Presentation on theme: "MOLECULAR BASIS OF CANCER Assoc. Prof. Işık G"— Presentation transcript:
1 MOLECULAR BASIS OF CANCER Assoc. Prof. Işık G MOLECULAR BASIS OF CANCER Assoc.Prof. Işık G. Yuluğ Bilkent University Department of Molecular Biology and Genetics
2 Cellular Basis of Cancer Cancer is a collection of diseases characterized by abnormal and uncontrolled growthCancer arises from a loss of normal growth controlIn normal tissues, the rates of new cell growth and old cell death are kept in balanceIn cancer, this balance is disruptedThis disruption can result from1) uncontrolled cell growth or2) loss of a cell's ability to undergo apoptosisCancer 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 uncontrolled cell growth or loss of a cell's ability to undergo "apoptosis."Apoptosis, or programmed cell death, is the mechanism by which old or damaged cells normally self-destruct.
3 Cancer Cell Do Not Grow Faster Than Normal Cells Rather, Their Growth is JustUncontrolled
5 Cellular equilibrium Proliferation Death Differentiation Transit RenewingTransitProliferatingExiting
6 Cancer: disruption of cellular equilibrium ProliferationDifferentiationDeath
7 Stem cells as the target of carcinogens Post mitoticStem cellNormal senescent differentiated cellDifferentiatedGrade 3 or 4 malignancyGrade 2 malignancyBenign tumor
8 Invasion and Metastasis Abnormal cells proliferate and spread (metastasize) to other parts of the bodyInvasion - direct migration and penetration into neighboring tissuesMetastasis - cancer cells penetrate into lymphatic system and blood vesselsCancers are capable of spreading through the body by two mechanisms: invasion and metastasis.Invasion refers to the direct migration and penetration by cancer cells into neighboring tissues.Metastasis refers to the ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body.
9 Malignant versus Benign Tumors Benign tumors generally do not spread by invasion or metastasisMalignant tumors are capable of spreading by invasion and metastasisDepending on whether or not they can spread by invasion and metastasis, tumors are classified as being either benign or malignant.Benign tumors are tumors that cannot spread by invasion or metastasis; hence, they only grow locally.Malignant tumors are tumors that are capable of spreading by invasion and metastasis.By definition, the term "cancer" applies only to malignant tumors.
10 What causes Cancer? Carcinogenic chemicals Radiation Some viruses Cancer is caused by alterations or mutations in the genetic codeCan be induced in somatic cells by:CarcinogenicchemicalsRadiationSome virusesHeredity - 5%Cancer is often perceived as a disease that strikes for no apparent reason. This is because scientists don't know all the reasons. But many of the causes of cancer have already been identified. Besides heredity, scientific studies point to the existence of three main categories of factors that contribute to the development of cancer: chemicals (e.g., from smoking or diet), radiation, and viruses or bacteria.In some cases, we don't know.We do know that there are chemical, physical and biological agents that trigger the cell mutations that cause cancer.These are called carcinogens, and include tobacco, ultraviolet radiation and asbestos.A number of cancers share risk factors. One in eight cancers and one in five cancer deaths are due to smoking and about 1 per cent of cancers are related to alcohol consumption. Many cancers occur as a direct result of dietary influences, from infectious agents or exposure to radiation (especially skin cancers from ultraviolet radiation), while a few result from inherited faulty or altered genes.Myths: It is a common myth that injuries can cause cancer. Cancer is not caused by a fall, fracture, bruise or bump. Sometimes it is when a person seeks medical help for an injury that a tumour is discovered, but it may have been there for a long time and is not due to the injury. Some people believe that cancer may be caused by stress, but there is not yet any reliable evidence to support this.Cancer is caused by mutations in somatic cells. They can be induced (by carcinogens, radiation and some viruses and bacteria), or some individuals have inherited genetic mutations that predispose trhem to develop specific types of cancer.
