Neoplasia

1,549 views
1,267 views

Published on

Published in: Technology, Health & Medicine
0 Comments
5 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,549
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
101
Comments
0
Likes
5
Embeds 0
No embeds

No notes for slide
  • Poorly differentiated carcinoma of breast . Histopathology
  • Colonic polyp.(Adenoma )
  • Figure 7-4 A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth .
  • Dysplasia means potential PRE-cancer. Anaplasia means cancer. The three words: pleomorphism, hyperchromasia, and increased mitoses, are the three most widely used terms to describe malignant tumors on pathology reports .
  • Anaplastic tumor
  • Do you remember from chapter 1 that DYS- was one of the seven -plasia brothers ?
  • This epithelium shows severe dysplasia: Note that dysplastic basal cells characterized by cuboidal shape, high nuclear cytoplasmic ratio, hyperchromatism, mitotic activity, and some loss of orientation to the basement membrane, occupy the lower two thirds of the surface rather than just the basal row of cells. More differentiated cells which occupy the outer third, though still retaining some dysplastic nuclear features have the appearance of maturing squamous cells rather than basal cells, and eventually become flattened on the surface .
  • Carcinoma in situ: This section shows that the dysplastic basiloid cells go all the way to the surface and never undergo significant differentistion towards more differentiated flattened squamous cells. Note however that the basement membrane is still intact. The torturingly and unnecessary insane pressure to differentiate “severe” dysplasias from carcinomas-in-situ has prompted the various “-IN” classification systems, e.g., CIN-III, VIN-III, PIN-III. Is high grade dysplasia any different from carcinoma-in-situ from a microscopic, behavioral, or medical-legal point of view? Ans: NO !
  • leukoplakia
  • Low risk gp HPV
  • Moderate dysplasia
  • Carcinoma in situ
  • A  proto-oncogene  is a normal gene that can become an  oncogene  due to mutations or increased  expression . Proto-oncogenes code for  proteins  that help to regulate  cell growth  and   differentiation .
  • The various aspects of “malignant transformation”. Just like cancer itself is a progression of increasingly disturbing processes, so is malignant transformation. These are not necessarily exactly linear events, but close .
  • Telomeres are a sequence of repetitive bases at the ends of linear chromosomes that prevent adjacent chromosomes from attaching to each other . Think about this? If a telomere is interfered with, perhaps by telomerase, it LOSES its ability to limit mitoses !
  • This is a BEAUTIFUL chart! Another way of understanding the development of malignancy in a logical way !
  • important diagrammatic explanation of malignancy .
  • FOUR orderly steps of “INVASION” (aka, INFILTRATION, or INVASIVENESS )
  • FOUR orderly steps of “INVASION” (aka, INFILTRATION, or INVASIVENESS )
  • Signal transduction  is a generic term which refers to any process by which a  cell converts one kind of  signal  or stimulus into another .
  • These are the TWO other most important and widely studied genes in cancer .
  • . NOTE: Problems of GROWTH SUPPRESSION, result in GROWTH being UN-regulated . THESE ARE ALL GROWTH SUPPRESSOR GENES WHICH, WHEN MUTATED, LOSE THEIR NORMAL ABILITY TO SUOPPRESS !!!
