Tumor markers
Etiopatogenesis of tumors
13_tumor markers 1
Tumors
• Tumor is a pathological state (disease) due to impaired control of cell division
- genetic variation often one somatic (but germinal) cells causes impaired regulation
- cells resulting from pathological clone proliferate uncontrollably (at different rates), and then
eventually spreading to secondary sites (metastasis)
 according to the rate of proliferation we distinguish tumors:
- benign - usually grow only in the point of origin, not aggressive, they retain differentiation
- malignant - they grow quickly, invasive and spread to other places, undifferentiated
• All tumors are due to genetic defects, namely the key genes controlling cell cycle
 (Proto)oncogenes - normally promote cell growth and division, if mutated, uncontrolled
division
 suppressor genes - normally suppress the cell division, if mutated, allowing uncontrolled
division
 DNA repair genes - normally repair (repairable) DNA modifications, if mutated, uncorrected
changes can be transferred to daughter cells
- however only some of them are also heritable (ie. Familial) = mutation in the germinal cell
- most tumors are random, ie. sporadic = mutations in somatic cell
213_tumor markers
Tumors
• Genetic variation may develop
- by error during DNA replication and cell division
- by action of external factors (carcinogens)
- physical - eg. UV and ionizing radiation
- chemical - organic substances, toxins, heavy metals
- biological - some RNA and DNA viruses
• The tumor usually originally comes from mutations of 1 cell (monoclonal)
- however the process of neoplastic transformation is
multi-stage (the gradual accumulation of
several mutations) so that gradually becomes
genetically heterogeneous
-tumor switches from precancerous stage, via benign to malignant
• Histologically - depending on which tissues derived,
we distinguish 3 groups:
- epithelial: skin, mucous membrane (Papilloma, adenoma, carcinoma)
- mesenchymal: connective tissue, endothelial, muscle tissue, lymphatic
and hematopoietic tissue, bone (fibroma, hemanginom, myoma, sarcoma,
lymphoma, leukemia)
- neuroectodermal: CNS and peripheral nerves, pigmented nevi (astrocytoma, glioma,
blastoma, neuroma, melanoma) 3
TEST
13_tumor markers
Which genes are altered during
carcinogenesis?
• The tumor is not monogenic disease
• It is estimated that for tumor development is
necessary 4-7 events (hits)
• Many specific genes can be altered during
carcinogenesis (tens)
• Generally, there are six basic characteristics of fully
malignant tumor:
413_tumor markers
Six acquired characteristics of a malignant
tumor
acquired characteristics example
1. self- sufficiency in growth signals H-ras activation
2. insensitivity to signals stopping the cell cycle loss of RB
3. damage apoptosis IGF production
4. limitless replicative potential telomerase
activation
5. strengthening angiogenesis VEGF production
6. metastasis E-cadherin inactivation
Instability of the genome as a condition for accumulation of necessary
changes.
5
TEST 13_tumor markers
Classification of tumors
• Morphological diagnosis = typing
- determining the histological type
• Rating invasiveness = grading
- determining benignity x malignancy
• Determining the initial scope = staging
- TNM classfication(T = tumor, N = node, M = metastasis)
613_tumor markers
The process of neoplastic transformation
Mutation in a critical spot DNA
(protooncogen, suppressor, reparation gene)
- Chromosomal aberrations (translocations, insertions, deletions, duplications
- Gene mutations (point mutations, the length (ins / del) )
Mutagenes/carcinogens
-physical: UV (carcinoma and basalioma of skin, melanoma)
ionizing radiation and RTG radiation (leukemie, thyroid gland, bones)
- chemical: polycyclic aromatic hydrocarbons and chlorinated
aromatic amines, nitrosamines, heavy metals, mycotoxins
- Tumors of the gastrointestinal tract as a result of exposure to carcinogens in the diet
- Lung cancer as a result of smoking
- Alcoholcirrhosis
- biological = incorporation of the viral genome into the host,
again in critical places
- DNA viruses (hepes EBV- lymfomas; hepadnaviruses HBVhepadnacellular
ca; papovaviruses - papillomaviruses, adnoviruses)
- RNA viruses – retroviruses (HIV – Kaposiho sarkoma, B- lymfoma
HTLV – T-cell leukemia)
- precancerous = chronic irritation from inflammation
- Barrett's esophagus in GER
- ulcerative colitis and Crohn's disease
- diverticulitis
713_tumor markers
Tumor growth
• Dividing tumor cells in clone: N=2n
- 2, 4, 8, 16, 32, …
- 10 division= ~ 1 000 bb.