11 Oncogenes Cell cycle Apoptosis Tumor Suppressor Inv. and Mets AngiogenesisCell cycleHanahan and Weinberg, Cell 100: 57, 2000
12 What is the molecular basis of cancer? Cancer is a genetic disease. Mutations in genes result in altered proteinsDuring cell divisionExternal agentsRandom eventMost cancers result from mutations in somatic cellsSome cancers are caused by mutations in germline cells
13 Theories of cancer genesis Standard DogmaProto-oncogenes (Ras – melanoma)Tumor suppressor genes (p53 – various cancers)Modified DogmaMutation in a DNA repair gene leads to the accumulation of unrepaired mutations (xeroderma pigmentosum)Early-Instability TheoryMaster genes required for adequate cell reproduction are disabled, resulting in aneuploidy (Philadelphia chromosome)
14 CANCER AND GENETICS Cancer: genome disease Causes of genomic changes Effects of genomic changesRevolution in cancer treatment: ‘Smart Bullets Period’
15 Changes in nucleotides Epigenetic effects CANCER: GENOME DISEASELoss of DNAGain of DNAChanges in nucleotidesEpigenetic effects
16 Signs for Genomic Changes in Cancer Changes in chromosome numbers- AneuploidyChromosomal changesIncrease in DNA copy number -15 different region- Loss in chromosomal regionsMicro changes- Microsatellite changes Mikrosatellite- Nucleotide changes
18 Chromosomal changes in the genome of cancer cells: tip of the iceberg ReciprocaltranslocationRingChromosomeDeletionDuplicationTerminalDeletionInsertionInversionRobertsonianTranslocationIsochromosomes
19 Nucleotide changes in the genome of cancer cells: unseen site of the iceberg DeletionsNucleotideInsertionsNucleotideSubstitutions
24 Genetic and Epigenetic Silencing of Tumor Suppressor Genes Plass
25 THE CAUSES OF GENOMIC CHANGES IN CANCER UVReplication ErrorsCarcinogenic chemicalsRadiationNormal cellVirusesDamaged DNARearrangements (translocation, deletions, amplifications)Point mutationsAlters DNA of genes controlling cell proliferation. (Proliferation becomes abnormal)Cancer cell
26 Virus DNA İntegrasyonu THE CAUSES OF GENOMIC CHANGES IN CANCER:Somatic ChangesHasarEtken TürüEtkeniKanser RiskiİşaretiFizikselMorötesi IşınlarDeri Ka., MelanomaP53 (CC-TT)RadyasyonTiroid Ka., LösemiTranslokasyonKimyasalBenzoprenAkciğer Ka.p53 (G-T)AflatoksinKaraciğer Ka.p53 (249 G-T)Oksidatif StresYaşlılık KanserleriP53 (C-T)BiyolojikHBVVirus DNA İntegrasyonu
27 THE CAUSES OF GENOMIC CHANGES IN CANCER: Hereditary Predisposition GenesDiseaseFunctionInheretanceCancer RiskFA GenesF-ADNA Damage respose ?ORLösemiXP GenesX-PNER TypeDNA RepairSkin Ca.BLMBloomDNA Helicase ?Various cancersWRNWernerSarcomaRECQ4Rothmund-ThomsonDNA HelicaseMLH1, MSH2,PMS1, PMS2MMRODColon, Endometrium Ca.Lösemi, NF1BRCA1, BRCA2Breast, Ovary,Prostate, Pancreas CaATMA-TDNA Damage sense ?Lymphoma, LeukemiaBreast Ca. ?p53Li-FraumeniDNA Damage sense
28 CANCER AND GENETICS Approximately 90-95% of all cancers are sporadic. 5-10% are inherited.
29 GENES PLAYING ROLE IN CANCER DEVELOPMENT • Oncogenes• Tumor suppressor genes• DNA repair genes
30 - What are the genes responsible for tumorigenic cell growth? + ++ Normal+-Proto-oncogenesCell growthandproliferationTumor suppressor genesCancerMutated or “activated”oncogenes++MalignanttransformationLoss or mutation ofTumor suppressor genes
31 ONCOGENES Oncogenes are mutated forms of cellular proto-oncogenes. Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation.
