Tumor markers

Contents..

Definition
History
Ideal tumor marker
Clinical applications
Classification
Methods of detection
Tumor growth markers
Markers of tumor suppression & anti tumor
response

Cont
Angiogenesis markers
Markers of tumor invasion & metastatic
potential
Cell surface markers
Intracellular markers
Markers of anomalous keratinization
Arachidonic acid products
Enzymes

Cont.

Odontogenic markers
Oncofetal markers
Commonly used markers
Genomics & Proteomics
Conclusion

Definition
Tumor marker: Substances present in, or
produced by, a tumor itself or produced by
host in response to a tumor that can be used
to differentiate a tumor from normal tissue or
to determine the presence of a tumor based
on measurements in blood or secretions.

 A molecule, a process or a substance that is

altered quantitatively or qualitatively in
precancerous or cancerous conditions, the
alteration being detectable by an assay.
OR
Biochemical indicators of the presence of a
tumor.

History
The first known attempt to find markers for malignancy
was made 2000 years ago and is described in an Egyptian
papyrus, where breast cancer was distinguished from
mastitis.
Incidentally the first tumor marker in modern medicine
was identified by Bence-Jones, who in 1846 detected a
heat precipitate in samples of acidified urine from
patients suffering from "Mollities osseum".

In 1965, Gold et al., isolated a glycoprotein molecule

from specimens of human colonic cancer and thus
discovered the first "tumor antigen," later identified as
carcino-embryonic antigen (CEA).

IDEAL TUMOR MARKER

(a) highly specific to a given tumor type
(b) provide a lead-time over clinical diagnosis
and
(c) highly sensitive to avoid false positive results.

 In addition to the above, Kaplan and Pesce have

stated that the ideal tumor marker should relate
to the clinical setting and comply with the
following:
1. They should prognosticate a higher or lower risk for
eventual development of recurrence.
2. They should change as the current status of the tumor
changes over time.
3. They should precede and predict recurrences before
they are clinically detectable.

Clinical Applications

Chan & Sell

Screening in general population
Differential diagnosis of symptomatic patients
Clinical staging of cancer
Estimating tumor volume
As a prognostic indicator for disease
progression
Evaluating the success of treatment

Detecting the recurrence of cancer

Monitoring reponse to therapy
Radioimmunolocalization of tumor masses
Determining direction of immunotherapy

 CLASSIFICATION OF TUMOR MARKERS

Broadly classified as.

Proliferation markers
Oncogenes
Growth factors and receptors
Tumor suppressor gene
Cell surface markers
Intracellular markers
Basement membrane markers
Matrix markers

Odontogenic markers

Cytokeratins
Ameloblastin
Calretinin
BMP
Tenascin
Nestin
HMGA-2
Basement membrane
proteins

RANK, RANKL, OPG

Integrins
MMPs
Wnt 1
Podoplanin
EMT

Oncofetal markers

Alpha fetoprotein
Anaplastic lymphoma kinase
BCR-ABL
Beta-2-microglobulin
BRAF
CA 15-3, 19, 125
Calcitonin
Chromogranin A

 SQUAMOUS:
-Pancytokeratin
-CEA
-EMA
MELAOCYTIC
-S-100 protein
-HMB-45
-Mart-1

 ODONTOGENIC:
-CK-5,13,14,19
-Enamelin
-Amelogenin
GLANDULAR
-S-100 protein
-Actin
-Calponin
-CK-14
-CEA, EMA

 SKELETAL MUSCLE:
-Desmin
-Muscle actin
-Myoglobin
-Myogenin
-Skeletal muscle actin
SMOOTH MUSCLE:
-Desmin
-Muscle actin
-Smooth muscle -actin

 General connective tissue marker

-Vimentin
ENDOTHELIAL MARKERS
-Factor-VIII
-VEGF
-CD-31
-CD-34
-ULEX lectin
-Podoplanin
-Podocalynin

 SALIVARY GLAND TUMORS:

-CK-7,8,13,14
-Vimentin
-Smooth muscle actin
-S-100
-Calponin
-Caldesmon

Lymphoid markers
1.T-CELL LYMPHOMAS
-CD3
-CD43
-CD45-RO
2. B-CELL LYMPHOMAS:
-CD 20
-CD 79a

3. ANAPLASTIC LARGE CELL LYMPHOMA:

-CD30
-ALK 1
4. Hodgkins lymphoma:
-CD 15
-CD 20
-CD 30
-CD 45 RA

 NEURAL MARKERS:
-S-100 protein
-CD 57
-Neuron specific enolase

METHODS OF DETECTION
BLOOD CIRCULATION:
I. Radio-immuno assay
2. Enzyme-immuno assay
3. Immunochemical reactions.
TISSUES:
1. Immunofluorescence
2. Immunoperoxidase
3. Monoclonal antibody technology

Measurements
1. Enzymes & isoenzymes:
Spectrophotometric- determination of
enzymatic activity
RIA- mass of enzyme, ELISA
2. Hormones:
Specific RIA/ELISA
3.Genetic markers
PCR techniques

 TUMOUR GROWTH MARKERS

EGF (Epithelial Growth Factor)

The epithelial growth factor receptor (EGFR) is
localised on chromosome 7.
It belongs to the erbB family (of tyrosine
kinase receptors) comprising the EGFR gene,
erbB-1, erbB-3 and erbB-4, and is a
transmembrane glucoprotein of 170 kDA.

EGFRs or C-erbB-2s

transduction of the differentiation,

development and emission of the mitogenic
signal in normal cells.

 Studies have found an overexpression of the

EGFR gene in several human cancers, including
oral squamous cell carcinoma.

Acc to Werkmeister et al: The gene is 20.2%

overexpressed in oral carcinomas.

 The oncogene erbB-2 is localised on the short

arm of chromosome 17 and its overexpression
(14.7% in oral carcinomas) increases
metastatic potential.
Werkmeister et al. stated that aberrations of
erbB-1 and erbB-2 are signs that a
carcinogenic process may be produced in the
lesion, and point out that genetic alterations
are very common in histologically nondysplasic, premalignant oral lesions.

Cyclins
(cyclin A, B1, D1, E)
Cyclins are essential in controlling the cell
cycle. Their activation triggers the start of the
cell cycle and increases replication.

 A high cdk2 expression is a critical factor in the

progression of cancer and can be used as a
predictive marker in its prognosis .
The cyclin protein D1 plays an important role
in the later stages of the malignisation
process.

CD1 has been found to be 39.62%

overexpressed in oral squamous cell and
pharyngeal carcinomas.

-Nuclear cell proliferation antigens

These are nuclear proteins associated with
DNA-polymerase.
They appear in the final phase of G1 and in
the S phase.
Form part of the cdk - cyclin complex, where
they are involved in phases of the cell cycle.
They are indicative of cell proliferation .

-Ki-67/MIB
These two markers, which are monoclonal
antibodies, increase when there is tissue
proliferation.
Ki-67 levels are closely related to the
histological degree of carcinoma in oral
squamous cells.

AgNOR
(argyrophilic nucleolar organiser region)
associated Proteins
The AgNOR proteins have been defined as
loops of nuclear DNA that code for ribosomal
DNA.
They are argyrophilic and serve as an indicator
of nuclear proliferation.

 Although the quantification and distribution

of AgNOR are subjective and non-diagnostic
parameters of specific lesions, they are useful
as a complement to histopathological study in
terms of identifying the degree of any cell and
nuclear alterations

It is the only marker of this group to show an

important association with prognosis and may
be indicative of the degree of malignity.

Skp2
(S-phase kinase-interacting protein 2)
High expression of this protein is linked to a
decrease in p27 and has been associated
with poor prognosis.

Bcl2/BAG1
The anti-apoptotic protein Bcl2 is located in
the mitochondrial membrane and is regulated
by the protein p53.
It forms part of the regulatory system that
controls the cell cycle and the induction of
apoptosis.

