BIOCHEMISTRY OF

CANCER
• “Tumors destroy man in a unique
and appalling way, as flesh of his
own flesh which has somehow
been rendered proliferative,
rampant, predatory and
ungovernable.”
(From Peyton Rous – Nobel Lecture, December 13, 1966. The
Challenge to Man of the Neoplastic Cell)
 CANCER
• Cancer is the second most common cause of death
after cardiovascular disease.

• About 6-7 million people die of cancer around the

world each year with the projection of increase in
figure .

• The most cancer that account for most death are

cancer of the lungs, stomach, colon, rectum, liver
and breast.

• The incidence of cancer increases with age. Hence

as people live longer many will develop the disease.
• An increase in tissue size can result from an increase in cell
size (hypertrophy) or an increase in cell number
(hyperplasia).

• Thus the term neoplasia is used when the proliferating

cells are morphologically abnormal. (Note neoplasm refers
to abnormal new growth of tissue which may be benign or
malignant)

• Such proliferation will usually give rise to a tissue mass

which is described as a tumor. Although increased cell
numbers are a feature of cancer, the rate of cell division is
not always greater than for normal cells.

• An increased life span, as in leukemic cells, will result in a

selective increase in numbers. However, neoplastic tissue
usually grows more rapidly than the normal tissue of origin.

• This may arise from a shortening of the cell cycle or from

an increase in the proportion of cells undergoing division.
 Terms related to normal and
abnormal cell growth
• Anaplasia: Loss of differentiation of cells and/or tissues

• Aneuploidy: Possessing an abnormal number of chromosomes

• Carcinoma: Malignant neoplasm of endodermal or ectodermal origin

• Dysplasia: Abnormal tissue development

• Hyperplasia: Increased number of cells in a tissue

• Hypertrophy: Increase in the size of a tissue

• Metastasis: Growth of cells distant from the site of origin

• Neoplasm: An altered, relatively autonomous tissue growth

• Papilloma: Benign epithelial tumor

• Sarcoma: Malignant neoplasm of connective tissue origin

• Note- tumor can arise in any organ in the body and thus resulting in
 Properties of Cancer cells
• The proliferate rapidly and display diminished growth control

• The display loss of contact inhibition in-vitro

• They invade local tissues and spred (metastasize) to other part

of the body.

• They are self sufficient in growth signals

• They are insensitive to anti-growth signals

• The stimulate local angiogenesis

• They often evade apoptosis

Note the two types of cancer we have are BENIGN AND MALIGNANT
TUMORS
 Hallmarks of Cancer

Six fundamental changes of cell

Physiology
1. Self sufficiency in growth factors
2. Insensitivity to growth-inhibitory
signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize
 Differences between Benign
and Malignant Tumors
Benign Malignant

• 1. Usually encapsulated Non encapsulated

• 2. Usually non invasive Invasive

• 3. Highly differentiated Poorly

differentiated

• 4. Rare mitoses Mitoses relatively common

• 5. Slow growth Rapid growth

• 6. Little or no anaplasia Anaplastic to

varying degrees

• 7. No metastases Metastases
 Cellular origin and
nomenclature of tumors
▪ Sometimes a distinction is made between
solid tumors and those tumors of the hemopoietic
and immune system in which there is an increase
in circulating abnormal cells.

▪ A neoplasm is termed a carcinoma if it arises

from tissue derived from embryonic ectoderm or
endoderm.

▪ Those tumors of epithelial cells may be

distinguished from tumors of connective tissue
which are described as sarcomas. Most human
neoplasms are carcinomas.
 HISTORY OF ONCOLOGY

The term carcinoma was described by Hippocrates (460-377? B.C.).

Galen (131-201?)A.D. used the term cancer. He attributed cancer to an
excess of black bile (melancholia).

In 1775, a London surgeon, Percival Pott, recorded the high incidence of

cancer of the scrotum in chimney sweeps. He attributed the condition to
prolonged exposure to soot.

In 1802, a Medical Committee of the Society for Investigating the Nature

and Cure of Cancer met in London and formulated the following thirteen
queries:

Query 1st: What are the diagnostic signs of cancer?

