Cancer BiologyCancer Biology
Tumour MarkersTumour Markers
Prof. Kenneth Bagshawe FRSProf. Kenneth Bagshawe FRS
Tumour MarkersTumour Markers Widest DefinitionWidest Definition
The concept of tumour markers can The concept of tumour markers can mean anything that helps in the mean anything that helps in the diagnosis of cancerdiagnosis of cancer
In a more restricted sense it refers to In a more restricted sense it refers to the biochemical detection of cancerthe biochemical detection of cancer
Imaging TechniquesImaging Techniques
Detected by:Detected by:
x-ray +/- contrast mediax-ray +/- contrast media
Ultra sound Ultra sound
Computerised Tomography (CT)Computerised Tomography (CT)
Magnetic resonance imaging (MRIMagnetic resonance imaging (MRI) )
Gamma Camera and radioisotopes Gamma Camera and radioisotopes
(Nuclear Medicine)(Nuclear Medicine)
Cannon BallCannon Ball
Multiple MetastasesMultiple Metastases
Diffuse Metastases-Before and Diffuse Metastases-Before and After ChemotherapyAfter Chemotherapy
Detection of Tumour MarkersDetection of Tumour Markers
Those detected on cancer tissueThose detected on cancer tissue i) Biochemical methodsi) Biochemical methods Oestrogen receptors in breast cancerOestrogen receptors in breast cancer
ii) Genetic methodsii) Genetic methods Mutated genes BRCA1 and BRCA2 in breast cancerMutated genes BRCA1 and BRCA2 in breast cancer
iii) Antibody methodsiii) Antibody methods Carcinoembryonic antigen (CEA)Carcinoembryonic antigen (CEA)
Secreted by cancers into the blood Secreted by cancers into the blood
Detection byDetection by:: Biochemical techniquesBiochemical techniques steroids in adrenocortical cancer steroids in adrenocortical cancer Immunoassay Immunoassay proteins, glycoproteinsproteins, glycoproteins
Ancient HistoryAncient History
1848 Bence Jones 1848 Bence Jones Multiple myelomaMultiple myeloma
1929 Ascheim-Zondek 1929 Ascheim-Zondek hCG-trophoblasthCG-trophoblast
1932 Harvey Cushing1932 Harvey Cushing Pituitary BasophilsPituitary Basophils
The First Tumour MarkerThe First Tumour Marker
It is known as Bence –Jones proteinuria, a It is known as Bence –Jones proteinuria, a marker for multiple myeloma a marker for multiple myeloma a
malignancy of the plasma cell.malignancy of the plasma cell.
Often referred to as a paraproteinuriaOften referred to as a paraproteinuria
It is a monoclonal gammopathy with any It is a monoclonal gammopathy with any class of immunoglobulinclass of immunoglobulin
Cancers of Endocrine OrgansCancers of Endocrine Organs
AdrenocorticalAdrenocortical PhaeochromocytomaPhaeochromocytoma
Insulinoma Insulinoma Gastrinoma Gastrinoma Carcinoid Carcinoid Medullary Ca ThyroidMedullary Ca Thyroid
CortisolCortisol adrenaline & nor adrenaline & nor
adrenalineadrenaline insulin, C peptide insulin, C peptide gastrin gastrin 5-HIAA 5-HIAA CalcitoninCalcitonin
Ectopic product syndromesEctopic product syndromes
Cancers sometimes produce substances Cancers sometimes produce substances inappropriate to the cell type of origininappropriate to the cell type of origin
Bronchial carcinomas may produce Bronchial carcinomas may produce
ACTH, parathormone andACTH, parathormone and
human Chorionic Gonadotrophin (hCG)human Chorionic Gonadotrophin (hCG)
Protein markers of common cancers Protein markers of common cancers detected by immunossay in blooddetected by immunossay in blood
Human Chorionic gonadotrophin (hCG)Human Chorionic gonadotrophin (hCG)
PregnancyPregnancy Trophoblastic disease - ChoriocarcinomaTrophoblastic disease - Choriocarcinoma Germ cell cancers of testis and ovaryGerm cell cancers of testis and ovary Alfa- feto protein (AFP)Alfa- feto protein (AFP)
Germ cell cancers of testis and ovary Germ cell cancers of testis and ovary
HepatomaHepatoma
Protein markers continuedProtein markers continued
Carcinoembryonic antigen (CEA)Carcinoembryonic antigen (CEA)
Colon, stomach etcColon, stomach etc
Prostate Specific antigen (PSA)Prostate Specific antigen (PSA)
CA125- OvaryCA125- Ovary
CA153- BreastCA153- Breast
Measurement of Tumour MarkersMeasurement of Tumour Markers
1930-1963 Bioassays on Urine1930-1963 Bioassays on Urine 1958 Immunoassays- serum1958 Immunoassays- serum 1960 Radioimmunoassay-1960 Radioimmunoassay- serum or urineserum or urine 1968 Immunometric assay1968 Immunometric assay serum or urine-serum or urine- Commercial KitsCommercial Kits 1975 Dip Stick Tests1975 Dip Stick Tests
What Is An Assay ?What Is An Assay ?