  • Malig.melanoma eye
  • Experiment was done on skin of rat treated with carcinogenic agent such as tar ,was treated with a second ,non carcinogenic agent acting as promoter
  • Neoplasia

    1. 1. NeoplasiaNeoplasia
    2. 2. NeoplasmDefinition Is a new growth0r abnormal mass of tissue ,the growthof which exceed & uncoordinated withthat of normal tissue & persist in thesame excessive manner even aftercessation of stimuli which evoke thechangesTumor : (Greek ,swelling)
    3. 3. Tumor classify intobenign or malignant on the basis of:• Histologic and cytologic features• The biological behavior of tumorAll malignant tumor : are Cancer
    4. 4. Tumor basic componentAll tumor compose of1-proliferating neoplastic cells (parenchyma).• The parenchyma determine the biologicbehavior & this component from which thetumor derives its name2-supportive stroma non neoplastic (c.t & bl.v).• tumor growth and evolution is criticallydependent on their stroma
    5. 5. Nomenclature of Tumors• All have the suffix omaDepending on histogenesis (cell ortissue of origin ) tumor can broadlydivided into those derived fromepithelial or mesenchymal
    6. 6. EPITHELIAL NEOPLASMS• Adenoma A benign epithelial neoplasm thatarises within a gland (eg, thyroid adenoma, colonicadenoma)• papilloma (Latin, papilla = nipple) when arisingfrom an epithelial surface.Papillomas may arise from squamous, glandular, ortransitional epithelium .• Carcinoma Malignant epithelial neoplasms(adenocarcinomas if derived from glandularepithelia;squamous carcinomatransitional cell carcinoma
    7. 7. MESENCHYMAL NEOPLASMS• Benign mesenchymal neoplasms arenamed after the cell of origin followedby the suffix -oma• E.g fibroma• Malignant mesenchymal neoplasms arenamed after the cell of origin, to whichis added the suffix -sarcoma.liposarcomas
    8. 8. Papilloma of the tongue
    9. 9. Microscopical appearance of squamous papilloma
    10. 10. Mixed tumorsMixed tumors• Tumors with mixed differentiationTumors with mixed differentiation– e.ge.g.. pleomorphic adenoma of salivarypleomorphic adenoma of salivaryglandgland– carcinosarcomacarcinosarcoma
    11. 11. TeratomaTeratoma• Tumor contain elements of all threegerm layers: endoderm, ectoderm, andmesoderm. Thus, brain, respiratory andintestinal mucosa, cartilage, bone, skin,teeth, or hair may be seen in theneoplasm.• The constituent tissues are not limitedto those normally present in the area oforigin.
    12. 12. - Arise from totipotent cells (usually gonads)- Arise from totipotent cells (usually gonads)testis or ovarytestis or ovary- benign cystic teratoma of ovary is the most- benign cystic teratoma of ovary is the mostcommon teratomacommon teratomaTeratomas are classified as• mature (well-differentiated and composedof adult-type tissues) benign.• immature (made up of fetal-type tissues).are malignant,
    13. 13. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)© 2005 Elsevier
    14. 14. • The names of some malignant neoplasmsare formed by adding the suffix -oma tothe cell of origin, eg,• lymphoma (lymphocyte),• plasmacytoma (plasma cell),• melanoma (melanocyte),• Neoplasms of blood-forming organs arecalled leukemias
    15. 15. some confusing terminologyAberrant differentiation (not trueAberrant differentiation (not trueneoplasms)neoplasms)• Hamartoma :is disorganized mass ofdisorganized mass oftissue (malformation)tissue (malformation) compose ofmature cell normally present in thattissue in haphazard arrangmente,g Hamartoma of lung (containbronchial cell,bl.v., cartilage,lymphoidtissue )
    16. 16. choristoma• (ectopic normal tissue in abn.location )e.g arrest of adrenal cell under kidneycapsule or small nodule containingpancreatic tissue found in submucosaof the stomach.
    17. 17. Character ofbenign & malig.neoplasmDifferentiation by following feature1.Differentiation & anaplasia.2.Growth rate3.Local invasion4.metastasis
    18. 18. DifferentiationDifferentiationDifferentiation refers to the extent to whichDifferentiation refers to the extent to whichneoplastic parenchymal cells resemble theneoplastic parenchymal cells resemble thecorresponding normal parenchymal cells, bothcorresponding normal parenchymal cells, bothmorphologically and functionallymorphologically and functionally- Well differentiated- Well differentiated Resembles mature cells of tissue of originResembles mature cells of tissue of origin- Poorly differentiated- Poorly differentiated neoplasmneoplasm– Composed of primitive cells with little diffrerentiation.Composed of primitive cells with little diffrerentiation.– In general all benign t.are well diff.In contrast malig.t. range from well to poorly diff.• Differentiation determine the tumor grade• Lack of differentiation (UndifferentiatedLack of differentiation (Undifferentiatedtumor) are “anaplastic” tumortumor) are “anaplastic” tumor