Query 2nd: Does any alteration in the structure of a part take place, preceding
that more obvious change which is called cancer; and if there be an alteration,
what is its nature?
Query 3rd: Is cancer always an original and primary disease; or may other
diseases degenerate into cancer?
Query 4th: Are there any proofs of cancer being an hereditary disease?
Query 5th: Are there any proofs of cancer being a contagious disease?
Query 6th: Is there any well-marked relation between cancer and other diseases?
If there be, what are those diseases to which it bears the nearest resemblance in
its origin, progress, and termination?
Query 7th: May cancer be regarded at any period, or under any
circumstances, merely as a local disease? Or does the existence of
cancer in one part afford a presumption that there is a tendency to
a similar morbid alteration in other parts of the animal system?
Query 8th: Has climate or local situation any influence in rendering
the human constitution more or less liable to cancer, under any
form, or in any part?
Query 9th: Is there any particular temperament of body more liable
to be affected with cancer than others? If there be, what is the
nature of that temperament?
Query 10th: Are brute creatures subject to any disease resembling
cancer in the human body?
Query 11th: Is there any period of life absolutely exempt from the
attack of this disease?
Query 12th: Are the lymphatic glands ever affected primarily in this
disease?
Query 13th: Is cancer, under any circumstances, susceptible of a
natural cure?
Johannes Muller was the first person to describe cancer as an
abnormal growth of cells (1838). This abnormal growth was
attributed by Rudolf Virchow to chronic irritation.

The nature of the cells which give rise to cancer has long been
debated.

Cohnheim (1877) suggested embryonic rest cells were

responsible while others favored changes in mature cells.

Progress in experimental tumor research has often been

achieved using transplanted tumors.

In 1875, Novinsky transplanted a sarcoma in dogs. However,

this peculiar tumor was capable of venereal transmission.

In 1889, more conventional tumors were transplanted in rats by

Hanau and in dogs by Wehr. At the beginning of the twentieth
century tumors were being transplanted in several species.
 Epidemiological evidence has been important in
detecting carcinogenic substances. Rehn (1895) reported an
increased incidence of bladder cancer in aniline dye workers in
Germany. The major carcinogen involved is now believed to be
2-naphthylamine.

Work with radium suggested the induction of skin cancer

by repeated X-ray burns and in 1910 to 1912, Marie, Clunet and
Raulot-Lapointe reported the induction of sarcoma in rats by the
application of X-irradiation.

The first chemical induction of cancer in laboratory

animals was achieved by Yamagiwa and Ichikawa (1915) by
painting coal tar on the ears of rabbits every 2-3 days for more
than a year.

The first pure carcinogen, 1,2,5,6-dibenzanthracene, was

synthesized in 1929 and in the 1930s Kenneway and Cook and
their associates isolated carcinogenic polycyclic aromatic
hydrocarbons including benzo(a)pyrene from coal tar.
 Evidence for a viral induction of cancer was
obtained in 1908 when Ellerman and Bang
demonstrated that cell-free filtrates of a chicken
leukemia would transmit the disease.

In 1910, Rous published work on a viral agent causing

sarcomas in chickens.

In the 1930s, there were publications on the

oncogenic viruses, such as the Shope papilloma virus
and the Bittner milk factor for mammary tumors in
mice,

but it was not until the early 1950s that the possibility
of oncogenic viruses became generally accepted.
 In the early 1900s, Boveri proposed a
mutation theory of carcinogenesis but
at that time it was not amenable to
chemical investigation.

Later theoretical approaches to

carcinogenesis reflected advances in basic
biochemistry.

From his work on the glycolysis and

respiration of tumors, Otto Warburg
concluded in the 1920s that cancer arose
from damaged respiratory mechanisms.
 The possibility of a two-step mechanism for
cancer was noted by Berenblum in 1941.

In the 1940s, Greenstein concluded that there

was a tendency for tumors to resemble each other
biochemically which gave rise to the convergence
theory of cancer.

The Millers, Van Potter and their associates

placed emphasis on deletions in cancer.