 High concentrations of Bcl2 may prevent the

induction of several forms of apoptosis, giving
rise to the development of carcinomas,
promoting mutations and tumor progression.
The function of BAG1 is the opposite to that of
Bcl2.

HSP27 and 70 (heat shock proteins)

These appear to be associated with mutations
of the p53 gene. The HSP27 protein is found in
normal mucosa and small tumors.
High levels of HSP70 have been detected in
oral squamous cell carcinomas. Both proteins
interact with Bcl2, lending support to the
proliferation effect.

Telomerase
This is a DNA protein structure located at the
end of eukaryote chromosomes.
Telomeric activity is essential for controlling
the unlimited potential for division and the
immortality of eukaryote cells.
This activity, which is not detected in normal
somatic cells, can be evaluated in biopsied
tissue

 As in other tumors, this activity is used as a

marker in the diagnosis of pre-neoplastic or
neoplastic oral mucosa lesions, as 80-90% of
such tumours have high levels of telomeric
expression.

MARKERS OF TUMOR SUPPRESSION AND

ANTI-TUMOR RESPONSE

Retinoblastoma protein (pRb)

This protein is a key factor in the G1 check point,
and is therefore the key to the R point.

Koontongkaew et al. found this protein to be

58.49% overexpressed in the oral carcinomas
they studied.

 Deregulation of the pRb gives rise to

aberrations in various cell proteins such as
CD1 and CDK4; this mechanism is necessary
for the development of oral and pharyngeal
cancer.

Cyclin-dependent kinase inhibitors

There are two families of CDKIs: the p21
family and the INK4 family.
p21 is the universal inhibitory gene of the
CDKs, and is localised on chromosome 6.
Under normal conditions it forms a complex
with cyclins.

 An association has been found between p21

expression and the degree of tumour
differentiation.
It is likely that the overexpression of p21 is
caused by p53-independent transactivation
mechanisms.

p53
p53 is a phosphoprotein of 53 kDA ,discovered
in 1970.
It plays an important role in control of the cell
cycle, acting as a factor in transcription,
genomic stability, cell differentiation and
apoptosis.
Aberrations of the p53 gene are the most
common genetic alterations in oral cancer.

 Detection of this protein usually indicates that

stabilizing mechanisms are inefficient, that is,
there is a loss of pro-apoptotic function, giving
rise to continued tumor growth.
This gene is not detected in the
immunohistochemical study of normal cells.

 The detection of p53 in pre-invasive adjacent

areas in squamous carcinoma and dysplastic
lesions suggests that it may constitute an
advance in the natural history of oral cancer.

Bax
This is a p53 co-factor which acts in the
induction of apoptosis; it is induced by p53.
Low levels of Bax have been linked to poor
prognosis in squamous cell carcinoma.

Fas/FasL
These apoptosis mediators belong to the TNFR family.
FasL has been found to be overexpressed in
squamous cell carcinoma. The absence of Fas
receptors indicates poor tumour
differentiation.

 ANGIOGENESIS MARKERS

VEGF/VEGF-R
(vascular endothelial growth factor/receptor)
This is a multifunction cytokine that controls
angiogenesis and also serves as a survival
factor in endothelial cells.
The latter regulate the expression of the
proangiogenic cytokine interleukin 8 (IL8).

NOS2
(nitric oxide synthase type II)
This is thought to be responsible for both
angiogenesis in cancers and tumour
dissemination.
The enzyme NOS2 has been found in
lymphatic metastases.

PD-ECGF
(platelet-derived endothelial cell growth
factor)
This is an angiogenic cytokine derived from
platelets. It has been found in the
microvessels of oral squamous cell carcinoma.

FGFs (fibroblast growth factor)

This family of polypeptides regulates cell
proliferation and differentiation.
Although FGF-1 is not directly related to the
process of cell proliferation in squamous cell
carcinoma, a lower concentration of this
polypeptide in carcinogenesis may be a factor in
poor differentiation.
FGF-2 and FGF-3 may be involved in
carcinogenesis through an autoregulation
mechanism.

