CANCER

DR ROHINI C SANEPROFESSOR

DEPARTMENT OF BIOCHEMISTRY DR D Y PATIL MEDICAL COLLEGE

EBENE

CANCER• CANCER DISEASE- IN WHICH CELL GROW ABNORMALLY –MALIGNANT NEOPLASM

• (NEW GROWTH )-NEOPLASIA

• A MASS OF TISSUE ---ABNORMAL ,EXCESSIVE,UNCORDINATED ,PURPOSELESS PROLIFERATION

• ONCOLOGY = ONCOS ( TUMOR ) + LOGY (STUDY )

• BENIGN TUMOR---THAT DOSE NOT INVADE /SPREAD –NON CANCEREROUS

• MALIGNANT TUMOR /CANCER –INVADES DESTROY TISSUE IN WHICH ORIGINATES –CAN SPREAD IN OTHER TISSUES VIA BLOOD STREAM & LYMPHATIC SYSTEM

PROPERTIES OF CANCER CELLS

• UNRESTRAINED GROWTH

• INVANSION OF LOCAL TISSUE

• METASTASIS

MORPHOLOGICAL CHANGES

SHAPE ---ROUNDER

MOTILITY ---LOSS OF CONTACT INHIBITION OF MOVEMENTS

GROWTH --- LOSS OF CONTACT INHIBITION –MULTILAYER /NUMBER OF NUCLEI

BIOCHEMICAL CHANGES

ALTERED GENE REGULATION ---DNA SYNTHESIS ---RNA SYNTHESIS ---PROTEIN SYNTHESIS---ANABOLISM---GROWTH

BIOCHEMICAL CHANGESALTERED GENE REGULATION

INCREASED DNA SYNTHESIS

INCREASED RNA SYNTHESIS

INCREASED PROTEIN SYNTHESIS

ANABOLISM---GROWTH FACTORS &HORMONES

INCREASED AEROBIC & ANAEROBIC GLYCOLYSIS

SYNTHESIS OF LACTIC ACID & LACTIC ACIDOSIS

ALTERATION OF CELL SURFACE DUE CHANGES IN COMPOSITION OF GLYCOPROTEINS & GLYCOSPHINGOLIPIDS

DECREASED

BIOCHEMICAL CHANGES

• CARCINOMAS –CANCER ARISES FROM EPITHELIAL TISSUE

• SARCOMAS –MESENCHYMAL TISSUE

• LEUKAEMIAS-WBC

• LYMPHOMAS

• HEPATOMAS –HEPATOCYTES

ETIOLOGYFAMILIAL GENETIC FACTOR

GEOGRAPHIC FACTORS

• ASIANS-NASOPHARYNGEAL

• JAPNESE –BREAST

• AFRICA –SKIN

• EUROPEANS--COLON

• ENVRIMENTAL FACTORS

• AGE->50YRS

• SEX-MEN >WOMEN

ENVIROMENTAL FACOTRS

• CIGARETTE SMOKING

• ALCOHOL ABUSE

• TOBACCO

• BETEL NUT

• ARSENIC

• VINYL CHLORIDE

• ASBESTOS

• BENZENE

• NAPHTHYLOMINE

PHYSICAL CARCINOGENS• RADIENT ENERGY ---UV LIGHT ,IONIZING RADIATIONS

• EXAMPLS –SUNLIGHT ,WELDERS ARC ,UV LAMPS ---SKIN CANCER

• FORMATION OF PYRIMIDINE DIMER IN DNA STRAND

• FORMATION OF APURINIC OR APYRIMIDINE SITE ELIMINATION OF BASES

• BREAKING OF CROSS LINKING OF SINGLE OR DOUBLE STRAND OF DNA

IONIZING RADIATIONS –X RAYS ,ALPHA ,BETA ,GAMMA RAYS ,RADIOACTIVE ISOTOPES ,PROTONS ,NEUTRONS

• IONIZING RADIATIONS---DAMAGE DNA ,DISLODGE IONS FROM H2O& BIOMOLECULES ,INTERACT WITH PROTEINS, DNA-----CANCER (MUTAGENESIS)

HORMONAL CARCINOGENESIS

• HORMONE SENSITIVE TISSUE ---BREAST ,ENDOMETRIUM, MYOMETRIUM,VAGINA THYROID, ,LIVER ,PROSTRATE,TESTIES

• ESTROGENS---OVARIAN,ENDOMETRIUM CARCINOMA

• CONTRACEPTIVE HORMONES ---BREAST CANCER

• ANABOLIC STEROIDS---ATHLETS,LIVER CANCER

Biological carcinogens • Viruses, parasites ,bacteria

DNA VIRUS

• PAPOVIRUS ---HPV (HUMAN PAPILLOMA VIRUS),SV40B,POLYOMA VIRUS

• HERPES VIRUS –EPSTEIN BAR VIRUS

• ADENOVIRUS –12,18,31

• HEPITITIS B VIRUS (HBV)