- 20 division = ~ 1 000 000 bb.
- 30 division = ~ 1 000 000 000 bb.
- 40 division = m = 1kg (at 12-hour cell cycle for about 20 days)
• however in reality is the growth of tumors much
slower - dividing x cell death
- extending the duration of the cell cycle
- Non-proliferating fraction of cells (differentiated))
- Cell death (malnutrition, cytotoxic. Lymphocytes)
- Mechanical losses cells (peeling e.g. in the intestine)
• Condition for growth is the creation of tumor stroma and capillary
networks (angiogenesis)
- then dominate proliferation over the of cell death 813_tumor markers
Tumor growth: other factors affecting the cell cycle
• intercellular communication
(~ contact inhibition)
- integrins– together with ECM
• - cadherins – the connection between each cell
913_tumor markers
Tumor growth: other factors affecting the cell cycle
• Metabolism = energy demand
(Oxygen and substrates)
- Cell mass the size of about 1 mm3 (about 1x106 cells)
without vascularization isn´t capable of further growth
(proliferation is in equilibrium with apoptosis)
- In response to hypoxia is regulated hypoxia-1a (HIF-1a)
which, after translocation into the nucleus affects
transcription of a number genes:
- Repression of E-cadherin
- Expression of GLUT1 and 3 = substrates
(Also the effect of hormones and growth factors)
- vascular endothelial growth factor (VEGF) and angiopoietin
- This stimulates the formation of new blood vessels (angiogenesis) required for
tumor growth
- Chemotaxis of macrophages in tumor production and other angiogenic growth
factors
- VEGF, bFGF (basic fibroblast growth factor), TGF-b (transforming growth factor –b),
PDGF (platelet-derived growth factor)
1013_tumor markers
Immune system vs. tumor
• Tumor cells have some immunological differences
- Changes in natural surface antigens (e.g. MHC loss)
- Escape immune recognition and destruction
- Expression of the novel (oncofetal) antigens
- diagnostic markers (e.g. CEA, alpha-fetoprotein etc.)
• Cytotoxic mechanisms are applied in the anti-tumor immunity
- CD8 + T- lymfocty
- NK b.
1113_tumor markers
Hormonal stimulation
• Growth of some tumors is significantly potentiated by
hormones (usually sex hormones)
- ca breast, uterine, ovarian, prostate
1213_tumor markers
Invasiveness of tumor
• Cancer cells acquire a "motility" phenotype
by loss of adhesion proteins (E-cadherin)
(epithelial-mesenchymal transition, EMT)
- Loss of apikobazal cell polarization
- Epithelial tumors (carcinomas) form
2/3 of all cancers
- Production of proteolytic enzymes by tumor cells
- The matrix metalloproteinase (MMP) and uPA
- Degrade extracellular matrix and
It allows for "sprouting" of new blood vessels and
extravasation of tumor cells
- Resistance to anoikis
- A form of apoptosis initiated
"Peeling away" of the epithelial
cells from the ECM
1313_tumor markers
Metastasis
• Creating secondary tumors distant from the primary site
- by blood
- often downstream (e.g. from the gastrointestinal tract into the liver, venous blood
to the lungs, of pulmonary arterial blood to the bone and brain)
- by lymph
- first closest lymph nodes,
then farther
1413_tumor markers
Some consequences of tumors
• hyperkalemia
• hypoglycemia
• Anemia
• acidosis
• hormonal disorders
• Cancer cachexia
15
Hyperkalemia : increased potassium levels in the blood.
Normal values range from 3.8 to 5.0 mmol/l. Given that
kalemia depends on the acid-base status, it must be
considered in relation to pH
Cancer cachexia syndrome is a progressive loss of
body mass, which causes significant morbidity and
mortality of cancer patients. Metabolic changes
conditioned by activity of proinflammatory
cytokines, leading ultimately to the depletion of
muscle and fat mass, are often present at the
beginning of the disease, and therefore must be
considered as early cancer cachexia phenomenon.
13_tumor markers
• Malignant neoplasms are the most common
causes of death
• Growth of incidence of what types of tumors?
