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CCHM 312
LECTURE / SECOND SEMESTER
Dianne Rose C. Mendoza, RMT, MPH

WEEK 7: TUMOR MARKERS

MAJOR PROCESSES INVLOVED IN CELL GROWTH  Multistep processes involving numerous tumor cell- host cell and cell-matrix
interactions.
 Proliferation  Tumor cells at the primary site à penetrate their adjacent surroundings
 Differentiation (epithelial basement membrane and the interstitial stroma.)
 invade blood or lymphatic vessels to distant sites
 venous/capillary beds or solid tissue of a distant organ.
TUMORGENESIS  It is a highly selective process.

 Formation of solid mass or tumor

 Activation of growth factors (e.g., epidermal growth factor [EGF]) SIGNAL TRANSDUCTION PATHWAY
 Activation of oncogenes (e.g., K-ras),
 Inhibition of apoptosis, tumor suppressor, and cell cycle regulation genes  Controls both cell cycle and apoptosis
(e.g., BRCA1, p53, cyclins)  Orderly and specific transmission of growth-regulatory messages from
outside the cell to the machinery controlling replication inside the cell
nucleus.
HYPERPLASIA

 Involves the multiplication of cells in an organ or tissue, which may CELL CYCLE
consequently have increased in volume.
 Serves a useful purpose and is controlled by stimuli  It involves the passage of a cell through a complete round of replication.
 Elevation of tumor markers is transient.  It is one of the most important determining factors controlling cell
proliferation.
 In most mammalian cells, the cell cycle is composed of four phases
BENIGN o G1 – defined as the interval between the conclusion of mitosis and
start of DNA replication
 Tumors remain at the primary site and present a smaller risk to the host o S – interval during which the nuclear genome is replicated
 At this stage the patient stands a good chance of being successfully treated o G2 – interval between completion of DNA replication and the onset
by the complete removal of the tumor.
of mitosis.
 Early detection is critical to cancer prevention in general to high-risk o M or mitosis
families in particular
o Go – fifth phase – metabolic compartment of reversibly quiescent
 Well differentiated and composed of cells resembling the nature of normal
cells occupy
cells from the tissue of origin of the neoplasm.
 Encoded by a separate category of genes  when mutated, will not only
increase genetic instability but also accelerate cellular evolution and the
NEOPLASIA progression to malignancy.
 Tumors is result from the absence of certain cell cycle controls
 Involves the possibility of normal cells undergoing cancerous proliferation  Defects in the cell cycle machinery may help cause cancer.
 Pathologic hyperplasia
 Unregulated and serves no purpose
 Elevation of tumor markers will be a long lasting phenomenon if not treated APOPTOSIS

 A programmed cell or physiologic death

 It is a natural self-destruct system present in all cells
 Failure of cells to undergo apoptotic cell death may lead to cancer.
 It is the natural process the body  replacement of cells and the deletion
of damaged cells inherent to normal functioning of multicellular
microorganism.
 It is a control mechanism for tissue remodeling during growth and
development.
 Provides a way for the body to eliminate cells that have been produced in
MALIGNANT
excess, that have developed improperly, or that have sustained genetic
o Due to genetic instability of tumor cells. damage.
 Markers: p53 protein, Bcl 2, and Fas/Fas ligand
o They can be both inducers and inhibitors of cell-death
o These markers would have tremendous potential for diagnosis,
prognosis, and therapeutic application

WHAT IS CANCER?
ANGIOGENESIS
refers to the uncontrolled growth of cells that can develop into a solid mass or tumor and
spread to other areas of the body  New blood vessels are formed. Tumor growth and metastasis are
angiogenesis-dependent.
METASTASIS
 It is critical, not only for the growth of solid tumors, but also for the
shedding of cells from the primary tumor and the development of metastases
 Cause of the most cancer deaths
at distant sites.
 Due to multiple genetic changes that result to uncontrolled proliferation