RNA VIRUS

ACUTE TRANSFORMING VIRUS :ROUS SARCOMA VIRUS :LEUKEMIA VIRUS

SLOW TRANSFORMING :MOUSE MAMMARY TUMOR VIRUS

HUMAN T CELL LYMPHOTROPIC VIRUS --- HTLV -1,HTLV II

RNA REVERSE TRANSCRIPATASE

RNA –DNA NEOPLASIA

NOT ALL RETROVIRUSES ARE CARCINOGENIC

CARCINOGENESIS &CHEMICAL CARCINOGENS

INITIATORSDIRECT –DO NOT REQUIRE METABOLIC ACTIVATIONEXAMPLES ---ALKYLATING AGENTS—CYCLOPHOSPAHMIDE

ACYLATING AGENTS-- NITROSOUREA

CARCINOGENESIS & CHEMICAL CARCINOGENS

INDIRECT –AROMATIC HYDROCARBONS---BENZOPYRENES

TOBACO

COAL TAR

SMOKE

AROMATIC AMINES AZO DYES BETA NAPHTHYL AMINE

ACETALAMINO FLUORENE

NATURALLY OCCURING ALF TOXIN

BETEL NUT

MISCELLENEOUS ----- VINYL CHLORIDE ,ASBESTOS ,NI, CARBON MONOXIDE

PROMOTERS OF CARCINOGENS

• NOT CARCINOGENS BUT INITIATE CARCINOGENESIS

• EXAMPLES –PHENOLS,ESTROGENS,ARTIFICIAL SWEETNER SACCHARINE,CYCLAMATES

• METABOLIC ACTIVATION

Pro-carcinogens

Proximate carcinogens

Ultimate carcinogens

(free radicals)

Mechanism of action of chemical carcinogens

DIRECT REACTING CARCINOGEN (WITH NO METABOLIC ACTIVATION )&INDIRECT (WITH METABOLIC ACTIVATION FORMS REACTIVE ELECTROPHILES

Electrophiles (free radicals)—deficient in electrons

Interact with DNA Neutrophiles (chiefly DNA,RNA,PROTEINS)

DAMAGE (DNA MUTATION ,DNA repair enzymes fail)

Neoplastic transformation

Development of cancer

Apoptosis• Dropping /falling of the normal programmed destruction of cells

.,during embryogenesis, development of adult life.

• Destruction of apoptosis promote inappropriate cell division ,cell survival ---development of cancer

Proto-oncogenes –normal genes –stimulate cell divisionProto-oncogenes (activated by physical, chemical, biological carcinogens )-----oncogenes ---growth factor ,growth factor receptors ,signal transduction proteins Tumor suppressor gene –inhibit cell divisionNormal cell –balanced activity of tumor suppressor & protooncogene activator genes ---normal growth & repairNeoplasia –uncontrol cell division ---(1)decreased suppressor activity (2)increased proto-oncogene activity

Oncogene expressionproto –oncogenes control normal growth &cell division

Mutated versions of proto-oncogenes act as oncogenes

examples

• Growth factors

• Growth factor receptors

• Protein involved in signal transduction(protein kinase that phosphorylates tyrosine /serine residue )---GTP binding protein

• Proteins involved in signaling gene expression in nucleus

• some growth factor induce growth but not cell division –cell grows large in size without ever dividing

• 50 types of growth factors identified –first platelet diving growth factor (PDGF)

Mechanisms of activation of proto-oncogenes to oncogenes

• Promoter and enhancer insertion

• Chromosomal translocation

• Gene amplification

• Point mutation

• Effect of oncogene on growth ---putting one foot on accelerator of automobile

• Tumor suppressor gene ---taking one foot from the break

ONCOGENES CHROMOSOMES VIRUS ONCOGENE PRODUCTS

abl 9 Abbleson leukemia in mouse

Tyrosine kinase

erb B 7 Erythroblastosis in chicken Receptor for E & PR

erb –A 17 Erythroblastosis in chicken Transforming growth factor receptors

myc 08 Myelocytoma in chicken Platelet derived growth factor

ras 12 Rat sarcoma GTPase

ONCOSUPPRESSOR ABBREVATIONS CHROMOSOMES

RETINOBLASTOMA RB 13

FAMILLIAL BREAST CANCER

BRCA1BRCA2

17

GENE FOR PROTEIN 53 P53 17

Retinoblastoma gene RB gene

• Nucleo phosphoprotein –regulates DNA SYNTHESIS

• SWITCH OF CELL PROLIFERATION—SUPPRESS TUMOR FORMATION

MODE OF DNA VIRAL ONCOGENESIS VIRUS + DNA

ALTERATION IN GENE EXPRESSION

CELL TRANSFORMATION

TYPE OF PROTEIN ALTERED

INACTIVATION OF TUMOR SUPPRESSOR

NEOPLASM

MODE OF RNA VIRAL ONCOGENESIS

RNA

DNA (SINGLE STANDED )