    19. 19. The degree of anaplasia correlate withaggressiveness of the tumor( biologicbiologicbehavior)behavior)– Poorly differentiated malignant tumorsPoorly differentiated malignant tumorsusually have worse prognosisusually have worse prognosis
    20. 20. • PleomorphismPleomorphism : tumor cell display variation in both: tumor cell display variation in both(cytologic abn,)(cytologic abn,)– SizeSize– Shape (Bizzar tumor giant cell )Shape (Bizzar tumor giant cell )• Abnormal nuclear morphologyAbnormal nuclear morphology– HyperchromasiaHyperchromasia– High nuclear cytoplasmic ratioHigh nuclear cytoplasmic ratio– Chromatin clumpingChromatin clumping– Prominent nucleoliProminent nucleoli– nuclear-to-cytoplasm ratio may approach 1 : 1 insteadnuclear-to-cytoplasm ratio may approach 1 : 1 insteadof the normal 1 : 4 or 1 : 6of the normal 1 : 4 or 1 : 6 thethe• MitosesMitoses– Mitotic rateMitotic rate– Type of mitoses (atypical )Type of mitoses (atypical )• Loss of polarityLoss of polarity ,,• presence large area of necrosispresence large area of necrosis““ANAPLASIAANAPLASIA””
    21. 21. DysplasiaDysplasia• DysplasiaDysplasia is a term that meansis a term that meansdisordered growth.disordered growth.• Dysplasia often occurs in metaplasticDysplasia often occurs in metaplasticepitheliumepithelium• Dysplasia is encounteredDysplasia is encountered in epitheliain epithelia• Dysplastic cells exhibit considerableDysplastic cells exhibit considerablepleomorphism and often contain largepleomorphism and often contain largehyperchromatic nuclei with a high nuclear to-hyperchromatic nuclei with a high nuclear to-cytoplasmic ratio.cytoplasmic ratio.• The architecture of the tissue may beThe architecture of the tissue may bedisorderdisorder
    22. 22. DysplasiaDysplasiaMalignant transformation is a multistep processMalignant transformation is a multistep process• In dysplasia some but not all of the features ofIn dysplasia some but not all of the features ofmalignancy are present, microscopicallymalignancy are present, microscopically• DysplasiaDysplasia maymay develop into malignancydevelop into malignancy– Uterine cervixUterine cervix– Colon polypsColon polyps• Graded as low-grade or high-gradeGraded as low-grade or high-grade• Dysplasia mayDysplasia may NOTNOT develop into malignancydevelop into malignancy• HIGH grade often classified with carcinoma-in-situHIGH grade often classified with carcinoma-in-situ
    23. 23. High-grade dysplasiaHigh-grade dysplasia::• The abnormal dysplastic cells involveThe abnormal dysplastic cells involvewhole thickness of epith.whole thickness of epith.• The lesion remain confine by theThe lesion remain confine by thebasement membrane ,it is pre-invasivebasement membrane ,it is pre-invasiveor called (or called (carcinoma in situ)carcinoma in situ)• Dysplasia does not necessarily progress toDysplasia does not necessarily progress tocancercancer..Mild to moderate changes that do not involveMild to moderate changes that do not involvethe entire thickness of epithelium may bethe entire thickness of epithelium may bereversible, after removal of the inciting agentreversible, after removal of the inciting agent
    24. 24. Growth rate• Benign : slowly growing• Malig. : rapid growth
    25. 25. Features of Malignant TumorsFeatures of Malignant Tumors• Cellular featuresCellular features• LocalLocal invasioninvasion– CapsuleCapsule– Basement membraneBasement membrane• MetastasisMetastasis– Unequivocal sign of malignancyUnequivocal sign of malignancy– Seeding of body cavitiesSeeding of body cavities– LymphaticLymphatic• HematogenousHematogenous
    26. 26. Invasion• Invasiveness is the most reliable featuredifferentiate malig.from benign t.• Some cancer are in pre-invasive stage called(ca.in situ) e.g ca.in situ of cervix withoutinvasion to basement memb.• Metastasis tumor implant discontinues withthe primary tumor .• It is unequivocal mark that the tumor malig withthe exception B.C.C. of skin& C.N.S. glioma,both locally invasive but not give rise for distantmetastasis
    27. 27. • Benign t. :slowly growing tumor remainlocalized, amenable to local surgicalremoval• Malignant: spread distant
    28. 28. FeatureFeature BenignBenign MalignantMalignantRate of growthRate of growth Progressive butProgressive butslow. Mitosesslow. Mitosesfew and normalfew and normalVariable.Variable.Mitoses moreMitoses morefrequent andfrequent andmay bemay beabnormalabnormalDifferentiationDifferentiation WellWelldifferentiateddifferentiatedSome degree ofSome degree ofanaplasiaanaplasiaLOCALLOCALINVASIOINVASIONNCohesive growth.Cohesive growth.Capsule & BMCapsule & BMnot breachednot breachedPoorly cohesivePoorly cohesiveand infiltrative.and infiltrative.