0
200000
400000
600000
800000
0 0.002 0.004 0.006 0.008 0.01
Concentration of Reference Standard
Res
po
nse Unknown
Antibody ProductionAntibody Production
Immunogen (Antigen) RabbitImmunogen (Antigen) Rabbit Sheep AntiserumSheep Antiserum MouseMouse Horse etcHorse etc
Antisera contain many different antibodies directed at Antisera contain many different antibodies directed at one or more sites on immunogen (polyclonal)one or more sites on immunogen (polyclonal)
Burnett (1957)- Clonal selection TheoryBurnett (1957)- Clonal selection Theory One Cell - identical antibodiesOne Cell - identical antibodies
Antibody ProductionAntibody Production
Kohler & Milstein (1975) Kohler & Milstein (1975) Immortalise an antibody producing Immortalise an antibody producing
cell cell by fusion with a malignant cellby fusion with a malignant cell
HybridomaHybridoma Hybridomas proliferateHybridomas proliferate Identical (monoclonal) antibodies Identical (monoclonal) antibodies
RISING levels of these serum markers RISING levels of these serum markers
indicate disease progressionindicate disease progression
FALLING levels and slowing of rate of FALLING levels and slowing of rate of increase may indicate response to increase may indicate response to therapytherapy
BUT interpretation has to take account BUT interpretation has to take account
of the HALF -LIFE (t1/2)of the HALF -LIFE (t1/2)
Half Life Of Common Tumour Markers Half Life Of Common Tumour Markers Depends On Molecular WeightDepends On Molecular Weight
MW TM T1/2(D) ROUTEMW TM T1/2(D) ROUTE <70 hCG, PSA 2.3 renal<70 hCG, PSA 2.3 renal 70 aFP 6 mixed70 aFP 6 mixed > 70 all others 10 hepatic > 70 all others 10 hepatic
Median Doubling TimesMedian Doubling Timesreflect different growth rates of cancersreflect different growth rates of cancers
CANCER TM T2(D)CANCER TM T2(D) Choriocarcinoma hCG 3Choriocarcinoma hCG 3 Germ cell aFP 6Germ cell aFP 6 Breast CA153, CEA 30Breast CA153, CEA 30 Ovary CA125 30 Ovary CA125 30 Pancreas CA199 30Pancreas CA199 30 Colon CEA, CA199 30Colon CEA, CA199 30 Prostate PSA 128 Prostate PSA 128
Cell NumbersCell Numbers
Time Scale- Cell NumbersTime Scale- Cell Numbers
Human Chorionic Gonadotrophin-Human Chorionic Gonadotrophin-(HCG) C-Terminal Peptide(HCG) C-Terminal Peptide
Normal Placental VilliNormal Placental Villi
hCG V Cell NumbershCG V Cell Numbers
Human Chorionic Human Chorionic Gonadotrophin (hCG)Gonadotrophin (hCG)
Normal Pregnancy: Normal Pregnancy:
Mostly Intact molecule (Mostly Intact molecule (αα and and ββ subunits) subunits)
Mole, Choriocarcinoma: Mole, Choriocarcinoma:
Fragmented hCG moleculesFragmented hCG molecules
Trophoblastic TumourTrophoblastic Tumour
ChoriocarcinomaChoriocarcinoma
Germ Cell TumourGerm Cell Tumour
Germ Cell TumourGerm Cell Tumour
Prostate Specific Antigen (PSA): Age Effect
Carcinoembryonic AntigenCarcinoembryonic Antigen
CEACEA
Radioimmunolocalisation-CEARadioimmunolocalisation-CEA
Therapeutic ApplicationTherapeutic Application
Radiolabelled Antibodies (RIT)Radiolabelled Antibodies (RIT)
Drug-Antibody ConjugatesDrug-Antibody Conjugates
ProblemsProblems
Only a fraction of the i.v injected antibody Only a fraction of the i.v injected antibody gets into tumour: gets into tumour:
Most of the antibody stays in blood until Most of the antibody stays in blood until excreted or metabolisedexcreted or metabolised
Heterogeneity of cancer cell:Heterogeneity of cancer cell:
not all cancer cells express the markernot all cancer cells express the marker
Potential SolutionsPotential Solutions
Antibody directed enzyme prodrug Antibody directed enzyme prodrug therapy (ADEPT)therapy (ADEPT)