Chapter 20

Tumor marker

• Substance produced by a tumor or by the host in response

to a tumor, which is used
(1) to differentiate a tumor from normal tissue, or
(2) to detect the presence of a tumor based on measurements
in the blood or secretions.

• are found in cells, tissues, or body fluids.

• are measured qualitatively or quantitatively by chemical,
immunological, or molecular biological methods.
 Tumors

• Tumors are graded according to their degree of differentiation

as:
(1) well differentiated,
(2) poorly differentiated, or
(3) anaplastic (without form).

• Tumor markers are the biochemical or immunological

counterparts of the differentiation state of the tumor.
 Some tumor markers represent re-expression of substances
produced normally by embryogenically closely related tissue

AFP: alpha fetoprotein

CEA: carcinoembryonic Ag
CG: human chorionic gonadotropin
 Cancer
• In 2013 :
Prostate cancer was the leader among men
Breast cancer was the leader in women
followed by cancer of the lung, colon-rectum, and bladder
(men) or uterine corpus (women).

• Trends support the conclusion that:

Early detection and more effective treatment combined with
prevention will reduce the mortality rate of cancer in the future.
 Cancer
• “a relatively autonomous growth of tissue.”
• “a term used for diseases in which abnormal cells divide
without control and are able to invade other tissues.
The National Cancer Institute

• The determination of which carcinogen

(any cancer producing agent)
is responsible for any given cancer is important in the
search for a cure to cancer.
• Carcinogen may be:
(1) physical (e.g., radiation)
(2) Chemical (e.g., a polycyclic hydrocarbon), or
(3) biological (e.g., a virus).
 Cancer
• Early detection of cancer offers the best chance for cure,
as the tumor is still small enough to be completely
removed surgically.
• Although other modes of therapy, such as administration
of chemical toxins or irradiation, are effective in
destroying most tumor cells, they usually are not curative.
The few residual viable tumor cells are able to:
(1) proliferate,
(2) develop resistance to further therapy, and
(3) eventually cause death.
Potential uses of Tumor Markers
• Screening in general populations
• Differential diagnosis in symptomatic
individuals
• Clinical staging of cancer
• Estimation of tumor volume
• Prognostic indicator of disease progression
• Evaluation of success of treatment
• Detection of recurrence cancer
• Monitoring of response to therapy
• Radioimmunolocalization of tumor masses
• Determination of detection for immunotherapy
Potential uses of tumor markers
Potential uses of tumor markers
 Clinical Applications
• Tumor markers may be used :
(1) for diagnosis, prognosis, and prediction
(2) for monitoring the effects of therapy
(3) as targets for localization and therapy.

• The clinical staging of cancer:

Quantification of the concentration of marker that is
considered a reflection of the tumor burden.
Marker concentration at the time of diagnosis may be
used as a prognostic indicator of disease progression and
patient survival.
 Clinical Applications
• Most tumor marker concentrations correlate with
effectiveness of treatment and responses to therapy:

In breast cancer:
the concentration of markers (CA 15-3 or CA 27.29) changes
with treatment and with the clinical outcome of the patient.

Concentrations usually:
(1) increase with progressive disease
(2) decrease with remission
(3) do not change significantly with stable disease.
 Clinical Guidlines
• The diagnosis and staging of cancer involve a number of
tools, including:
(1) physical examination
(2) imaging
(3) laboratory studies.