    29. 29. Cancer epidemiology• Cancer incidence• Geographic & env.variables• Occupational cancer
    30. 30. neoplasia• AgeAge– Most cancers occur in persons ≥ 55Most cancers occur in persons ≥ 55yearsyears– Childhood cancersChildhood cancers• Leukemias & CNS neoplasmsLeukemias & CNS neoplasms• Bone & soft tissue sarcoma.Bone & soft tissue sarcoma.• LymphomaLymphoma
    31. 31. • Acqiured causes orAcqiured causes orpredispostionpredispostion• Heredity form or predispostionHeredity form or predispostion(5%-10%of all human(5%-10%of all humancancer)which can be dividedcancer)which can be dividedinto three categories)into three categories)
    32. 32. Genetic inheritedpredispostion of cancercan be divided into three categories :1- Familial cancer syndromessyndromesExample :• BRCA1&BRCA2 ca.breast, ovaryFeature cc.familial cancer:1-early age at onset2-tumor arise in two or more close relatives3-some time multiple & bilateral tumor
    33. 33. Inherited cancer syndInherited as A.D mutation (point mutation) int.supp.gene e.g• RB-Familial retinoblastoma ,40% inherited• APC- (familial adenomatous polyposis) FAPof colon,germ line mutation of APC• NF-Neurofibromatosis type 1& 2• MEN(multiple endocrine neoplasia)syndromes• MSH2&MSH6-hereditary non polyposiscolonic cancer(HNPCC),inherit defectivecopy of mismatch repair gene• P53 :various t.
    34. 34. Aut.Recessive syndromesInherited defective of DNA repair geneexample :• Xeroderma pigmentosa (photosensitive)• Fanconi anemia• Ataxic telangiectasia
    35. 35. Acquired pre-neoplastic disorder1. Persist regenerative activity 80%of hepatocellularca.arise in cirrhotic liver& HBV play imp.role2. hyperplastic Endometrial hyperplasia &end .ca.3. dysplastic proliferation• leukoplakia of oral cavity ,vulva• Cervical dysplasia &ca.cx• Smoking – sq.metaplasia,dysplasia- ca.bronchus4- chronic atrophic gastritis5- Chr.infl. dis.&cancer (ulcerative colitis crohns dis.),.Helicobacter pylori gastritis ,viral hepatitis,chr.pancreatitis)6- Villous adenoma of colon
    36. 36. Molecular Basis of CancerNON-lethalNON-lethal genetic damagegenetic damage(or mutation)may be• Acquired by the action of environmentalagents, caused by exogenous agents such aschemicals, radiation, or viruses• or it may be inherited in the germ line.• Not all mutations, are “environmentally”induced. Some may be spontaneous , falling intothe category of bad luck.
    37. 37. Molecular Basis of Cance….cont.• tumors are monoclonal formedby the clonal expansion of asingle precursor cell that hasincurred genetic damage.• Carcinogenesis is aCarcinogenesis is a multistepmultistepprocessprocess.