Investigations on the so-called minimal

deviation hepatomas, induced by Harold Morris in the
1960s, suggested that many biochemical features of
tumors were not essential features of the neoplastic
transformation.
 CAUSES OF CANCER
• INHERITED Mutation: In genes that affect cell cycle,
DNA repair, Apoptosis,
These mutation gives a genetic predisposition for
cancer
• Somatic Mutation of these same genes cased by
Exposure to risk factor
⮚ Environmental mutagens ( chemical carcinogenic
agents, radiation)
⮚ Hormone
⮚ Weakening of the Immune system (AIDS)
⮚ Oncogenic (Tumor) Virus Infections
Epstein Barr Virus (Burkitt lymphoma)
Human Papiloma Virus ( causes Cervical cancer)
 Principles of Carcinogenesis
• Neoplastic transformation is a
progressive process involving multiple
“hits” or genetic changes.
• Alterations in DNA cause changes in one or
more of the following types of genes:
– Proto- oncogenes
– Tumor suppressor genes
– Genes regulate apoptosis
– DNA repair genes
 Oncogenes
• The first oncogene (src) was discovered in 1970 in a chicken
retrovirus. In 1976, Bishop and Varmus demonstrated that
oncogenes were defective proto-oncogenes that coded for
normal growth and differentiation proteins (‘the enemy
within”), for which they received the Nobel Prize in 1989.

• Oncogenes are “driver” mutations that encode

– Receptor/cytoplasmic tyrosine kinases (EGFR, PDGFR, Ras/MAPK)
– Ser/thr kinases (AKT, mTOR)
– Lipid kinases (PI-3K)
– Transcription factors (c-MYC, STATs, c-JUN, c-FOS)
– Cyclins/CDKs (Cyclin D)
– Regulators of protein stability (MDM2)
– Anti-apoptotic factors (BCL-2, BCL-XL)

• They gain function by

– Domain deletion (EGFRvIII, Her2)
– Point mutation (Ras)
– Translocation (BCR-Abl, Myc)
– Altered subcellular localization (BCR-Abl)
– Gene amplification (Myc, EGFR, Her2)
 Oncogenic Mutations in Cancer

H-Ras K-Ras
Increased expression N-Ras Neu int-1
EGFR int-2
mos
Myc Altered protein
K-Ras
Myb
RelA
EGFR Amplification Point mutation
Insertion

Protooncogene

Translocation Deletion

Normal
protein

Altered protein
Altered Protein Increased expression EGFR, (ERB-B1), NF-κB
Abl, Trk C-Myc, Bcl-2
 C-Myc translocations and disease

Translocation Genes Disease

t(8;14)(q24;q32) c-myc/IgH Burkitt’s lymphoma

t(2;8)(p12;q24) Igκ/c-myc Burkitt’s lymphoma

t(8;22)(q24;q11) c-myc/Igλ Burkitt’s lymphoma

t(8;14)(q24;q32) c-myc/IgΗ Diffuse large cell lymphoma

t(8;14)(q24;q11) c-myc/TCRα,β T-cell acute lymphoblastic leukemia

t(8;14)(q24;q32) c-myc/IgΗ Multiple myeloma
t(2;8)(p12;q24) Igκ/c-myc Multiple myeloma
t(8;22)(q24;q11) c-myc/Igλ Multiple myeloma
 Multiple Mutations are Required for
Oncogenesis
• Transfer of a single oncogene to a normal cell is
normally not sufficient to transform it

• Loss of one allele of a Ts gene is insufficient

• Cancer frequency increases with age, suggesting that

transformation of cells requires the accumulation of
multiple mutations

• Most oncogenes can induce both growth and apoptosis,

indicating that transformation requires one mutation
that enhances cell growth and another that inhibits cell
death (oncogene “cooperation”).
Examples of “two hit” gene pairs in tumors:
Ras/p16 BRCA1/p53 p27/Rb Myc/p53 Myc/Ras
 Oncogene Cooperation
(validation of the “two hit” hypothesis)

Expression of c-myc or ras alone fails to transform cells

C-myc Ras

P16
P19 Arf
p53

Apoptosis Senescence

Transformed focus

Expression of both c-myc and ras is transforming

 GROWTH FACTORS (GF)
•Paracrine and autocrine

•Cancer cells acquire self-

sufficiency in growth signals by
acquiring the ability to
synthesize GF

• Examples: PDGF
in glioblastoma GF
TGF-alpha in sarcomas

• Mutation of GF genes or the

products of other genes e.g.
RAS cause
Overexpression of GF genes
 GROWTH FACTOR RECEPTORS