• There is a shift to younger ages
• The objective is the earliest possible diagnosis
• Imaging methods vs. immunochemical methods
• Methodological improvements
1613_tumor markers
• Diagnosis of tumors
• Given that cancer is in our society frequent and dreaded disease there is much
effort to understand and improve diagnosis and treatment.
• Treatment of cancer depends on early diagnosis and diagnose cancerous
disease is not always easy.
• Clinical diagnosis is determined mostly only in the tumor size of
about 1 cm - 1 g, containing about 109 cells.
• Histological examination, imaging (US, CT, NMR, PET, scintigraphy)
• Tumors often have no symptoms and can only appear after onerous and costly
investigations that can not be done for each patient.
• Inevitably, the question emerged: Would it be possible to detect the presence
of tumor in some conventional testing, e.g. from blood?
• It was found that in the case of many tumors to some degree we really can. It
was demonstrated that the presence of a tumor in the body is associated with
increased concentrations of certain substances that we can detect in the
laboratory from a blood sample.
• These substances are called tumor markers.
1713_tumor markers
TUMOR MARKERS
• Tumor markers are molecules predominantly of a
protein character, which are present in the
organism due to the formation and development of
a malignant process.
Resolution of tumor markers allows in favorable cases to reveal
tumor weighing 1 mg, about 106 malignant cells, determined by
clinical diagnosis it is usually only in the tumor size of about 1 cm -
1 g, which contains about 109 cells.
TEST
13_tumor markers 18
Tumor markers are produced either
• tumor itself (then called tumor-associated antigens ) or
• other tissues in response to a malignant process in the organism (then it
is induced tumor markers, e.g. acute phase proteins).
We can distinguish tumor markers
• cellular (occurring in tissue cancer)
• humoral (occurring in body fluids).
The concentration of tumor markers in serum is usually in a direct
relationship with the type and extent of disease.
13_tumor markers 19
TEST
The ideal tumor marker should meet the following criteria:
• It is produced only in malignant diseases
• is organ-specific
• in biological fluids are present in high concentrations (sufficient sensitivity)
• its level correlates with tumor size
with stage of disease
prognosis
with a therapeutic effect
• allows the identification residual tumor tissue
• At present, such an ideal marker not known.
20
The universal tumor marker is yet to be discovered, or the specificity
or sensitivity of the method is below 100%. This means that failure to
raise the concentration of the tumor marker is not evidence of
absence of malignant disease and, conversely, a positive result does
not necessarily mean cancer.
13_tumor markers
TEST
They can be defined as a laboratory detectable marks in
biological fluids, tissues or cells, by which it can be
demonstrated:
• risk of formation
presence
prognosis
efficiency (harmfulness) of therapy
metastasis or residual disease.
• The main role of tumor markers (in medicine and
laboratory) is
tracking the disease
monitor the effectiveness of therapy.
13_tumor markers 21
CLASSIFICATION OF TUMOR MARKERS
by chemical structure
by function
by organ-specificity
by origine
2213_tumor markers
• humoral - detection in body fluids
• cellular – immunohistochemistry - directly in
the tumor tissue
23
Methodology for determination of soluble markers:
Enzymatic analysis using commercial sets
CLASSIFICATION OF TUMOR MARKERS
13_tumor markers
24
Chemical structure
• glykoproteins
• glykolipids
• peptides
• imunoglobulins
• polyamines
• carbohydrates
13_tumor markers
TEST
25
Internal specificity
• high: calcitonin - medullary carcinoma of the thyroid
PSA - prostate cancer
NSE - small cell lung cancer
hCG - germ-cell tumors
AFP - hepatocellular and germ-cell carcinoma
• moderate: CA 19-9 - pancreatic cancer
CA 125 - ovarian cancer
CA 15-3 - breast cancer
• low: CEA
TPA
13_tumor markers
TEST
26
Function
• oncofetal antigens
• oncoplacental antigens
• enzymes
• hormones
• serum proteins
• receptors
• others
13_tumor markers
TEST
27
1) Oncofetal antigens
• substances produced during fetal life
• present in high concentrations in the sera of fetuses,
decrease to low levels or disappear after the birth
• reappear in patients with cancer
• Their production demonstrates that certain genes are
reactivated as a result of the malignant transformation of
the cell.