    38. 38. • The process which result intransformation of normal cell toneoplastic cell by causing permanentgenetic alteration.• No single gene mutation is sufficient tocause cancer• Occur by accumulation of geneticlesions that result in tumorprogression
    39. 39. MOLECULAR BASISMOLECULAR BASISof CANCERof CANCER• Four classesFour classes of normal regulatoryof normal regulatorygenesgenes– PROTO-oncogenesPROTO-oncogenes– Growth inhibitor gene (cancer suppressorgene)– DNA repair genesDNA repair genes– Apoptosis genesApoptosis genes
    40. 40. TRANSFORMATION &TRANSFORMATION &PROGRESSIONPROGRESSION• Self-sufficiency in growth signalsSelf-sufficiency in growth signals• Insensitivity to growth-inhibiting signalsInsensitivity to growth-inhibiting signals• Evasion of apoptosisEvasion of apoptosis• Defects in DNA repair: “Spell checker”Defects in DNA repair: “Spell checker”• Limitless replicative potential: TelomeraseLimitless replicative potential: Telomerase• AngiogenesisAngiogenesis• Invasive abilityInvasive ability• Metastatic abilityMetastatic ability
    41. 41. ESSENTIAL ALTERATIONS FORMALIGNANT TRANSFORMATIONThe seven key changes are the following• Self-sufficiency in growth signals: Tumorshave the capacity to proliferate without externalstimuli, usually as a consequence of oncogeneactivation.• Insensitivity to growth-inhibitory signals:Tumors may not respond to molecules that areinhibitory to the proliferation of normal cells suchas transforming growth factor β (TGF-β) anddirect inhibitors of cyclin-dependent kinases(CDKIs). •
    42. 42. • Evasion of apoptosis: Tumors may beresistant to programmed cell death, as aconsequence of inactivation of p53 oractivation of anti-apoptotic genes.• Limitless replicative potential: Tumorcells have unrestricted proliferativecapacity, avoiding cellular senescenceand mitotic catastrophe.
    43. 43. LIMITLESS REPLICATIVELIMITLESS REPLICATIVEPOTENTIALPOTENTIAL• TELOMERES determine theTELOMERES determine thelimited number of duplicationslimited number of duplications• TELOMERASETELOMERASE, present in >90%, present in >90%of human cancers, changesof human cancers, changestelomeres so they will havetelomeres so they will haveUNLIMITED replicative potentialUNLIMITED replicative potential
    44. 44. • Sustained angiogenesis: Tumor cells,like normal cells, are not able to growwithout formation of a vascular supply tobring nutrients and oxygen and removewaste products. Hence, tumors mustinduce angiogenesis.
    45. 45. TUMOR ANGIOGENESISTUMOR ANGIOGENESIS• Activation of VEGF and FGF-bActivation of VEGF and FGF-b• Tumor size is regulated (allowed) byTumor size is regulated (allowed) byangiogenesis/anti-angiogenesisangiogenesis/anti-angiogenesisbalancebalance
    46. 46. • Ability to invade and metastasize: Tumormetastases are the cause of the vast majority ofcancer deaths and depend on processes thatare intrinsic to the cell or are initiated by signalsfrom the tissue environment.• Defects in DNA repair: Tumors may fail torepair DNA damage caused by carcinogensduring unregulated cellular proliferation, leadingto genomic instability
    47. 47. TRANSFORMATIONTRANSFORMATIONGROWTHGROWTHBM INVASIONBM INVASIONANGIOGENESISANGIOGENESISINTRAVASATIONINTRAVASATIONEMBOLIZATIONEMBOLIZATIONADHESIONADHESIONEXTRAVASATIONEXTRAVASATIONMETASTATIC GROWTHMETASTATIC GROWTHetcetc..
    48. 48. Invasion FactorsInvasion Factors• DetachmentDetachment ("loosening up") of("loosening up") ofthe tumor cells from each otherthe tumor cells from each other• AttachmentAttachment to matrixto matrixcomponentscomponents• DegradationDegradation of ECM, e.g.,of ECM, e.g.,collagenase, etc.collagenase, etc.• MigrationMigration of tumor cellsof tumor cells
    49. 49. Invasion FactorsInvasion Factors• 11stststep:E-cadherin (keep n.cell together),-itstep:E-cadherin (keep n.cell together),-itwill bind to B-catenin .-lead to B cateninwill bind to B-catenin .-lead to B cateninsequestation .in malig.cell E cadherin issequestation .in malig.cell E cadherin islost .lost .• 2ns step degradation of b.m &ECM by2ns step degradation of b.m &ECM byproteolytic enzy (MMP-9&cathespin –proteolytic enzy (MMP-9&cathespin –D)which cleave type IV collgen.D)which cleave type IV collgen.
    50. 50. Elaboration of variety of enzyme byt.cell aid in degradation of ECM&invasiveness .Cathepsin D proteinase enzy.thatcleaves fibronectin & lamininHigh level of this enzy are ass withgreater invasiveness.