Mutation and overexpression

of GROWTH FACTOR
RECEPTORS found in many
tumors
e.g. EGF receptor family:

ERBB1, 80% of SCC of Lung

ERBB2 (HER2), 25-30% of

breast CA, adenocarcinoma
of lung, ovary and salivary
glands
Percentage of Human Tumors Overexpressing
EGFR

Tumor type Percentage of tumors

Bladder 31-48
Breast 14-91
Cervix/uterus 90
Colon 25-77
Esophageal 43-89
Gastric 4-33
Glioma 40-63
Head and neck 80-100
Ovarian 35-70
Pancreatic 30-89
Renal cell 50-90
Non-small-cell-lung 40-80
Signaling completed successfully - transcription proceeds …
 MAP kinase

• Mitogen-activated protein kinase (mitogens

are hormones that cause mitosis)
• Activated by a kinase cascade:
MAP kinase is phosphorylated and activated by MEK
(MAP kinase)
MEK (MAP kinase) is phosphorylated and activated
by Raf
Raf is activated by Ras
 SIGNAL-TRANSDUCING PROTEINS
ABL gene
•Found in 90% of chronic
myeloid leukemia
•BCR- ABL hybrid has potent
tyrosine kinase activity that
activates cell growth by several
pathways including
RAS-RAF cascade
• Normal ABL protein localizes in
nucleus to promote apoptosis
• Drug STI 571 act in both
ways
 NUCLEAR TRANSCRIPTION FACTORS

MYC gene bind to DNA and

activate transcription of several
growth related genes e.g. CDKs

C-MYC gene is amplified in CA

breast, colon lungs

N- MYC gene is amplified in

neuroblastomas

L-MYC gene is amplified in

small cell CA
 NUCLEAR TRANSCRIPTION FACTORS

• MYC gene is dysregulated

in 90% of Burkitt
lymphoma
 CYCLINS AND CYCLIN-
DEPENDENT KINASES ROLE IN CELL CYCLE AND CANCER
CYCLINS AND CDKs INFLUENCE IN CELL
CYCLE
 Cell cycle: checkpoints
CDK6/cyclinD/CDK4
cyclin2/CDK2
complex

Rb Rbpp

1
Release
of E2F TF

1a
Transcription
begins
2a
Completion of S

Spindle
p53 protein
checkpoint
binds p21
)block inhibition(
 CYCLINS AND CYCLIN-
DEPENDENT KINASES

• Cyclin D gene is overexpressed in cancers of breast,

esophagus, liver and some types of lymphoma
• Amplification of CDK4 gene occur in melanoma,
sarcoma and glioblastoma
• At least one of the four key regulators of cell cycle is
mutated in most human cancers (INK4a, cyclin D,
CDK4, RB)
INSENSITIVITY TO GROWTH-INHIBITORY
SIGNALS
Tumor (Cancer) suppressor genes

The products of tumor suppressor genes apply

brakes to cell proliferation whereas oncogenes
encode proteins that promote cell growth
• Disruption of cancer suppressor genes renders
cells refractory to growth inhibition.
• e.g. Retinoblastoma (RB gene), TP53, TGF-β, APC
• Two hit hypothesis.
Two hit hypothesis.

•Heterozygous.
•Homozygous.
•Lose of heterozygosity.
•Recessive cancer genes
 Cancer suppressor genes
• Prevent cell proliferation by two
complementary mechanisms:
1- Cause dividing cells to go into G0
2- Cell enter a postmitotic, differentiated pool
and lose its replicative potential.
 Cancer suppressor
Subcellular location genes
Gene Function Tunor
Cell Surface TGF-β RECEPTOR Growth inhibition Carcinomas of colon
E-cadherin Cell adhesion Carcinoma of stomach

Inner aspect of NF-1 Inhibition of RAS Neuroblastoma

plasma membrane signal transduction Neruofibromatosis type1
and of p21 cell
cycle inhibitor
Cytoskeleton NF-2 Cytoskeleton NF-2 schwannomas and
stability meningiomas