 MARKERS OF TUMOR INVASION AND

METASTATIC POTENTIAL

MMPs
(matrix-metallo proteases)
The expression of these zinc metalloenzymes
has been found in oral squamous cell
carcinoma and is associated with the tumor
stage.

Cathepsins
lysosomal proteases
appears to cleave a variety of substrates such
as fibronectin and laminin.
promote the effect of tumor invasion and its
metastases.

Integrins
A family of transmembrane, cell surface
receptors composed of two sub-units: alpha
and beta.
Expression of the integrin v6 is induced
during tumour genesis and epithelial repair.
Various studies have shown that the integrin
v6is expressed in squamous cell carcinoma
of the oral cavity.

 Hamidi et al. found that 41% of leukoplakias

expressed the integrin v6, which may be
associated with processes of epithelial repair,
inflammation or malignant transformation.
The expression of this integrin seems to be
necessary, but not sufficient, to produce this
transformation.

Cadherins and catenins

Their main function is maintaining polarity
and tissue architecture.
The expression of these molecules is inversely
proportional to tumour differentiation.

Desmoplakin/placoglobin
Low expression of these molecules has been
associated with distant metastasis.

Ets-1
A protooncogene that acts as a transcription
factor. It has been linked to tumour stage and
lymphatic metastases.

 CELL SURFACE MARKERS

Carbohydrates
Increased levels of the mucin complex at the
cell surface are associated with a heightened
degree of dysplasia.

Histocompatibility antigen (HLA)

The molecules which form the class-I
immunohistocompatibility complex play a
highly important role in immunity.
The class-II HLA antigen is expressed in some
oral carcinomas, and more commonly in those
with little differentiation.

CD57 antigen
This is found in the membrane of lymphoid
and neural cells.
The percentage of CD57 lymphocytes is
increased in oral leukoplakias with moderate
or severe dysplasia compared with normal
tissue.

 INTRACELLULAR MARKERS

Cytokeratins
These are epithelial cell proteins. There are 19
cytokeratins, divided into two sub-families.
Changes in the expression of these proteins
cannot be considered predictive of the
development of dysplasia.

 The malignization of oral lesions is associated

with the disappearance of cytokeratins.
Research has shown that the expression of
CK19 in the suprabasal cell layer of the oral
mucosa can be used as a diagnostic marker of
pre-cancerous oral lesions; CK19 expression
has also been localised in the early stages of
carcinogenesis.

 MARKERS OF ANOMALOUS KERATINISATION

Filagrins
These proteins, rich in histadine, are found in
the granular and corneal layers of the normal
epithelium.
They are responsible for aggregating keratin
between the filaments in the final stages of
keratinocyte differentiation.

 In oral leukoplakias, filagrins appear in the

corneal layer, while in oral carcinomas they
form keratin pearls.
Their expression is thought to be independent
of the degree of atypical histology.

-Involucrin
The expression of this product of keratinocyte
differentiation is thought to be independent
of tumour aggressivity and atypical histology.

Desmosomal proteins
A study of desmosomal glycoprotein 1 found
that its expression was greatly reduced in
primary tumors with low differentiation and
when there was metastasis in cervical
lymphatic ganglia.

Intercellular substance antigen

This is partially or totally absent in 92% of oral
leukoplakias with dysplasia and in 26% of
leukoplakias without dysplasia. The loss of
expression of this antigen is observed in 95%
of oral carcinomas.

Nuclear analysis
One of the most sensitive methods for
studying clonal changes in tumors and
premalignant lesions is analysis based on the
polymerase chain reaction (PCR). The
advantage of this procedure is that it requires
a small amount of DNA.