    51. 51. .angiogenesis is mediated byfibroblastic growth factor &VEGF
    52. 52. oncogenes• Gene promote autonomous cell growthin cancer cell in the absence of normalmitogenic signals.• Their normal counterpart areprotooncogenes which involve inphysiologic regulation of cellproliferation& differentiation
    53. 53. ONCOGENESONCOGENES• Are MUTATIONS of NORMAL genesAre MUTATIONS of NORMAL genes(PROTO-oncogenes)(PROTO-oncogenes)– Growth FactorsGrowth Factors– Growth Factor ReceptorsGrowth Factor Receptors– Signal Transduction Proteins (RAS)Signal Transduction Proteins (RAS)– Nuclear Regulatory ProteinsNuclear Regulatory Proteins– Cell Cycle RegulatorsCell Cycle Regulators
    54. 54. oncogens & their functionNeoplastic cell prolif. self stimulation mediated by :1-Over-expression of GF gene sis2 - Receptor for epidermal growth factor HER2 –orERBB2 located at cell surface3- signal transducerRas oncogen act on intracellular signaling (signaltransducer)e.g: pancreatic adenoca ,cholangioca, ca.colon showspoint mutation4- DNA Binding nuclear proteinmyc oncogen :stimulate direct DNA synthesistranslocation t8:14 in Burkitt lymphoma.5- cell cycle protein (regulator) Cyclin & CDK6- Inhibitor of apoptosis (bcl-2).
    55. 55. Most common type of nonrandom karyotypicchanges in tumor cell e.g of balanced translocation1-philadelphia chromosome in C.M.L.representtransl.bet.chr.9&222- Burkitts lymphoma in 90% transl.bet chr 8 &14 e.g of deletion–solid t. of non hematopoietic origin –embryonal t.ofchildhood (retinoblastoma ,wilms t)Loss of some normal cancer suppressor genes locatedon chr.13 &11 in case of wilms t. Gene amplificatione.g neuroblastoma the amplified gene is oncogencalled N-myc ,or in case of ca.breast.
    56. 56. Tumor suppressor gene& their function• P53 : nuclear protein• TGFB: potent inhibitor for proliferationmutation seen in ca.colon• APC Inhibitor for transcription regulatorindividual born with one mutant allel develop hundreds tothousands of adenomatous polyp in the colon in10-20 yr.• RB gene : in nucleus ,cell cycle inhibitor(retinoblastoma,osteosarcoma)• WT1 : location in nucleus• NF1&NF2 : in plasma membrane ,inhibitor for signaltransducer• BRCA 1& BRCA 2 (DNA repair)
    57. 57. P53 geneThe Guardian of the Genome• The most common mutated gene in human cancer• It is DNA binding protein ,regulate DNA repair & preventDNA transcription errorFunction in normal cell (regulate cell proliferation) through1-Activation of temporal cell cycle arrest (quiescence )through p212- permanent cell cycle arrest (senescence)3-promotes cell death through BAX gene which inhibitsBCL2 (Apoptotic inhibiting gene)4- help in repair process (through GADD 45)
    58. 58. P53 &P53 & RASRASp53p53• Activates DNAActivates DNArepair proteinsrepair proteins• Sentinel of G1/SSentinel of G1/Stransitiontransition• Initiates apoptosisInitiates apoptosis• Mutated in moreMutated in morethan 50% of allthan 50% of allhuman cancershuman cancersRASRAS• H, N, K, etc.,H, N, K, etc.,varietiesvarieties• Single mostSingle mostcommoncommonabnormality ofabnormality ofdominantdominantoncogenes inoncogenes inhuman tumorshuman tumors• Present in about 1/3Present in about 1/3of all humanof all human
    59. 59. Tumor (really “GROWTH”)Tumor (really “GROWTH”)suppressor genessuppressor genes• TGF-TGF-ββ  COLONCOLON• E-cadherinE-cadherin  STOMACHSTOMACH• NF-1,2NF-1,2  NEURAL TUMORSNEURAL TUMORS• APC/APC/ββ-cadherin-cadherin  GI, MELANOMAGI, MELANOMA• SMADsSMADs  GIGI• RBRB  RETINOBLASTOMARETINOBLASTOMA• P53P53  EVERYTHING!!EVERYTHING!!• WT-1WT-1  WILMS TUMORWILMS TUMOR• p16 (INK4a)p16 (INK4a)  GI, BREAST (MM if inherited)GI, BREAST (MM if inherited)• BRCA-1,2BRCA-1,2  BREASTBREAST• KLF6KLF6  PROSTATEPROSTATE
    60. 60. Function of P53 In normal cell• Activates DNA repair proteinsActivates DNA repair proteins• Sentinel of G1/S transitionSentinel of G1/S transition• Initiates apoptosisInitiates apoptosisactivation of P53 occur by DNA damagingagent or hypoxia lead to cell cycle arrest inG1 phase & induction of DNA repair .The mechanism of arrest is mediated by cellcycle inhibitor protein P21Successful repair of DNA allow cell to proceedwith cell cycleIf DNA repair fail ,then P53 trigger eitherapoptosis or senescence.
