T U M O R M A R K E R S THE CANCER PROBLEM

• Lung cancer – CA 125, CEA • One of the leading cause of death

• Liver cancer – AFP • <15% decrease is observed in Hodgkin’s disease and cancers of the cervix,
• Prostate cancer – PSA stomach and uterus.
• Testicular cancer – AFP, HCG • >15% increase is observed in lung cancer, melanoma, multiple myeloma, and
• Breast cancer – CA125, CEA, HER-2/NEU non-Hodgkins syndrome
• Stomach cancer – CEA • Early detection and more effective treatment
• Pancreas cancer – CA125, CEA
CANCER – DEFINITION
• Colon cancer – CEA
• Ovaries cancer – CA125, CEA
• A relative autonomous growth of tissue
• A carcinogen is an agent that causes cancer
CANCER STAGING AND PROGRESSION
- Physical – radiation
• Stage I – localized primary tumor - Chemical – polycyclic hydrocarbon
• Stage II- invasion of primary tumor through epithelium and into blood vessels - Biological – virus
• Stage III- migration tumor into regional lymph nodes
EXPOSURE TO THESE AGENTS MAY CAUSE CANCER BY:
• Stage IV- metastasis and invasion of tumor distant to tissues

a. Producing direct genotoxic effects on DNA – radiation

Monitoring Effectiveness of Therapy and disease
b. Increasing all proliferation- hormone or;
recurrence
c. Both- use of tobacco
Many markers have a lead time of several months before the disease would be
MOLECULAR GENETICS
detected. This would allow early identification and treatment during relapse.

• ONCOGENES- growth promoting that regulates the proliferation of normal

• Most useful and common applications of tumor markers is monitoring therapy
cells
efficacy and detecting disease recurrence.
• TUMOR SUPPRESSOR GENES – counteract the effect of oncogenes
• After surgical resection, radiation or drug therapy of cancer (chemotherapy),
tumor markers are routinely followed serially SPECIFIC TUMOR MARKERS
Elevated tumor Decrease or The appearance of
disappearance of the circulating tumor 1. Enzymes
marker (diagnosis)
tumor marker – initial markers can then be 2. Hormones
treatment is used as a highly 3. Oncofetal antigens
effective sensitive marker of 4. Carbohydrate markers
recurrence 5. Blood group antigens
6. Proteins
7. Receptors
8. Genes
 HISTORY OF TUMOR MARKERS DEGREE OF DIFFERENTIATION

YEAR AUTHOR I. Well differentiated

1846 [Link]-Jones Bence- Jones Protein II. Poor differentiated
1928 W.H. Brown Ectopic hormone syndrome III. Anaplastic- without form (most aggressive type of cancer)
1930 B. Zondele HCG
1932 [Link] ACTH USES OF TUMOR MARKERS
1949 [Link]-uti Deletions blood group
antigens § Screening in general population
1959 [Link] isoenzymes § Differentiate diagnosis in symptomatic patients
1963 G.I. Abelav AFP § Clinical staging of cancer
1965 P. Gold and S. Freeman CEA § Estimating tumor volume
1969 [Link] and G. Todaro Oncogenes
§ Prognostic indicator for disease progression
1975 [Link] and G. Milstein Monocolonal antibodies
§ Evaluating the success of treatment
1980 [Link], [Link] and Oncogene probes and
§ Detecting the recurrence of cancer
M. Bishop transfection
1985 [Link], [Link] and A. Suppressor gene § Monitoring responses to therapy
Knudson § Radioimmunolocalization of tumor masses
§ Determing direction for immunotherapy

TUMOR MARKERS ENZYMES

• Substance present in or produced by tumor itself or produced by the host in § Enzymes are found in the cell and release when:
response to a tumor that can be used to differentiate a tumor from a normal Ø Tumor necrosis/membrane permeability of cancer cells
tissue or determine the presence of a tumor based on hormonal secretions Ø Seen also in lockage of pancreatic or biliary ducts and renal insufficiency
§ Not specific
“LEVELS” OF EXPRESSION OF ONCODEVELOPMENT § Not sensitive
MARKERS Ø For cancer identification or organ involvement