• Application of these tools has resulted in several tumor

markers that are used for:
(1) screening
(2) diagnosis
(3) staging
(4) prognosis
(5) directing treatment modalities.
 Specific Tumor Markers

• Enzymes
• Hormones
• Oncofetal antigens
• Cytokeratins
• Carbohydrates Antigens
• Blood group antigens
• Proteins
• Receptors
• Genetic Markers
– Oncogenes
– Tumor suppressor genes
 Enzymes
Enzyme
Alkaline Phosphatase
Alkaline Phosphatase, placental
Creatine kinase
Lactate dehydrogenase
Neuron-specific enolase
Prostatic acid phosphatase
Prostate specific antigen
Urokinase-Plasminogen
Activator System
Cathepsins
Matrix Metalloproteinases
type of cancer
bone, liver, leukemia, sarcoma
ovarian, lung, gastrointestinal
brain, prostate, lung, breast, colon
liver, lymphoma, leukemia, various
lung (small cell), neuroblastoma,
melanoma, pancereatic
prostate, breast cancer, multiple
myeloma
prostate
breast mainly, colorectal, gastric and
esophagus, ,,,,
breast, SCC of head & neck
metastasis and poor prognosis
 Enzymes
Prostate-specific antigen (PSA):
• protein that is produced by the prostate gland.
• serine protease of the kallikrein family.
• has been widely used to:
Screening and Early Detection of Prostate Cancer.
Monitor for recurrence after initial treatment and response
to therapy.
Staging of Prostate Cancer.
 Enzymes
Urokinase-Plasminogen Activator System:

• Three component:
– Urokinase-Plasminogen Activator (uPA):
serine protease
– uPA membrane bound receptor (uPAR)
– Plasminogen activator inhibitor (PAI-1)
• Converts plasminogen to active plasmin degrade ECM to
release growth factors [FGF]2 and [TGF]-β
• Breast mainly, colorectal, gastric and esophagus.
• Prognosis predictor for survival in breast.
 Enzymes
Cathepsins:
– Lysozomal proteases (B, D, and L)
– Cathepsin B is activated by Cathepsin D and matrix
metloproteinase MMPs , which in turn activates uPA
and other specific MMPs.
– Used mainly in breast cancer, also useful in
squamous cell carcinoma (SCC) of head & neck.
– Prognosis predictor
Matrix metloproteinase MMPs;
– Zinc-dependent endopeptidases
– Degrades components of ECM
– Tissue remodeling and repair
– Urothelial carcinoma, ovarian, lymph node metastasis
 Hormones
The production o hormones in cancer involves two separate
Routes:
1. The endocrine tissue that normally produces it produces
excess amounts of a hormone.
2. A hormone may be produced at a distant site by a
nonendocrine tissue that normally does not produce the
hormone (ectopic syndrome).
Example:
Adrenocorticotropic hormone (ACTH)
• Normotropic by the pituitary
• Ectopic by the small cell of the lung
 Oncofetal antigens
• proteins produced during fetal life.
• Present in high concentration in the sera of fetuses and
decrease to low concentrations or disappear after birth.

In cancer patients:
Oncofetal Ags often reappear, revealing that certain genes
are reactivated as the result of the malignant transformation
of cells.

e.g.
AFP: α-Fetoprotein
CEA: Carcinoembryonic Antigen
Oncofetal antigens
 Cytokeratins
• Large group ~20 proteins
• Make up the Cytoskeletal intermediate filaments of epithelial cells
• Two types:
– Type 1: smaller and acidic
– Type 2: larger and neutral to basic
• Clinically useful members of this family are:
1. Tissue Polypeptide Antigen (TPA)
– Proliferative activity of cell -pregnenacy (breast cancer)
2. Tissue Polypeptide -Specific Antigen (TPS)
– Lung tumors
3. Cytokeratin 19 fragment (CYFRA21-1)
– Lung cancer
4. Squamous Cell Carcinoma Antigen (SCCA)
– SCCs of cervix, lung, skin, head, neck, digestive tract, ovaries, and
urogenital tract
– Useful in detecting recurrence of cancer and in monitoring treatment
and disease progression.
Carbohydrate Markers
• Carbohydrate-related tumor markers may be:
(1) Antigens on the tumor cell surface, or
(2) secreted by the tumor cells.