 The parameters evaluated in nuclear analysis

include:
1) DNA ploidy state (of chromosomal pairing),
which reflects the risk of oral cancer:
- Anaploidy: high risk
- Tetraploidy: intermediate risk
- Diploidy: low risk

 As a guideline, 32% of oral leukoplakias and

45% of squamous cell carcinomas have
anaploid nuclei.

Anaploid nuclei are found in 29% of

leukoplakias without dysplasia, in 22% of
leukoplakias with mild dysplasia, and in 67% of
leukoplakias with severe dysplasia.

 Therefore, it can be said that molecular

information enables the evaluation of the risk
of oral cancer to be redefined and serves as a
treatment guide in the case of lesions such as
leukoplakia.
In other words, anaploid oral leukoplakias
require more aggressive treatments in order
to prevent them becoming more malignant.

 2) Chromosomal polysomy: this determines

genetic instability.
Kim et al. reported extensive chromosomal
polysomy in areas classified as high risk of
malignisation compared with low-risk areas.
These polysomies are much more numerous
in dysplasic epithelia compared with
hyperplasic epithelial cells.

 ARACHIDONIC ACID PRODUCTS

 Levels of lipoxygenase metabolites, including

the prostaglandin E2, hydroxyeicosatetraenoic
acid and the leucotriene B4, have been found
to be increased in oral squamous carcinoma.

 ENZYMES

Glutathione S-transferase
(GSTS) is an isoenzyme that acts in the second
phase of cell metabolism. It belongs to a
complex family of multifunctional proteins
and plays an important role in protecting the
cell against cytotoxic and carcinogenic agents.

 There are three types of GST: , and . Various

studies have shown that GST- is overexpressed
in human cancer tissue, in premalignant oral
lesions and during experimental oral
carcinogenesis.
Therefore, it may be used as a tumour marker of
premalignant oral epithelial lesions.
Epithelial dysplasia and GST- have been found to
be related to local immunological dysfunction.

 ODONTOGENIC MARKERS

Cytokeratins
Monospecific keratin antibodies are useful for
evaluation of epithelial differentiation changes
in oral dysplasias and oral SCC.

SCC
19

In suprabasal layer (normally in basal)

4/13 with 1/10

Well differentiated SCC

4/13
substituted
by1/10

In moderately differentiated SCC

Absent

Poorly differentiated

EPITHELIAL DYSPLASIA
1/10

Synthesis enhanced in N.K

4/13

Retained in

1/10 replace
4/13 cmpltly

N.K

1/10 & 4/13

Absent

5/14

In parabasal & spinous layer in dysplastic epithelia

19

Basal & suprabasal ; moderate to severe

MILD
MODERATE
SEVERE

ODONTOGENIC CYSTS
19

Dentigerous & Radicular cyst

17 &10

OKC

5 , 6 & 13

In all three

ODONTOGENIC TUMORS
HMW

Ameloblastomas

LMW
CK 1

Basal layer
Upper spinous layer in Squamous odontogenic Tumor

1,5,6,8,13,16

CEOT

14
10/13

Basal cell layer

Upper cell layer in CCOT

19 with 5

Cell rests of various odontogenic epithelia

19

Suprabasal layer & cyst lining

4/13

Periapical cyst

Ameloblastin
Perdigao et al (2004) demonstrated that
AMBN gene mutations are associated with the
development of ameloblastoma, AOT,
squamous odontogenic tumor (SOT) and
CEOT.
Mutations in the AMBN gene are responsible
for the tumorigenesis of epithelial
odontogenic tumors without odontogenic
ectomesenchyme.

Calretinin
(calbindin-2) is a 29-kDa calcium-binding protein
(CaBP). CaBP acts as a mediator of signalling intracellular calcium ions which are considered to be
important second messengers intervening in
cellular proliferation and differentiation.
Calretinin is primarily expressed in neurons of
central and peripheral nervous system and it is the
diagnostic marker for malignant mesotheliomas.

 specific IHC marker for neoplastic ameloblastic

epithelium which is expressed only in solid
and unicystic ameloblastomas and not in any
other odontogenic cysts/tumors.