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 The new blood vessels embedded in a tumor provide a gateway for tumor CLINICAL UTILITIES
cells to enter the circulation and to metastasize to distant sites
 The degree of angiogenesis in an initial primary tumor correlates with OF TUMOR
metastatic spread and survival rates in patients
MARKERS
 Assessment of tumor angiogenesis may, therefore, prove valuable in
selecting patients with early breast carcinoma for aggressive therapy.
 Most well known angiogenic factors:
o Vascular endothelial growth factor (VEGF) None of the tumor markers discovered had
o Acidic and basic fibroblast growth factor (aFGF and bFGF)
o Transforming growth factor alpha (TGF-alpha) sufficient specificity and sensitivity for screening

in the general population

ADHESION
It is not recommended for most tumor markers,
 These are specific class of transmembrane glycoprotein involved whenever
cells are moving and interacting. especially in an asymptomatic population
 They regulate the migration of leukocytes to sites of inflammation or into
The screening of primary hepatoma in Asian
lymphatic tissue.
 Increasing evidence has shown that the appearance of certain membrane countries is based on the measurement of
molecules is related to metastatic potential or a sign of the conversion of
normal to malignant cells. serum AFP.
 Three classes of adhesions:
o Selectins First tumor marker recommended for screening for prostate
o Integrins
o Immunoglobulin family cancer in men older than age of 50.

The purpose was to detect prostate cancer at early curable

stages, when the tumor is still confined inside the organ.

Metastasis
Two major forms: Free PSA and a PSA –alpha1-
Loss of cell adhesion proteins (e.g., β-catenin
antichymotrypsin (PSA-ACT)
and E-cadherin)
Free PSA percentage of free PSA to PSA-ACT ratio may help
Activation of angiogenesis genes (e.g., VEGF)
differentiate benign prostate hyperplasia (BPH) from prostate

cancer.
Tumor size
Several familial cancers are associated with
Histology
germline mutations in various genes.
Regional lymph
The most prominent are genes for susceptibility
Node involvement
to breast and ovarian cancer, such as BRCA1 and
Presence of metastasis
BRCA2 are now available to screen these
Four Stages – Roman Numerals I-IV
families for the identification of carriers.
Disease severity
One of the two most useful applications of tumor
higher stages are indicative of significant spreading
markers involves their use in monitoring the course
and severe systemic disease
during treatment of the cancer patient.
Disease Progression
The measurement of serum tumor markers during
proliferation and metastasis occur at the expense
treatment gives an indication of the effectiveness of
of normal organ processes à cause of morbidity
the antitumor drug used and provides a guide for the
and mortality
selection of the most effective drug for each individual

case.
Tumor Markers
Monitoring tumor markers for the detection of the
Produced either directly by the tumor or as an
recurrence following the surgical removal of the tumor.
effect of the tumor on healthy tissue (host)
It is desirable to monitor the patient using a highly
Used to:
sensitive tumor marker test to detect recurrence as
Differentiate a tumor from normal tissue
early as possible.
Detect the presence of a tumor based on
It should be noted that the appearance of the most
measurements in the blood or secretions

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circulating tumor markers have a lead time of several (2) proteins occurring in epithelial cells that

months (3-6 months) prior to the stage at which many become elevated in tissue and serum in adenoand squamous cell carcinomas, such as the
CA
of the physical procedures can be used for the
19-9, CA 125, and CA 15-3 proteins
detection of the cancer.
(3) polypeptide hormones, such as the β chain
Determination is based on the assessment of tumor
of human chorionic gonadotropin (β-hCG), and
aggressiveness, which, in turn, determines how a
(4) specific enzymes, such as the placental
patient should be treated.
isoform of alkaline phosphatase, that become
Prognostic factors measured in the clinical laboratory
elevated in the serum of patients with specific
also indicate risk and predict the length of a relapse- free, as well as overall, survival
period at the time of tumors

the primary therapy. a. α- Fetoprotein

High levels of serum tumor marker measured during - AFP is a major fetal serum protein and is also one

diagnosis would indicate the presence of a malignant of the major carcinoembryonic proteins

or metastatic tumor associated with a poor prognosis. - Elevated in patients with primary hepatoma

Detecting the phenotypes in the blood circulation carcinoma cell (HCC) and yolk-sac-derived germ

corresponding to early mutations of a cancer allows cell tumors.

the detection of early neoplasm at the curable stage. - Most useful serum marker for diagnosis and

It should be noted that several risk factors may lead to management of HCC

tumorigenesis, which can be identified and eliminated b. b2 – Microglobulin (b2M)

with diet adjustment and lifestyle change - It is nonspecific tumor marker because it is elevated, not

Measurement of all mutant phenotypes and risk only in solid tumors but also in lymphoproliferative

factors in the circulation would help to identify diseases (including B-cell chronic lymphocytic leukemia,

individuals at risk for cancer or detect early tumors in non-Hodgkin's lymphoma, and, importantly, multiple

benign state. myeloma) and variety of inflammatory disorders

Previously, drugs used in chemotherapy were predominantly including: RA, SLE, Sjogren’s syndrome, and Crohn’s

DNA-active drugs that were considerably toxic and had limited disease.

efficacy. - Normal serum level – 0.9-2.5 mg/L

Inhibition of tumor cell proliferation may also be effective by c. Cancer Antigen 125 (CA 125)

introducing agents (or genes) that turn off the signaling pathway - Defined first by a murine monoclonal antibody

or pathways that specifically drive proliferation within a given OC 125 raised against a serous ovarian

tumor or tumor type. carcinoma cell line.