Production of Tumor Markers by various tissues Enzymes not used for marker:
MARKER NORMAL ENDOCRONIGICALLY DISTANTLT UNRELATED
PRODUCING CLOSELY RELATED RELATED § Present in their fetal form (isozyme) or ectopic production
CEA Colon Stomach, liver, Lung, breast Lymphoma § Measurements are either assays used to measure enzyme activity or mass
pancreas
concentration using radio immunoassay (RIA) or immunometric assay (IMA)
AFP Liver, yolk sac Colon, stomach, cancer Lung
HCG Placenta Germinal tumors Liver Epidermal
ENZYMES ACTIVITY TYPE OF
lung
Activity
Serotonin Endocrine adrenal Oat cell, lung Epidermal
Activity
carcinoid lung
Activity
Activity
 Activity LACTATE DEHYDROGENASE
Activity
Activity § An enzyme in the glycolytic pathway and is release as the result of cell damage
§ Nonspecific – seen elevated in almost all types of malignancies
§ LD 5 isoenzymes has marginal specificity associated with liver metastases
Other tests used for determination:
NEURON-SPECIFIC ENOLASE (NSE)
§ 5’Nucleotidase
§ Gamma-glutamyltransferase § a glycolytic enzyme also known as phosphopyruvate hydratase
§ it is found in neuronal tissue and in cells of the diffuse neuroendocrine
Other malignancies than liver and bones are: system, the amine precursor uptake and decarboxylation (APUD) tissues
§ malignancies (>12.5 ug/mL)
§ Leukemia
§ small cell lung cancer (SCLC)
§ Lymphoma complicated with hepatic infiltration
Ø 80% sensitive; 80-90% specific
PLACENTAL ALKALINE PHOSPHATASE § Neuroblastoma
Ø In children – 80%
§ Synthesized by trophoblast § Pheochromocytoma
§ Physiologically elevated in pregnant women first identified as REGAN § Carcinoid
isoenzyme in 1968 by Fischerman and colleagues § Medullary carcinoma of the thyroid
§ Considered first oncodevelopment markers along with AFP and CEA § Melanoma
§ Elevated in: § Pancreatic endocrine tumors
Ø Ovarian Ø High levels of NSE are associated with prognosis
Ø Trophoblastic
Ø Carcinoma PROSTATIC ACID PHOSPHATASE (PAP)
Ø Lung
§ Optimal pH of 5.0 to 6.0
Ø GIT cancers
§ Distinguished by the rest
Ø Hodgkin’s diseases
§ PAP is inhibited by tartrate
CREATINE KINASE § Hydrolyzes two substrates – thymolphthalein monophosphate (more specific)
and a-napthol phosphate (done in automation)
§ Catalyzes the phosphorylation of creatinine by adenosine triphosphate
§ CK 1 (BB)
Ø Brain, prostate gland, GIT, lung, bladder, uterus and placenta
§ CK 2 (MB)
Ø Cardiac muscles
§ CK 3 (MM)
Ø Skeletal and cardiac muscles
 Prostate Specific Antigen