• substances occurring in high concentrations in the fetus (on the
surface of differentiating cells) and the presence of cancer in
adults
• in healthy adults is very low level
• level correlates with the size of the tumor mass
• determination is mainly used for prognosis and therapy control
• examples: AFP, CEA, CAs, CYFRA 21-1, SCC, MCA,
MSA, TATI
13_tumor markers
TEST
28
2) Oncoplacental antigens
• produced by the trophoblastic cells of the
placenta in both pregnancy and pathological
conditions and also by germinative tumors as a
mark of malignant dedifferentiation
• ↑ levels show evidence of ↑ malignancy and
metastatic potency of the given tumor
• examples: hCG, SP-1
13_tumor markers
TEST
29
3) Enzymes
• present in much higher concentrations inside cells
• released into circulation as the result of tumor necrosis or a
change in the membrane permeability of the cancer cells
• elevated enzyme levels may signal the presence of malignancy but
usually are not specific enough to identify a cancer type or organ
involvement
• We can divide them into two groups:
• enzymes involved in cell division: their level is in excessive proliferation
significantly increased, therefore, apply in determining prognosis and stage
of disease.
• enzymes occurring even in healthy tissue, where they perform their
biological functions are the most highly organ-specific and therefore are
used to determine the primary location of the tumor.
• examples: NSE, TK, ALP, PSA, isoenzymys of LD, ALP13_tumor markers
TEST
30
4) Hormones
• The production of hormones in cancer involves two
separate routes:
1. the endocrine tissue that normally produces the given
hormone can produce its excess amounts
2. ectopic syndrome - hormone produced by a distant
nonendocrine tissue that normally does not produce this
hormone
• for instance: ACTH normally produced by the pituitary gland
ectopicaly produced by the lung small
cells
• elevation of a hormone is not specific ← it may be produced by
a variety of cancers
• examples: ACTH, ADH, PTH, calcitonin, STH, prolactin13_tumor markers
31
6) Serum proteins
• produced either by tumor cells or by an
organism in the presence of tumor
• non-specific
• monitoring
• examples: β2-microglobulin, ferritin,
paraprotein
13_tumor markers
32
7) Receptors
• cellular markers used in hormone-producing
tumors
• examples: estrogen and progesterone
receptors, Her2/neu, EGFR
13_tumor markers
33
8) Other tumor markers and
circulating cellular elements
• tissues - produced substances, which we
cannot class with the previously mentioned
groups
• circulating cellular elements (circulating tumor
cells, circulating endothelial cells and circulating
endothelial precursors).
• examples: TPA, TPS, CgA, neuropeptide Y, S-
100b, 5-HIAA
13_tumor markers
TEST
9) genetic abnormalities
Besides the usual applications of classical (soluble) tumor
markers appear to be clinically useful as tumor markers,
some genetic abnormalities and in particular to specify
the abnormality determining tumor cell treatment.
It is both a direct detection of mutations in DNA,
protein products of oncogenes (e.g. c-myc, c-fos, k-ras,
src), changes in their post-translational modifications in
malignant tissue or "new" genetic changes in malignant
cells (e.g. chromosomal rearrangement of bcr-abl)
or detection of mutations in tumor suppressor genes
(BRCA1, BRCA2, p53).
13_tumor markers 34
35
USE OF TUMOR MARKERS
• Screening: calcitonin in families with MEN syndrome, AFP in
patients with liver cirrhosis, PSA in men >50 years
• Dg and diff. dg in symptomatic individuals
• Clinical staging of cancer, is aided by quantitation of the
marker, i. e. the serum level of the marker reflects the number of
cancer cells present in the body
• Monitoring of the disease and estimation of tumor value
• Prognostic indicator of disease progression and patient
survival
• Detection of cancer recurrence, permits early treatment
or a change in therapy
• Monitoring of responses to therapy
13_tumor markers
TEST
•screening – for majority of markers inappropriate.,
with limitations in high-risk groups:
AFP in liver cirrhosis
calcitonin , eventually.RET oncogene in families with
MEN syndromes and relatives of a patient with
medullary Ca thyroidea
PSA in men over 50 years to exclude prostate Ca
•primary diagnosis and dif. dg. –
performance of other tests
3613_tumor markers
•staging – mostly inappropriate. High value can draw
attention to a poorly laid lower-stage disease.
•monitoring of disease and responses to
therapy – main and critical application of Tu markers
•prognosis –většinou nevhodnémostly inappropriate.