32 Five types of proteins encoded by proto- oncogenes participate in control of cell growth: Class I: Growth FactorsClass II: Receptors for Growth Factors and HormonesClass III: Intracellular Signal TransducersClass IV: Nuclear Transcription FactorsClass V: Cell-Cycle Control Proteins
36 Amino acid substitutions in Ras family proteins (inactivates GTPase) amino acid positionRas gene Tumorc-ras (H, K, N) Gly Ala Gln normal cellsH-ras Gly Ala Leu lung carcinomaVal Ala Gln bladder carcinomaK-ras Cys Ala Gln lung carcinomaArg Ala Gln lung carcinomaVal Ala Gln colon carcinomaN-ras Gly Ala Lys neuroblastomaGly Ala Arg lung carcinomaMurine sarcoma virusH-ras Arg Thr Gln Harvey strainK-ras Ser Thr Gln Kirsten strain
37 Activation mechanisms of proto-oncogenes proto-oncogene --> oncogene
38 CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogeneBurkitt lymphoma t(8;14) 80% of cases c-myc1t(8;22) 15% of casest(2;8) % of casesChronic myelogenous t(9;22) 90-95% of cases bcr-abl2leukemiaAcute lymphocytic t(9;22) 10-15% of cases bcr-abl2Leukemia1c-myc is translocated to the IgG locus, which results in its activated expression2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
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”)
41 The result: Overproduction of growth factors Flooding of the cell with replication signalsUncontrolled stimulation in the intermediary pathwaysCell growth by elevated levels of transcription factors
42 Tumor suppressor genes Normal function - inhibit cell proliferationAbsence/inactivation of inhibitor --> cancerBoth gene copies must be defective
43 KNUDSON TWO HIT HYPOTHESIS IN FAMILIAL CASES Familial RB (%30)RBrbNormal cellsrbRBrbRBLOHInactivation of a tumor suppressor gene requires two mutations, inherited mutation and somatic mutation.Tumor cellsNormal cells
44 KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES RBLOHMutationNormalCellsRBRBInactivation of a tumor suppressor gene requires two somatic mutations.Tumor cells
45 TUMOR SUPPRESSOR GENES Disorders in which gene is affectedGene (locus) Function Familial SporadicDCC (18q) cell surface unknown colorectalinteractions cancerWT1 (11p) transcription Wilm’s tumor lung cancerRb1 (13q) transcription retinoblastoma small-cell lungcarcinomap53 (17p) transcription Li-Fraumeni breast, colon,syndrome & lung cancerBRCA1(17q) transcriptional breast cancer breast/ovariantumorsBRCA2 (13q) regulator/DNA repair
46 CELL CYCLE S CELL CYCLE Daugther cell Gateway Mitosis Growth Factors DNA replicationControl PointGatewayGrowthFactorsCell cycle inhibitorsCELL CYCLES
47 Rb gene Rb protein controls cell cycle moving past G1 checkpoint Rb protein binds regulatory transcription factor E2FE2F required for synthesis of replication enzymesE2F - Rb bound = no transcription/replicationGrowth factor --> Ras pathway--> G1Cdk-cyclin synthesizedActive G1 Cdk-cyclin kinase phosphorylates RbPhosphorylated Rb cannot bind E2F --> S phaseDisruption/deletion of Rb geneInactivation of Rb protein--> uncontrolled cell proliferation --> cancer
48 p53 Phosphyorylated p53 activates transcription of p21 gene p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase activity)Cell cycle arrested to allowDNA to be repairedIf damage cannot be repaired--> cell death (apoptosis)Disruption/deletion of p53 geneInactivation of p53 protein--> uncorrected DNA damage--> uncontrolled cell proliferation --> cancer
49 DNA REPAIR GENESThese 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.
50 Molecular mechanisms of DNA double strand break repair BRCA1/2Van Gent et al, 2001
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