• 1971-Hara- y-seminoprotein
• 1978-Sensabaugh-“p30”
• 1979-Wang-prostate specific antigen derived from purified Hormones
prostatic
• The production of hormones in cancer involves in two routes:
• A single chain glycoprotein with 7% carbohydrates that contain
1. Endocrine tissue
237 amino acids and four carbohydrate side chains of amino
× Tissue normally produce hormone but at excessive amount
acids
2. Ectopic tissue
o 45 (asparagine)
× Tissues normally do not produce hormone but now produce
o 69 (serine)
hormone
o 70 (threonine)
× Examples: N* pituitaryàACTH
o 71 (serine)
× SCLC----àACTH
• Located at Chromosome 19
Adrenocorticotropic hormone (ACTH)
o Similar to kallikrein family with 82% homology
• Produced by corticotropic cells of the anterior pituitary
o Specifically a serine protease kallikrein
• Elevations in various malignancies and benign conditions (mental
o Produced by epithelial cells of the acini and ducts of the
depressions, obesity, COPD, DM and stress)
prostate gland secreted into the lumina of prostate duct
• Dexamethasone suppression test
• In the seminal fluid---PSA cleaves a seminal vesicle-specific
-distinguish endocrine or ectopic origin of the ACTH
protein into several low molecular weight proteins
o No suppression means ACTH is of ectopic origin
• Possesses chemo trypsin like and trypsin like activity part of
o 200 ng/L suggest ectopic in origin
the process of liquid faction of the semen coagulum
Human Chorionic Gonadotropin (hCG)
• Autodigestion of PSA is found in LYS (145) and LYS (185)
• Produced by syncytiotrophoblastic cell of the normal placenta
• Two major forms of PSA in the blood
o Alpha subunits (LH, FSH, TSH)
• Seminal fluid PSA can be fractionalized in 5 isoforms:
o Beta subunits (unique to hCG) à as tumor markers
o PSA-A and PSA-B are active and forms complexation
• Useful tumor markers for the tumors of the placenta
with ACT
(trophoblastic tumors) and tumors of the teste
o PSA-C, PSA-D and PSA-D possess low or no enzymatic
• Useful also in the diagnosing and monitoring prognosis
activity
Endocrine Tumor Markers
Enzyme Tumor Markers
Tumor markers Tumor type Method Specimen Clinical Utility
Tumor markers Tumor type Method Specimen Clinical Utility
 o Breast and Uterine-40%
o Ovaries-25%
Oncofetal Nature Type of Cancer
Antigen
Pancreatic oncofetal Glycoprotein, 40 kd Pancreatic
Oncofetal antigens
Squamous cell antigen Glycoprotein,44-48 kd Cervical, Lung, Skin, Head and Neck
• Proteins produced during fetal life (Squamous)
Tennessee antigen Glycoprotein, 100 kd Colon, Gastrointestinal, bladder
• Normally high concentrations in fetuses and decrease to low
Tissue polypeptide Glycoprotein, 8,18,19 Various (breast, colorectal, ovarian,
levels or disappear after birth antigen bladder)
• Reappear in malignant states
Alpha-fetoprotein (AFP) Carbohydrate Markers
• Normally less than 10ug/L • Either are antigens on the tumor cells surface or are secreted
• Physiologically elevated at 12 weeks gestation to a peak of 500 by the tumor cells
ug/L on the third trimester • High-molecular-weight mucin
• Also seen elevated with benign conditions such as hepatitis and Carbohydrates & Cancer Antigen Tumor
cirrhosis-lower than 200 ug/L Markers
• Concentrations greater than 1 000 ug/L is indicative of cancer Tumor Tumor type Method Specimen Clinical Utility
Carcinoembryonic Antigen (CEA) markers
• A marker for colorectal, gastrointestinal, lung, and breast CA 19-9 Gastrointestinal cancer Immunoassay Serum Monitoring
& adenicarcinoma pancreatic cancer
carcinoma
CA 15-3 Metastatic breast Immunoassay Serum Response to therapy
• Located at Chromosome 19 cancer detecting recurrence
• Part of the immunoglobulin gene “superfamily” because of the
CA-125 Ovarian cancer Immunoassay Serum Monitoring therapy
gamma heavy chain very similar to immunoglobulin IgG CA, cancer antigen
• Elevations of CEA in benign conditions Mucin Tumor Markers
o Cirrhosis-45% Name Antigen & Antibody Type of Cancer
o Pulmonary Emphysema-30% Source
o Ractal polyps, benign breast diseases and ulcerating -15% Ca125 Glycoprotein OC125 Ovarian, endometrial
Episialin • Glycoprotein • DF3 &115D8 • Breast,ovarian
• Elevations of CEA in variety of cancers • CA 15-3 • High-MW • BC4E549, • Breast,ovarian
o Colorectal-70% • CA 549 glycoprotein BC4N154 • Breast
• CA • High-MW • B27.29
o Pancreatic-85%
27.29 glycoprotein
o Gastric-60% MCA Glycoprotein Breast,ovarian
o Lung-25% DU-PAN-2 Mucin Pancreatic, ovarian,
gastrointestinal, lung
 Receptor Tumor Markers
Tumor Tumor Type Method Specimen Clinical
Blood Group Antigens
Marker utility
• Carbohydrates identified by monoclonal antibodies that have Estrogen Breast cancer IHC Biopsy Hormonal
been used as markers of cancers receptor therapy
indicator
Name Antigen & Source Antibody Type of Cancer
CA 19-9 Sialylated Le22, SW-1116 colon 19-9 Pancreatic, gastrointestinal, hepatic
Progesterone Breast cancer IHC Biopsy Hormonal
CA receptor therapy
CA 19-5 Le2 & sialylated Le22 19-5 Gastrointestinal, pancreatic, ovarian indicator
CA 50 Sialylated Le2 & afuccosyl C50 Pancreatic, gastrointestinal, colon Her-2/neu Breast, ovarian, IHC,FISH,ELISA Biopsy Prognostic &
form gastrointestinal tumor hormonal
CA 72-4 Sialylated Tn B27.3, cc49 Ovarian, breast, gastrointestinal, therapy
colon indicator
CA 242 Sialylated CHO C242 Gastrointestinal, pancreatic
Epidermal Head, neck, ovarian, IHC Biopsy Prognostic
growth cervical cancer Indicator
Proteins as Tumor Markers factor
receptor
Name Type of Cancer ELISA, enzyme linked immunosorbent assay
B2-Microglobulin Multiple myeloma, B-cell lymphoma, chronic
FISH, fluorescence in situ hybridization
lymphocytic leukemia, Walderstrom's
IHC, immunohistochemistry
macroglobulinemia
C-peptide Insulinoma
Ferritin Liver, lung, breast, leukemia Serum Protein Tumor Markers
Immunoglobulin Multiple myeloma, lymphomas Tumor Tumor Type Method Specimen Clinical Utility
Melanoma-associated antigen Melanoma Markers
Pancreas-associated antigen Pancreatic, stomach Serum M- Plasma cell SPE/IFE Serum Diagnosis, therapeutic
Pregnancy-specific protein 1 Trophoblastic, germ cell
protein dyscrasias monitoring of plasma
Prothrombin precursor Hepatocellular
cell malignancies
Tumor-associated trypsin inhibitor Lung, gastrointestinal, ovarian
Serum-free Plasma cell IA Serum Diagnosis, therapeutic
light chains dyscrasias monitoring of plasma
Other Tumor Markers cell malignancies
B2- Hematologic IA Serum Prognostic marker for
Name Nature Type of cancer
microglobulin malignancies lymphoproliferation
Estrogen & progesterone Tissue Breast
Catecholamines metabolites Urine-VMA,HVA,metanephrine Neuroblastoma,
disorders
pheochromocytoma IA, immunoassay
Hydroxyproline Urine Bone meatastasis (breast), IFE, immunofixation electrophoresis
multiple myeloma SPE, serum protein electrophoresis
Lipid-associated Sialic acid bound lipid Gastrointestinal, lung,
rheumatoid
polyamine CSF/urine brain