Bone morphogenetic proteins

BMPs belong to the transforming growth
factor (TGF) superfamily and play an
important role in cell proliferation,
differentiation, chemotaxis, extracellular
matrix production, apoptosis and
mesenchymal cell differentiation.

 According to Gao Y H et al; cementoblastoma,

dentinoma, odontogenic fibroma and
odontoma showed BMP positivity while
ameloblastoma, AOT, CEOT showed negativity.

Tenascin
Tenascin is a multifunctional glycoprotein
involved in cell-cell and cell-extracellular
matrix interactions and is expressed at
epithelial-mesenchymal interface during
embryonic development.
tumours forming calcifying masses i.e. CEOT,
ameloblastic fibro-odontoma (AFO) and
odontoma, have widespread stromal
immunoreactivity of tenascin.

Nestin
Nestin is an intermediate filament constituting
the cytoskeleton. It is known as a neural stem
cell marker.
Positive in odontogenic ectomesenchyme in
mixed tumours, ameloblastic fibrodentinoma
(AFD) and ameloblastic fibrosarcoma (AFS).

Highmobility group A protein -2

(HMGA2)
HMGA2 is a non-histone chromatin factor that
is primarily expressed in undifferentiated
tissues and tumors of mesenchymal origin.
rearrangement of the HMGA2 gene and
HMGA2 protein over expression are features
of odontogenic mesenchymal tumors. Eg
odontogenic myxofibroma

Basement membrane proteins

expression of laminins 1 and 5, collagen type
IV and fibronectin in ameloblastomas,
calcifying cystic odontogenic tumors (CCOT),
and AOTs.

RANK, RANKL and OPG

Higher intensity of RANKL expression than
that of OPG in mesenchymal cells is suggestive
of greater bone resorptive activity.
Higher the expression of RANKL in a tumor,
greater will be the bone resorption.

Integrins
Integrins are transmembrane receptors that
modulate cell-cell and cell-matrix binding.
intensity for 51 integrin was significantly
stronger in ameloblastomas.
Another role attributed to 51 integrin in the
mechanism of tumor invasion is that its
binding to fibronectin increases the secretion
and expression of metalloproteinases.

 Focal expression of 31 may lead to

basement membrane disorganization in some
regions, thus contributing to infiltrative
behaviour of ameloblastomas.

Wingless type 1 glycoprotein (Wnt 1)

Wnt is a family of 19 glycoproteins that
function as signal transducers for cell- cell
interaction, cell growth & differentiation.
involved in ameloblastoma tumorigenesis.
Thus, aberrations of the Wnt signaling
pathway play a role in oncogenesis and
cytodifferentiation of odontogenic epithelium
via deregulation of cell proliferation.

Podoplanin
Podoplanin, a transmembrane sialomucin-like
glycoprotein, is a specific marker of lymphatic
vessels and its expression is also considered to
be associated with tooth development and
tumor invasion.
expressed strongly in peripheral columnar
cells and slightly in central stellate reticulumlike cells of ameloblastomas.

Epithelialmesenchymal transition
(EMT)
Commonly used molecular markers for EMT
include increased expression of N-cadherin
and vimentin, nuclear localization of catenin, and increased production of the
transcription factors such as Snail1 (Snail),
Snail2 (Slug), Twist, E47 that inhibit E-cadherin
production.

 ONCOFETAL MARKERS

Alpha-fetoprotein (AFP)
AFP can help diagnose and guide the
treatment of liver cancer (hepatocellular
carcinoma). Normal levels of AFP are usually
less than 10 ng/mL (nanograms per milliliter).
AFP levels are increased in most patients with
liver cancer. AFP is also elevated in acute and
chronic hepatitis.

Anaplastic lymphoma kinase (ALK)

Some lung cancers have changes in the ALK
gene that cause the cancer cell to make a
protein that leads to out of control growth.
Tumor tissues can be tested for this gene
change.
If its found, the patient can be treated with a
drug that targets the abnormal protein, like
crizotinib.