High value can show higer staging of diseases
3713_tumor markers
INDICATION FOR EXAMINATION OF TUMOR MARKERS
• screening , presence
• primary diagnosis and dif. diagnosis
• staging (metastasis...)
• monitoring
• prognosis
• monitor the effectiveness of anticancer therapy
• The main role of tumor markers(in medical and laboratory) is
• tracking the disease
• monitor the effectiveness of therapy
TEST
Methods
• Molecular biology
13_tumor markers 39TEST
40
Frequency of tumor markers examination
Recommended intervals according to WHO:
• Before therapy initiation
• After therapy finalization (usually 3rd -4th week)
• 1 month in 1st ½year after primary therapy
• 2 months in 2nd ½ of 1st year
• 3 months in 1st ½ of subsequent year (y. 1-1,5)
• 6 months after 1.5 year and in subsequent years of
monitoring
• When therapy changes
• When course of disease is obscure
Minimal interval between two determinations in the same
patient is 14 days.
13_tumor markers
41
Tu markers kinetics
• Doubling time = time to double its (serum/plasma) level.
The shorter, the more aggressive Tu growth.
• biological half-life:
Marker Days Hours Marker Days Hours
ACTH 0.2 FER 2
AFP 5 NSE 1
B2M 0.7 P-ACP 2
CA 125 4 PRL 0.3
CA 15-3 7 PSA 2
CA 19-9 5 SCCA 0.3
CEA 14 TG 2.5
CT 0.2 TK 2
CYFRA 21-1 3 TPA 713_tumor markers
• 1) ENZYMES
• Alkaline Phosphatase (ALP)
• Increased alkaline phosphatase activities are seen in
primary or secondary liver cancer. Its level may be helpful
in evaluating metastatic cancer with bone or liver
involvement. Placental ALP, regan isoenzyme, elevates in a
variety of malignancies, including ovarian, lung,
gastrointestinal cancers and Hodgkin’s disease.
• Prostatic acid phosphatase (PAP)
• It is used for staging prostate cancer and for
monitoring therapy. Increased PAP activity may be
seen in osteogenic sarcoma, multiple myeloma and
bone metastasis of other cancers and in some benign
conditions such as osteoporosis and
hyperparathyroidism.
TEST
• Prostate Specific Antigen (PSA)
• The clinical use of PAP has been replaced by PSA. PSA is much
more specific for screening or for detection early cancer. It is
found in mainly prostatic tissue.
• PSA exists in two major forms in blood circulation. The majority
of PSA is complexed with some proteins. A minor component
of PSA is free.
• PSA testing itself is not effective in detecting early prostate
cancer. Other prostatic diseases, urinary bladder cateterization
and digital rectal examination may lead an increased PSA level
in serum.
• The ratio between free and total PSA is an reliable marker for
differentiation of prostatic cancer from benign prostatic
hyperplasia.
TEST
• The use of PSA should be together with digital rectal
examination and followed by transrectal ultrasonography
for an accurate diagnosis of cancer.
• Serum level of PSA was found to be correlated with
clinical stage, grade and metastasis
• The greatest clinical use of PSA is in the monitoring of
treatment.
• This treatment includes radical prostatectomy,
radiation therapy and antiandrogen therapy.
• The PSA level should fall below the detection limit.
• This may require 2-3 weeks. If it is still at a high level
after 2-3 weeks, it must me assumed that residual
tumor is present.
• Androgen deprivation therapy may have direct effect
on the PSA level that is independent of the antitumor
effect. This subject must be considered always.
• 2) HORMONES
• Calcitonin
• Calcitonin is a hormone which decreases blood calcium
concentration.
• Its elevated level is usually associated with medullary
thyroid cancer.
• Calcitonin levels appear to correlate with tumor volume
and metastasis.
• Calsitonin is also useful for monitoring treatment and
detecting the recurrence of cancer.
• However calcitonin levels are also at a high levels in some patients with
cancer of lung, breast, kidney, liver and in nonmalignant conditions such
as pulmonary diseases, pancreatitis, Paget’s disease,
hyperparathyroidism, myeloproliferative disordes and pregnancy.
TEST
• Human Chorionic Gonadotropin (hCG)
• It is a glykoprotein appears in pregnancy. Its high levels is a
useful marker for tumors of placenta and some tumors of
testes.
• hCG is also at a high level in patients with primary testes
insufficiency.