    61. 61. • .In mutant P53 :DNA damage cell go through cellcycle without DNA repair ,thisgenetically abn.cell proliferategive rise to malig.
    62. 62. •Two hit hypothesis,LOH & cancer• No.of syndromes result from germ linemutation in various t.supp.gene .Example :• Li-Fraumeni synd.(inherited predispos to ca.)due to germ line mutation of p53.• Familial polyposis coli synd : APC genemutation ,also cause m.m.& ov.ca• Hereditary wilms t.• Von Hipple Lindau synd.
    63. 63. Acquired Carcinogenic agent1-chemical carcinogen2-radiant energy3-Microbial agent(bact,virus.parasite)
    64. 64. Chemical carcinogenmultistep process through four stages•Initiation & promotion sequences•Progression: stage in which tumor growthbecome autonomus (independent ofcarcinogen or the promoter result fromacc.mutation result in immotalize cell)•Cancer: the end result of entire sequence
    65. 65. Initiation• Is the event that induce lesion in cellgenome (DNA)Result from exposure of cell to• appropriate dose of carcinogenic agent .• Initiator is mutagenic• Initiated cell (altered ,transformed cell )render it susceptible to give rise of tumor
    66. 66. • Initiation alone is not sufficient fortumor formation.• It give rise of tumor only after promotorapplication• initiation is rapid & irreversible• the initiating carcinogen producepermanent changes in DNA of thetarget cell
    67. 67. PromotionIs the event lead to clonal proliferation ofthe initiated transformed cell .• promotion can induce changes in theinitiated cell but they are nottumorogenic by themselves• tumor does not result when promotionapplied before rather than after theinitiating agent .
    68. 68. • promotion is reversible changes (not affectDNA directly )• promotion is dose-threshold" dependentconcentration of promoter below whichneoplasia will not occur.• The altered cell remain dependent on thecontinue presence of promoter stimuli whichmay be (exogenous chemical ,physical orendogenous like hormonal stimulation inbreast,endometrium ,prostate).
    69. 69. Major chemical carcinogens• Some chemical agent possess thecapability of both (initiation &promotion ) called• complete carcinogen like Alkyaltingagent ,anticancer drug ,busulphancyclophosphamide,chlorambucil.• Incomplete carcinogen capable ofproducing t. only after initiation
    70. 70. carcinogenic initiatorsExamples• Alkylating agents like cyclophosphamide.• (PCAH) polycyclic aromatic hydrocarbonsfound in smoked foods,cigarette smoke (havebroad range of target organs)produce cancer atsite of applicationThey are metabolized at cytochrome p450 whichwill oxidases to electrophilic epoxides which inturn react with cellular protein & nucleic acid• Nitrosamines in pickled foods. gut ca.• Preserved food contain nitrites which react withother dietary component to form nitrosamineswhich activated by hydroxylation to form reactiveion .
    71. 71. • Aromatic amines or azo dyes used in foodcoloring .• Vinyl choride-liver angiosarcoma• beta-naphthylamine-use in rubber industry–bladder ca.• microbial productFungi : aflatoxin b1 (produce by some strainof aspergillus flavus )cause hepatic cancerAct as initiator
    72. 72. Examples of promoters• hormones such as estrogen,• drugs such as diethylstibesterol,• chemicals such as cyclamates used assweeteners• Chemical act as both initiator &Promoter• (cigarette smoking & Asbestoses )
    73. 73. Viruses & Human cancer• HPV (DNA virus).• HCV(RNA) & HBV(DNA) :predipose toHCC.• HHV 8 (DNA virus )& kaposi sarcoma• EBV (DNA virus)• HTLV-1 virus: (RNA retrovirus )-T cellleukemia –lymphoma.