BCR-ABL
Chronic myeloid leukemia (CML) cancer cells
contain a new, abnormal gene called BCR-ABL.
PCR can find this gene in very small amounts
in blood or bone marrow.

Beta-2-microglobulin (B2M)
B2M blood levels are elevated in multiple
myeloma, chronic lymphocytic leukemia (CLL),
and some lymphomas.
Levels may also be higher in some non-cancerous
conditions, such as kidney disease and hepatitis.
Normal levels are usually below 2.5 mg/L
(milligrams per liter). B2M is useful in helping
predict the long-term prognosis in some of these
cancers.

BRAF
Defects (mutations) in the BRAF gene can be found in
melanoma, thyroid cancer, and colorectal cancer.
About half of melanomas have a BRAF mutation, most
often the one called BRAF V600.

This mutation causes the gene to make an altered BRAF

protein that signals melanoma cells to grow and divide.
This mutation can be tested for in tumor tissue.
If its found, the patient can be treated with a drug that
targets the altered BRAF protein, such as vemurafenib.

CA 15-3
CA 15-3 is mainly used to watch patients with
breast cancer. Elevated blood levels are found
in less than 10% of patients with early disease
and in about 70% of patients with advanced
disease.

CA 19-9
The CA 19-9 test used in people with
pancreatic cancer.

CA 125
CA 125 is the standard tumor marker used to
follow women during or after treatment for
epithelial ovarian cancer (the most common
type of ovarian cancer).

Calcitonin
Calcitonin is a hormone produced by cells called
parafollicular C cells in the thyroid gland. It
normally helps regulate blood calcium levels.
Normal calcitonin levels are below 5 to 12 pg/ml
(picograms per milliliter).
In medullary thyroid carcinoma (MTC), a rare
cancer that starts in the parafollicular C cells,
blood levels of this hormone are often greater
than 100 pg/ml.

 This is one of the rare tumor markers that can

be used to help detect early cancer. Because
MTC is often inherited, blood calcitonin can be
measured to detect the cancer in its very
earliest stages in family members known to be
at risk.

Chromogranin A (CgA)
Chromogranin A (CgA) is made by
neuroendocrine tumors, which include
carcinoid tumors, neuroblastoma, and small
cell lung cancer. The blood level of CgA is
often elevated in people with these diseases.
Taking drugs called proton-pump inhibitors
(such as omeprazole and lansoprazole) to
reduce stomach acid can raise CgA levels in
healthy people

Markers to predict response to

therapy:
A. Oestrogen and progesterone receptors
B. Androgen receptors
C. Steroid-regulated proteins- Cathepsin D and
pS2
D. c-erbB-2 Gene

Markers to monitor drug resistance:

- P-glycoprotein (a transmembrane protein)
- c-erbB-

 COMMONLY USED MARKERS

 SQUAMOUS:
-Pancytokeratin
-Carcinoembryonic antigen
-Epithelial membrane antigen The protein
serves a protective function by binding to
pathogens and also functions in a cell
signaling capacity.
Overexpression, aberrant intracellular
localization, and changes in glycosylationof
this protein have been associated
with carcinomas.

MELAOCYTIC
HMB-45 is a monoclonal antibody that reacts
against an antigen present in melanocytic tumors
such as melanomas, and stands for human
melanoma black 45.
MART-1/melan-A is a protein antigen that is
found on the surface of melanocytes. Used to
recognize cells of melanocytic differentiation,
useful for the diagnosis of a melanoma.

 General connective tissue marker

-Vimentin
Vimentin is a type III intermediate filament (IF)
protein that is expressed in mesenchymal cells.
the major cytoskeletal component of
mesenchymal cells.
Therefore often used as a marker of
mesenchymally-derived cells or cells undergoing
an epithelial-to-mesenchymal transition (EMT)
during both normal development and metastatic
progression.