• hCG does not cross the blood-brain barier. Higher levels in
BOS may indicate metastase to brain.
TEST
3) ONCOFETAL ANTIGENS
• Most reliable markers in this group are α-fetoprotein and
carcinoembryonic antigen (CEA)
• Carcinoembryonic antigen (CEA)
• It is a cell-surface protein and a well defined tumor marker.
• CEA is a marker for colorectal, gastrointestinal, lung and breast
carcinoma.
• CEA levels are also elevated in smokers and some patients
having benign conditions such as cirrhosis, rectal polips,
ulcerative colitis and benign breast disease.
• CEA testing should not be used for screening. Some tumors
don’t produce CEA. It is useful for staging and monitoring
therapy.
TEST
• α-Fetoprotein (AFP)
• α-fetoprotein is a marker for hepatocellular and germ cell
carcinoma.
• It is also increased in pregnancy and chronic liver diseases.
• AFP is useful for screening (AFP levels greater than 1000 µg/L are
indicative for cancer except pregnancy), determining prognosis
and monitoring therapy of liver cancers.
• AFP is also a prognostic indicator of survival.
• Serum AFP levels is less than 10 µg/L in healthy
adults. Elevated AFP levels are associated with shorter
survival time.
• AFP and hCG combined are useful in classifying and
staging germ cell tumors.One or both markers are
increased in those tumors.
TEST
4) CARBONHYDRATE MARKERS
• These markers either are antigens on the tumor cell
surface or are secreted by tumor cells.
• They are high-molecular weight mucins or blood group
antigens. Monoclonal antibodies have been developed
against these antigens.
• Most reliable markers in this group are CA 15-3, CA 125
and CA19-9.
TEST
• CA 15-3
• CA 15-3 is a marker for breast carcinoma. Elevated CA
15-3 levels are also found in patients with pancreatic,
lung, ovarian, colorectal and liver cancer and in some
benign breast and liver diseases.
• It is not useful for diagnosis. It is most useful for
monitoring therapy.
• CA 125
• Although CA 125 is a marker for ovarian and endometrial
carcinomas, it is not specific. CA 125 elevates in
pancreatic, lung, breast, colorectal and gastrointestinal
cancer, and in benign conditions such as cirrhosis,
hepatitis, endometriosis, pericarditis and early pregnancy.
• It is useful in detecting residual disease in cancer patients
following initial therapy.
• A preoperative CA 125 level of less than 65 kU/L is
associated with a greater 5 y survival rate than is a
level greater 65 kU/L.
• It is also useful in differentiating benign from
malignant disease in patients with ovarian masses.
• In the detection of recurrence, use of CA 125 level as
an indicator is about 75 % accurate.
• CA 19-9
• CA 19-9 is a marker for both colorectal and pancreatic
carcinoma.However elevated levels were seen in patients
with hepatobiliary, gastric, hepatocellular and breast
cancer and in benign conditions such as pancreatitis and
benign gastrointestinal diseases.
• CA 19-9 levels correlate with pancreatic cancer staging.
• It is useful in monitoring pancreatic and colorectal cancer.
• Elevated levels of CA 19-9 can indicate recurrence
before detected by radiography or clinical findings in
pancreatic and colorectal cancer.
7) PROTEIN MARKERS
• Most reliable markers in this group are β2-microglobulin, ferritin,
thyroglobulin and immunoglobulin.
• β2-microglobulin
• β2-microglobulin is a marker for multiple myeloma, Hodgkin
lymphoma. It also increases in chronic inflammation and viral
hepatitis.
• Ferritin
• Ferritin is a marker for Hodgkin lymphoma, leukemia,
liver, lung and breast cancer.
• Thyroglobulin
• It is a useful marker for detection of differentiated
thyroid cancer.
• Immunoglobulin: Monoclonal immunoglobulin has
been used as marker for multiple myeloma for more
than 100 years.
• Monoclonal paraproteins appear as sharp bands in
the globulin area of the serum protein
electrophoresis.
• Bence-Jones protein is a free monoclonal
immunoglobulin light chain in the urine and it is a
reliable marker for multiple myeloma.
8) RECEPTOR MARKERS
• Estrogen and progesterone receptors are used in
breast cancer as indicators for hormonal therapy.
• Patients with positive estrogen and progesterone
receptors tend to respond to hormonal treatment.
