Thousands of Targets HERCEPTIN STI-571 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?PowerPoint Presentation: 60 MOLECULAR BIO LOGY & INFORMATICS Biyoinformatik ~ 30.000 genes ~ 300.000 protein ~3.000.000 interaction 1 human cell ~ 3.000.000.000 bp DNA You do not have the permission to view this presentation. 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