ENDOTHELIAL MARKERS
-Factor-VIII
-VEGF

-CD-31- aka platelet endothelial cell adhesion

molecule (PECAM-1)
plays a key role in removing aged neutrophils
from the body.
-

 CD31 is normally found on endothelial cells,

platelets, macrophages and Kupffer cells,
granulocytes, T / NK cells, lymphocytes,
megakaryocytes, osteoclasts, neutrophils.
CD31 is also expressed in certain tumors,
including epithelioid hemangioendothelioma,
epithelioid sarcoma-like
hemangioendothelioma, other vascular
tumors, histiocytic malignancies, and
plasmacytomas.

 CD 34- show expression on early

hematopoietic and vascular-associated tissue.
CD34 is also an important adhesion molecule
and is required for T cells to enter lymph
nodes.

 ULEX lectin- is used to identify

the H blood group antigen.
-Podoplanin
-Podocalynin- upregulated in a
number of cancers and is frequently associated
with poor prognosis

SALIVARY GLAND TUMORS

-CK-7,8,13,14
-Vimentin
-Smooth muscle actin
-S-100
-Calponin
-Caldesmon- plays an essential role in the
regulation of smooth muscle and nonmuscle
contraction.
a marker for smooth muscle differentiation.

 SKELETAL MUSCLE:
-Desmin
-Muscle actin
-Myoglobin
-Myogenin
-Skeletal muscle actin
SMOOTH MUSCLE:
-Desmin
-Muscle actin
-Smooth muscle -actin

Lymphoid markers
1.T-CELL LYMPHOMAS
-CD3
-CD43
-CD45
2. B-CELL LYMPHOMAS:
-CD 20
-CD 79a

3. ANAPLASTIC LARGE CELL LYMPHOMA:

-CD30
-ALK 1
4. Hodgkins lymphoma:
-CD 15
-CD 20
-CD 30
-CD 45 RA

 NEURAL MARKERS:
-S-100 protein- is normally present in cells
derived from the neural crest (Schwann cells,
and melanocytes), chondrocytes, adipocytes,
myoepithelial cells, macrophages, Langerhans
cells, dendritic cells, and keratinocytes.

 It can be found in melanomas,100% of

schwannomas, 100% of neurofibromas
(weaker than schwannomas), 50% of
malignant peripheral nerve sheath tumors
(may be weak and/or focal), paraganglioma
stromal cells, histiocytoma and clear cell
sarcomas.

-CD 57
-Neuron specific enolase
Detection of NSE with antibodies can be used
to identify neuronal cells and cells with
neuroendocrine differentiation. NSE is
produced by small cell carcinomas which are
neuroendocrine in origin

Genomics
The study of patterns of DNA changes is likely
to prove more useful than looking for single
DNA changes. DNA changes in blood, stool or
urine can help determine cancers very early.

Proteomics
The study of the way proteins work inside cells
& how they interact with each other is called
as preteomics.
This type of profiling is being extensively
studied for its potential to detect diseases
earlier than is possible with current
methodology.

 Altered protein networks & signal pathways

are earliest signs of cancer & direct cancer
growth, cell survival, tumor invasion & distant
metastasis.
Creating sensitive & specific methodologies to
establish biosignature profiles that
discriminate against disease states is one of
proteomics goals.

CONCLUSION
Judicious application of tumor markers to
clinical practice needs a thorough
understanding of the basics of
pathophysiology, the techniques of
identification or testing, reasons (in cases of
both benign and malignant tumors) for out-ofrange levels of tumor markers, as well as the
knowledge of evidence of their role in any
given malignancy.

References :
Robbin & Cotran- Pathologic basis of disease. 7th
edition.
Godkar
Cancer biomarkers - Current perspectives.
Indian J Med Res 132, August 2010, pp 129-149
Tumor Markers in Clinical Practice: A Review
Focusing on Common Solid Cancers. Med Princ
Pract 2013;22:411
Molecular markers of tumor invasiveness in
ameloblastoma: An update

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SALIVARY TUMOR MARKERS - A REVIEW. IJPCBS
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