C DNA (DOUBLE STRANDED)

C DNA GETS INCORPORATED IN HOST DNA ---PROTEINS /ENZYMES ,

HORMONES SYNTHESIZED

NEOPLASTIC CHANGES

IMMUNOLOGIC SURVEILLANCE• IMMUNE SYSTEM

• RECOGNIZES SPECIFIC ANTIGENS

• DESTROY CANCER CELLS CARRYING ANTIGENS ---STOP ABNORMAL GROWTH

• IF IMMUNOLOGIC SURVELLIENCE FAILS CANCER GROWS

Tumor markers• DEFINITION –BIOLOGICAL SUBSTANCES SYNTHESIZED OR RELEASED

BY CANCER CELLS AND FOUND IN INCREASED AMOUNT IN BLOOD ,BODY FLUID OR TISSUES INDICATING PRESENCE OF CANCER

APPLICATIONS OF TUMOR MARKERS• DIAGNOSIS (SCREENING )

• DIFFENTIAL DIAGNOSIS

• STAGING OF CANCER

• DETECTION OF RECURRENCE

• MONITORING RESPOSE TO THERAPY (PROGNOSIS)

Tumor markers

ENZYMESPROSTATIC ACID PHOSPHATASE---PROSTRATE CANCER

ALKALINE PHOSPHATASE --- BONE SECONDARIES

PROTEINS

• PROSTRATE SPECIFIC ANTIGEN----PSA--PROSTRATE CANCER

• MULTIPLE MYELOMA----SERUM PROTEIN IMMUNOGLOBULIN/BENCE JONES PROTEINS

• C PEPTIDE ---INSULINOMA

• BETA MICROGLOBULINS –BETA CELL LYMPHOMAS

CARBOHYDRATE

• CARBOHYDRATE ANTIGEN (CA—125)—OVARIAN ,ENDOMETRIUM

• CARBOHYDRATE ANTIGEN (CA—549)—BREAST ,OVARIAN

Tumor markers

HORMONES & THEIR METABOLITE

• Beta HCG ---CHORION CARCINOMA

• CALCITONIN ---MEDULARYCARCINOMA

• VANILLYL MANDELLIC ACID –NEUROBLASTOMA

• PROLACTIN –PITUITARY ADENOMA

• PTH –RENAL,BREAST,LIVER

ONCOFETAL ANTIGENS

• ALPHA FETO PROTEINS ---(AFP) HEPATOMA

• CARCINOEMBRYONIC ANTIGEN---(CEA)--COLON ,LUNG ,GIT

CANCER & DIET • INCREASED ANIMAL FAT

• INCREASED BACTERIAL FLORA

• CONVERSION OF ACIDS & STEROLS

• CARCINOGENS

• BENEFIAL ROLE OF VITAMIN C ,E ,SELENIUM ,BETA CAROTENE

• TRACE ELEMENTS ---Manganese ,zinc ,selenium, copper

• Tomatto ,cabbage ,cauliflower

Cancer therapy• Chronic myeloid leukaemia (CML)

• ONCOGENES C—abl (9 ) ,bcr (22)---protein kinase ,tyrosine kinase

• Trnlocation of bcr gene to abl gene --bcr –abl gene –protein kinase enzyme

• Bcl---abl not regulated

• Increased protein kinase

• Gleevec ---antitumor drug ---STI 571 USED IN TREATMENT OF BCR-ABL GENE—(tyrosine KINASE) ---90% cancer patients respond to treatment –rapid growth decreased but side effects

MONCLONAL ANTIBODIES

TARGET USED AGAINST CANCER

Ritutab CD20 ON B CELLS BETA CELL LEUKEMIA

HERCEPTIN HER 2/EGFR 2 BREAST CANCER

BERACIZUMAB VGEF COLORECTAL CANCER

NILITINIB TYROSINE KINASE SOLID CANCER

IMATINIB TYROSINE KINASE NON SMALL CELL LUNG CANCER

GENTFITINIB TYROSINE KINASE CML

PANITUMUMAB EGFR COLORECTAL CANCER

IMAGES FROM GOOGLE