The prevailing new rationale is aimed at the development of - Useful for detecting ovarian tumors at an early

target-selective “smart” drugs on the basis of characterized stage and for monitoring treatments without

mechanisms of action. surgical restaging.

The specific defect of the tumor identified by these new tumor - Upper normal limit – 35 U/mL.

markers should, therefore, lead to the design of more specific d. Cancer Antigen 15-3 (CA 15-3) and CA 27.29

drugs, including antibodies and small molecules, which inhibit - >25 U/mL are observed in patients with metastatic

growth factor receptors tyrosine kinases. breast cancer

(1) oncofetal antigens, such as AFP and CEA, - More sensitive and specific marker for monitoring the

which are normally expressed during fetal clinical course of patients with metastatic breast

development but do not occur normally in the cancer and is more sensitive marker for metastatic

tissues or sera of children and adults breast cancer than CEA.

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e. Cancer Antigen 19-9 (CA 19-9) cancer

- The highest sensitivity of CA 19-9 was found in pancreatic and free β-subunit is useful for the detection of

gastric cancers recurrence or metastasis for choriocarcinoma

- CA 19-9 is also related to Lewis blood group substances. Only when the intact hCG may remain normal

serum antigen from cancer patients belonging to the Le (αβ+) or Seminomatous testicular cancer contains both

Le (α+β- intact hCG and β-hCG or free α subunits in equal

) blood group will be CA 19-9-positive amounts

- CA 19-5 and CA50 have also been defined by monoclonal elevated in the sera of patients with a number

antibodies that are only slightly different from CA 19-9 of different epithelial cell cancers, including

- False positives may occur in patients with benign liver disease breast, lung, colorectal, and ovarian cancers

and may be due to cholestasis in these patients It is a useful marker of exocytotic sympathoadrenal

useful marker for the management of patients with gastric activity in patients with pheochromocytoma.

and colorectal carcinoma medullary carcinoma of thyroid, and small-cell lung

proposed as a specific marker for tumor occurrence of carcinoma

resectable gastric cancer and a prognostic marker for survival increased serum chromogranin A levels are detected in

reported to be an independent prognostic marker for survival epithelial cancers with neuroendocrine differentiation,

in colorectal in multivariate analysis together with β-hCG and including prostate, breast, ovary, pancreas, and colon

CEA Above normal in tumors originating from neural

Most widely used tumor marker for gastrointestinal crest.

cancer today. Useful in detection and monitoring of patients

transforming growth factor (TGF)-α, fibroblast growth with pheochromocytoma and diagnosis of

factor, and Ras oncoprotein are all increased in neuroblastoma in children

colorectal cancer and decreased after surgical Found elevated in various malignant diseases,

resection such as, in the breast, GI or lungs.

mutations of DNA mismatch repair genes (e.g. hMSH2, It is also altered in leukemia, lymphoma,

hMLH1 and hMSH6) are shown to be associated with Hodgkin’s disease, and melamona, as well as in

hereditary nonpolyposis colorectal cancer nonmalignant infalammatory diseases.

one of the circulating peptide hormones that a. Neuron-Specific Enolase (NSE)

may become elevated in patients with increased - can be found in tumors originating from the

bone turnover rate associated with skeletal neuroendocrine cell system, including

metastases glucagonomas and insulinomas.

ectopically elevated in bronchogenic carcinomas b. Progesterone receptor (pgR)

and is also elevated in medullary carcinoma of - Associated with breast tumors

the thyroid. c. Prostate-Specific Antigen (PSA)

(CYFRA 21-1) - Major protein in seminal plasma

elevated serum CYFRA 21-1 have concentrated on Useful in monitoring squamous cell carcinomas

breast cancer and squamous cell carcinoma of the lung of the head and neck, lung, esophagus, and anal

reflect the tumor mass in multiple studies with canal.

correlation to tumor stage, survival, predictive role in Useful in detection and monitoring of patients

surgical treatment for early stage disease and with pheochromocytoma and diagnosis of

chemotherapy for advanced stage non-small cell lung neuroblastoma in childre

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