• Those with negative receptors will be treated by
other therapies.
TEST
• Cytoplasmic estrogen receptors are now routinely
measured in samples of breast tissue after surgial
removal of a tumor. Of patients with breast cancer, 60
% have tumors with estrogen receptor.
• Approximately two thirds of patients with estrogen
receptor (+) tumors respond to the hormonal therapy.
5% of patients with estrogen receptor (-) tumors
respond to the hormonal therapy.
• Hormone receptors also serve as a prognostic
factors in breast cancer. Patients with positive
receptor levels tend to survive longer.
• Progesterone receptor testing is a useful adjunt to the
estrogen receptor testing. Because progesterone
receptor synthesis appears to be dependent on
estrogen action.
• Measurement of progesterone receptors provides a
confirmation that all the steps of estrogen action are
intact. Indeed breast cancer patients with both
progesterone and estrogen receptor (+) tumors have
a higher response rate to hormonal therapy.
C-erbB2 (HER-2 Neu)
• It is receptor for epidermal growth factor (EGF) but it
doesn’t contain EGF binding domain. It serves as a coreceptor
in EGF action
• In the case of increased expression of C-erbB2 leads the
oto-activation and increased signal transduction
• Increased expression of C-erbB2 was determined in
some cancers. It was suggested as an important
factor for carcinogenesis and metastasis
• Routine measurement of C-erbB2 was started in
our hospital
GENETIC CHANGES
• Four classes of genes are implicated in development of
cancer:
• 1) protooncogenes which are responsible for normal cell
growth and differentiation
• 2) tumor suppressor genes which are involved in
recognition and repair of damaged DNA.
• 3)apoptosis-related genes are responsible for regulation
of apoptosis
• 4)DNA repair genes
• Alterations on these genes may lead tumor development.
TEST
• Susceptible protooncogenes:
• K-ras, N-ras mutations are found to be correlated
acute myeloid leukemia, neuroblastoma
Susceptible DNA repair genes:
• BRCA1 and BRCA2 are specific genes in inherited
predisposition for developing breast and over
cancer, and mutations on these genes are newly
measured in some laboratories.
• Mismatch-repair genes are mutated in some colon
cancers
• Susceptible tumor suppressor genes:
• Retinoblastoma gene
• P53 gene
• P21 gene
• Those genetic markers are very new and not routinely
measured in laboratories.
Chromosomal translocation
• c-myc gene has been found to be translocated from
8.chromosom to 14. chromosom and than become
activated in Burkitt’s lymphoma.
• myc gene encodes a DNA-binding protein which
stimulates cell dividing.
• In chronic myeloid leukemia, there is a
translocation between chromosomes 9 and 22.
Summary -The biological nature of the tumor markers
As tumor marker we mean substance presents in the tumor or produced by tumor or host as a
response to the presence of tumor.
This substance can be used to differentiate the tumor from normal tissue, or reflect the
presence of the tumor based on the analysis of body fluids.
The substance can be measured qualitatively or quantitatively by chemical methods,
immunological and molecular biology methods.
Among the markers produced by the tumor include:
enzymes (eg. LD, NSE, PSA, thymidine kinase, prostatic acid phosphatase),
immunoglobulins or their fragments or subunits (monoclonal immunoglobulins called "paraproteins"),
hormones (eg. hCG, PTH, ACTH, calcitonin, gastrin, prolactin, norepinephrine, epinephrine), fragments of
complex glycoproteins, (eg. CA19-9, CA15-3, CA125),
fragments of of cytokeratin (TPA, TPS, CYFRA21-1), oncofetal antigens (AFP, CEA),
Molecules of the groups of receptors (estrogen and progesterone receptor, interleukin 2, HER2 / neu, and
EGF) and circulating cellular elements (circulating tumor cells, circulating endothelial cells and circulating
endothelial precursors).
Besides the usual applications of classical (soluble) tumor markers appear to be clinically useful as tumor
markers, some genetic abnormalities and in particular to specify the abnormality determining tumor cell
treatment. It is both a direct detection of mutations in DNA, protein products of oncogenes (e.g. c-myc, cfos,
k-ras, src), changes in their post-translational modifications in malignant tissue or "new" genetic changes
in malignant cells (e.g. chromosomal rearrangement of bcr-abl) or the detection of mutations in tumor
suppressor genes (BRCA1, BRCA2, p53).
TEST