Name Type of cancer

CA 125 Ovarian, endometrial
CA 15-3 Breast, Ovarian
CA 549 Breast, Ovarian
CA 27.29 Breast
DU-PAN-2 Pancreatic, gastrointestinal
lung, ovarian,
Carbohydrate Markers
Blood Group Antigens
 Proteins as Tumor Markers

Name Type of cancer

β 2-microglobin Multiple myeloma, B-cell lymphoma

Chronic lymphocytic leukemia
C-peptide Insulinoma
Ferritin Liver, lung, breast leukemia
Immunoglobulin Multiple myeloma, lymphomas
NMP22(nuclear matrix protein) Transitional cell carcinoma
Melanoma associated Ag Melanoma
Proteins as Tumor Markers
 Receptors and other markers

Name Type of cancer

Estrogen and progesterone receptors Breast

Catacholamine metabolites Neuroblastoma
Hydroxyproline Bone metastasis (breast), m. myeloma
Polyamines (CSF) Brain
(urine) Various
 Genetic and Molecular Markers
Classes of genes implicated in the development of cancer:
(1) Oncogenes (cell activation genes)
(2) Tumor suppressor genes:
genes involved in the recognition and repair of damaged
DNA.

Oncogenes are derived from proto-oncogenes that may be

activated by dominant mutations, such as:
(1) point mutations
(2) insertions
(3) deletions
(4) translocations
(5) inversions
 Genetic and Molecular Markers
1. Oncogenes
activation to leads to cell division…
e.g. leukemia and solid tumors.

2. Tumor-suppressor genes
Mostly isolated from solid tumors.
• The major tumor suppressor gene: p53
to repair damaged DNA through apoptosis
activation of the production of p21,which blocks the cell
cycle in late G1 to allow repair.
Loss of p53 function may result in impaired DNA repair
…tumorigenesis
 Oncogenes
• Proto-oncogenes are normal cellular genes that are
similar to tumor virus genes.
• These genes code for products are involves in normal
cellular processes, such as growth factor signaling
pathways.
• Activation of proto-oncogenes is found to be associated
with cancer.
• Overexpression of the oncogene will lead to abnormal cell
growth, resulting in malignancy.

1. RAS genes
2. HER2
3. BCR/ABL
Oncogenes
 BCR/ABL

• 90% of CML (Chronic myelogenous leukemia) patients:

the formation of the Philadelphia chromosome:
translocation between chromosomes 9 and 22
[t(9;22)(q34;q11)].
Creating the BCR-ABL fusion gene.
Constitutively active cytoplasmic tyrosine kinase that
activates several signaling pathways, leading to:
(1) uncontrolled growth
(2) inhibition of apoptosis
(3) Other aspects of neoplastic transformation
 BCR/ABL
• Detection of the BCR-ABL gene is useful in:
diagnosing CML and in directing treatment:
– target the BCR-ABL gene by oligonucleotides
(antisense or ribozyme based)
– the BCR-ABL kinase domain by the tyrosine kinase
inhibitor: ST I571 (Gleevec).

• Detection by (RT-PCR)
monitoring minimal residual disease in patients who have
undergone bone marrow transplantation.

https://en.wikipedia.org/wiki/Philadelphia_chromosome
 Tumor-suppressor genes
• Healthy cells contain a gene that suppress the expression
of malignancy
• Mutations in tumor-suppressor genes results in malignancy.
• Detection of mutations in tumor-suppressor genes is useful:
1. Diagnosis of cancer
2. Prognosis of cancer
3. Prediction of susceptibility

Examples of tumor suppressors:

(1) RB: Retinoblastoma gene
(2) APC: Adenomatous Polyposis Coli
(3) BRCA1-2.
BRCA1 and BRCA2
• Predisposition to developing breast and ovarian cancer.
• Function:
BRCA1: transcriptional regulation & DNA repair.
BRCA2: DNA repair.

• By the age of 85, carriers of a BRCA1 gene mutation have:

85% risk of developing breast cancer
45% risk of developing ovarian cancer
Phosphatase and tensin homolog (PTEN) is a protein

Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt signaling promotes

primitive hematopoietic stem cell self-renewal and expansion