Cytosol APC/ β-catenin Inhibition of signalCA of stomach, colon,

transduction and pancreas, Familal
adenamotous polyposis
TGF-β signal transd coli
TGF-β (SMAD2) Colon, and pancreas CA
Nucleus RB Regulation of cell Retinoblastoma;
cycle osteosacroma
p53 Cell cycle arrest Most human cancer,
and apoptosis Li-Fraumeni syn.
 Cancer suppressor genes

• Retinoblastoma gene ( RB gene):

– Two mutations (hits) are required to produce
retinoblastoma
– These involve the RB gene, located on
chromosome 13q14.
– The RB gene product is a DNA-blinding protein
that is expressed in every cell type examined.
– Found in other neoplasms e.g. breast cancer,
small cell cancer of the lung, and bladder
cancer.
INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS

RB GENE AND CELL CYCLE

• RB serves as a brake in the advancement of

cells from G1 to the S phase of the cell type.
• Quiescent cells (in G0 to G1) contain the active
hypophosphorlyated form of RB.
• RB prevents cell replication by binding and
possibly sequestering, the E2F family of
transcription factors.
RB GENE AND CELL CYCLE

RB a brake
 INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS
RB gene
• Loss of normal cell cycle control is central to malignant
transformation
• at least one of the four key regulators of cell cycle is
mutated in most human cancers (INK4a, cyclin D, CDK4,
RB)
• Transforming proteins of several oncogenic
animal and human DNA viruses seem to act by
neutralizing the growth-inhibitory activities of RB.
e.g. SV40
polyomavirus large T antigens
adenoviruses EIA protein
human papillomavirus (HPV) E7 protein

bind to the hypophosphorylated form of RB (functionally

deleted).
INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS
Cancer suppressor genes
TRANSFORMING GROWTH FACTOR β PATHWAY

• TGF-β a member of a family of

dimeric growth factors that
includes bone morphogenetic
proteins.
• It is a potent inhibitor of
proliferation in epithelium, Ec
and hematopoietic cells
• At least one component of the
TGF-β pathway is mutated in
100% of pancreatic cancers and
83% of colon cancers.
 Cancer suppressor genes
TP53 GENE
GUARDIAN OF THE GENOME

• One of the most commonly mutated genes in human

cancers.

• TP53 can exert antiproliferative effects and regulates

apoptosis.

• TP53 assists in DNA repair by causing G1 arrest and inducing

DNA repair genes. A cell with damaged DNA that cannot be
repaired is detected by TP53 to undergo apoptosis.

• With homozygous loss of TP53, DNA damage goes unrepaired, mutations

become fixed in dividing cells and the cell become malignant
Cancer suppressor genes TP53 GENE
• More than 70% of human cancers have a defect in this gene
and the remaining have defects in genes up-stream or down-
stream of TP53.

• Homozygous loss of the TP53 gene is found in virtually every

type of cancer, including carcinomas of the lung, colon and
breast, the three leading causes of cancer deaths.

• Li-Fraumeni syndrome –
– inherited loss of TP53-
– 25 fold greater chance to develop cancer
– e.g. sarcomas, breast cancer, leukemia, brain tumors and
carcinomas of the adrenal cortex

• Normal TP53 can be rendered nonfunctional by

certain DNA viruses:
– oncogenic HPVs
– hepatitis B virus (HBV)
– possibly Epstein-Barr virus (EBV)
 METASTASIS IN CANCER
• Metastasis is the most serious aspect of
cancer
• It is estimated that about 85% of the mortality
associated with cancer results from metastasis
• The spreed of cancer is usually via lymphatics
or blood vessels
• Metastasis is a complex process and its bases
are yet to be fully elucidated
 Process of metastasis
• Detachment (tumor cells are detached from
the primary tumor)
• Intravastation (Access to circulation system
(Or lymphatics)) they tend to arrest in
the nearest small capilary bed.
• Extravasate and migrte (in that site the migrate
through the neighboring ECM, before
finding site to settle
• Grow . if they survive the host defence
mechanism they grow at variable
rate.
• Adequate blood supply (in other to survive, the
need adequate blood supply which
they generate as they earlier did
in the starting point)
TUMOR MARKERS
 tumor markers
• Tumor markers are defined as a biochemical substance
(e.g. hormone, enzymes or proteins) synthesized and
released by cancer cells or produced in the host in
response to cancerous substance.

• They are used to monitor or identify the presence of

cancerous growth.