    74. 74. (HPV)• Anogenital cancer• Sq.c.c. of cervix (HPVhigh risk gp.(16-18,31,33,35,51)• benign wart low risk gp.(HPV 6-11)The oncogenic potential of HPV is relatedto E6 & E7 viral protein which bind toP53 & RB gene respectively so theyovercome cell cycle inhibitor
    75. 75. Role of EBV• Infectious mononucleosis(a short lifedlymphproliferative dis.)• Oral hairy leukoplakia (in AIDS)• Nasopharyngeal carcinoma• African Burkitts lymphoma• Non-Hodgkins lymphomas in AIDS
    76. 76. Effect of tumor on the hostI- Local effect according to tumor location• Pressure effect e.g pituitary adenomawhen increase in size• ulceration &obstruction e.g ca.colon• secondary infection &bleedinge.g malena in ca.colon or hematurea inbladder ca
    77. 77. systemic effectCancer cachexiaIt is waisting syndrome: cc by loss ofbody fat .anemia• there are several factors contribute tomalnutrition in cancer pat.1-high prot.& fat turnover ,hypermetabolismanorexia ,reduced food intake,,2-Cachectin (TNF) - produced by tumor cell&macrophages & it is a mediator ofwaisting syndrome
    78. 78. other soluble factor produced by tumor cell .3- PIF proteolysis inducing factor whichinvolved in abn.metabolism by increasecatabolism of muscle & adipose tissue,4- Impair immune defenses –prone toinfection .
    79. 79. paraneoplastic syndrome• It is clinical syndrome with symptom complexesoccur in cancer pat, (10% of advanced malig)• Result from synthesis of bioactive sub. by tumorcells.symptom may be1- endocrinopathies :elaboration of hormon fromtumor cell which are not of endocrine origin(ectopic hr.production )Example:• Insulin release of by fibrosarcoma• Erythrpoitein hr.production by renal cell.ca.• Parathyroid like hr-sq.c.ca of lung
    80. 80. 2-Neuromyopathic paraneoplastic synd-Myasthenia Gravis. like synd.in small ellca.of lung3- cutaneous :Acanthosis nigrican cc bygrey black patches of hyperkeratotic skin4- Vascular & hematological changes.• DIC (hypercoagulability)-release ofPAF&procoagulant from tumor cell.
    81. 81. Tumor markerBiochemical indicator of presence of tumor• Aid in DX• Determine response to therapy• Indicate relapse in follow upHormones :• HCG :Trophoblastic t,Non seminomatesticular t.• Calcitonine : Medullary ca.of thyroid• Catecholamine : pheochromocytoma• Ectopic hr.: paraneoplastic synd.
    82. 82. Tumor marker cont….Isoenzy.:• PAP:prostatic ca.• NSE : small cell ca.of lung,neuroblastomaSpecific protein :• Immunoglobulins : multiple myloma• Prostatic specific Ag.:ca.prostate
    83. 83. Tumor marker cont….Mucins• CA-125 : ovary ca.• CA-19-9 : colon, pancreas ca.• CA-15.3 : Breast ca.Oncofetal Ag.:• (AFP)Alpha fetoprotein: liver ca,testicular t.• CEA : ca. pancreas,colon,lung,stomachNew molecular marker :• P53,APC,RAS in stool& serum ca.colon
    84. 84. Lab.Dx of cancer1- Biopsy2- Cytology3- FNA4- Immunocytochemistry(by specific monoclonal Antibody for identification of cell productor surface marker )5- flow cytometry :measure several cell character such as1- DNA content like aneuploidy seems to be associated with poorprognosis2- Identification of cell-surface antigenswidely used in the classification of leukemias and lymphomas
    85. 85. The value ofimmunohistochemistry1-categorization of undiff.malig.t(To determine line of differentiation )2-categorization of leukemia/lymphoma3- determination the site of origin of metastatictumorlike thyroglobulin marker for tumor of thyroidorigine.g Desmin –specific for muscle4- Detection of molecule that of prognostic &therapeutic significancelike ER,PR,erb B2 in ca.breast

    ×