• They are different from substances produced by normal

cell in quantity and quality.
• They are present
– Blood circulation
– Body cavity fluids
– Cell membranes
– Cell cytoplasm
– DNA
 Properties of a Good Tumor
Markers

1. A tumor marker should be present in or produced by tumor

itself.
2. A tumor marker should not be present in healthy tissues.
3. Plasma level of a tumor marker should be at a minimum level
in healthy subjects and in benign conditions.
4. A tumor marker should be specific for a tissue, it should have
different immunological properties when it is synthesized in
other tissues.
5. Plasma level of the tumor marker should be in proportion to
the both size of tumor and activity of tumor.
6. Half life of a tumor marker should not be very long
7. A tumor marker should be present in plasma at a detectable
level, eventhough tumor size is very small
8. The tumor marker is useful both for the prediction of the
presence of the tumor and recurrence of the tumor.
 Classification of tumor markers
• Tumor markers can be classified as respect with
the type of the molecule:

• 1. Enzymes or isoenzymes (ALP, PAP)

• 2. Hormones (calcitonin)
• 3. Oncofetal antigens (AFP, CEA)
• 4. Carbonhydrate epitopes recognised by monoclonal
antibodies (CA 15-3,CA 19-9, CA125)
• 5. Receptors (Estrogen, progesterone)
• 6. Genetic changes (mutations in some oncogenes
and tumor suppressor genes. Some mutations in
BRCA1 and 2 have been linked to hereditary breast
and overian cancer)
 Potential uses of tumor
markers
• 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

• In order to use a tumor marker for screening
in the presence of cancer in asymptomatic
individuals in general population, the marker
should be produced by tumor cells and not be
present in healthy people.

• However, most tumor markers are

present in normal, benign and cancer
tissues and are not spesific enough to
be used for screening cancer.
• Few markers are specific for a single individual
tumor, most are found with different tumors of
the same tissue type.
• They are present in higher quantities in blood
from cancer patients than in blood from both
healthy subjects and patients with benign
diseases.
• Some tumor markers have a plasma level in
proportion to the size of tumor while some
tumor markers have a plasma level in
proportion to the activity of tumor.
• The clinical staging of cancer is aidded by
quantitiation of the marker
 Serum level of marker reflects tumor burden.

• The level of the marker at the time of diagnosis

may be used as a prognostic indicator for disease
progression and patient survival. After successful
initial treatment, such as surgery, the marker
value should decrease. The rate of the decrease
can be predicted by using the half life of the
marker.
• The magnitude of marker reduction may reflect
the degree of success of the treatment.

• In the case of recurrence of cancer, marker

increases again.

• Most tumor marker values correlate with the

effectiveness of treatment.
• 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.

• 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.
• The use of PSA should not 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.
• 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.
• 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, hyperparathyroidism,
myeloproliferative disordes and pregnancy.
• Human Chorionic Gonadotropin
(hCG)

• It is a glycolprotein 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 CSF may indicate
 ONCOFETAL ANTIGENS
• Most reliable markers in this group are α-
fetoprotein and carcinoembryonic antigen (CEA)
• 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.
• 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.
 CARBOHYDRATE 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.

• 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
• 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.
 PROTEIN MARKERS

• Most reliable markers in this group are β 2-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.
 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.
• Hormone receptors also serve as a
prognostic factors in breast cancer. Patients
with positive receptor levels tend to survive
• 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.

• 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
 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
co-receptor in EGF action

• In the case of increased expression of

C-erbB2 leads the oto-activation and
increased signal transduction
 CANCER TREATMENT

• There are many types of cancer

treatment. The types of treatment that is
received will depend on the type of cancer
and how advanced it is. Some people with
cancer will have only one treatment. But
most people have a combination of
treatments, suchas surgery with
chemotherapy and/or radiation therapy.
They may also have immunotherapy,
targeted therapy, or hormone therapy.
 EXAMPLES OF CANCER
TREATMENTS
• CHEMOTHERAPY

• HORMONES

• HYPERTHERMIA TREATMENT

• IMMUNOTHERAPY

• PHOTODYNAMIC THERAPY

• RADIATION THERAPY

• STEM CELL TRANSPLANT

• TARGETED THERAPY

• SURGERY