CANCER

Characterized by uncontrolled cellular growth

& development, leading to excessive

proliferation & spread of cells.

Cancer is the second largest killer disease.

Cancer originated from the character of

cancerous cells which migrate & adhere and

cause pain to any part of the body.

Uncontrolled growth of cells result in tumors.

Benign tumors:

They usually grow by expansion & remain

encapsulated in a layer of connective tissue.

These are not life-threatening. Eg. Moles.

Malignant tumors or cancers:

Characterized by uncontrolled proliferation

& spread of cells to varies parts of the body,

a process referred to as metastasis.

These are life-threatening. Eg. Lung cancer.

Cancers arising from epithelial cells are

referred to as carcinomas, while that from

connective tissue are known as sarcomas.

General & morphological changes:

Shape of cells:

Rounder in shape

Alterations in cell structures:

The cytoskeletal structure of the tumor cells

with regard to actin filament is different.

Loss of contact inhibition:

The normal cells are characterized by contact

inhibition, i.e. they form monolayers.

They cannot move away from each other.

The cancer cells form multilayers due to loss

of contact inhibition.

Cancer cells freely move & get deposited in

any part of the body, a property referred to

as metastasis.

Loss of anchorage dependence:

The cancer cells can grow without

attachment to the surface.

But normal cells which firmly adhere to the

surface.

Tumor cells have altered permeability &

transport.

Increased replication and transcription:

Synthesis of DNA & RNA is increased.

Increased glycolysis:

Elevation in aerobic & anaerobic glycolysis

due to increased energy demands of

multiplying cells.

Reduced requirement of growth factors:

Require less quantities of growth factors.

Synthesis of fetal proteins:

During fetal life, certain genes are active,

leading to the synthesis of specific proteins.

These genes are suppressed in adult cells.

Alterations in the structure of molecules:

Changes in the structure of glycoproteins &

glycolipids.

Include physical, chemical, genetic &

environmental factors.

Chemical carcinogens:

Almost 80% of human cancers are caused by

chemical carcinogens in nature.

The chemicals may be organic

(dimethylbenzanthracene) or inorganic

(arsenic, cadmium) in nature.

Occupation e.g. asbestos, benzene.

Diet: e.g aflatoxin B produced by fungus

(Aspergillus flavus) contamination of

foodstuffs, particularly peanuts.

Drugs certain therapeutic drugs can be

carcinogenic e.g. diethylstibesterol.

Life style e.g. cigarette smoking.

Few of the chemicals are directly

carcinogenic.

Majority of them require prior metabolism to

become carcinogenic.

The enzymes cytochrome P450 responsible for

the metabolism of xenobiotics.

The carcinogens can covalently bind to

purins, pyrimidines & phosphodiester bonds

of DNA, causing unrepairable damage.

The chemical carcinogens frequently cause

mutations which may finally lead to the

development of cancer, hence they are

regarded as mutagens.

A laboratory test to check the carcinogenecity

of chemicals.

Use of a special mutant strain of bacterium,

Salmonella typhimurium (His-).

This organism cannot synthesize histidine.

Histidine should be supplied in the medium

for its growth.

Addition of chemical carcinogens causes

mutations (reverse mutation) restoring the

ability of bacteria to synthesize histidine (His+).

By detecting the strain of Salmonella (His+) in

the colonies of agar plates, the chemical

mutagens can be identified.

It can detect about 90% of chemical carcinogens.

This is a preliminary screening procedure.

Radiation energy:

Ultraviolet rays, x-rays and y-rays have

been proved to be mutagenic in nature

causing cancers.

These rays damage DNA.

Carcinogenic viruses:

Oncogenic viruses may be either DNA viruses

or RNA viruses.

Class Members

DNA viruses

Adenovirus Adenovirus 12 & 18

Herpesvirus Epstein-Barr virus, herpes simplex virus

Papovirus Papilloma virus, polyoma virus

RNA viruses

Retrovirus type B Mammary tumor virus of mouse

Retrovirus type C Leukemia, sarcoma

Cancer is caused by a genetic change in a

single cell.

Two types of regulatory genes – oncogenes &

antioncogenes.

Oncogenes:

The genes capable of causing cancer are

known as oncogenes.

These are discovered in tumor causing viruses.

Viral oncogenes are similar to certain genes

present in the normal host cells referred as

protooncogenes.

About 40 viral & cellular proto-oncogenes.

Proto-oncogenes encode for growth regulating

proteins.

The activation of protooncogenes to

oncogenes is an important step in the

causation of cancer.

Viral insertion into chromosome:

Certain retroviruses (genetic material RNA)

infect cells, a complementary DNA (cDNA) is

made from their RNA by the enzyme reverse

transcriptase.

This cDNA inserted into the host genome.

The integrated double-stranded cDNA is

referred as provirus.

This proviral DNA takes over the control of

the transcription of cellular chromosomal

DNA and transforms the cells.

This ultimately causes cancer (E.g. avian

leukemia).

Chromosomal translocation:

Some tumors exhibits chromosomal

abnormalities.

This due to rearrangement of genetic

material (DNA) by chromosomal

translocation i.e. splitting off a small

fragment of chromosome which is joined to

another chromosome.

It usually results in over expression of proto-

oncogenes.

Burkitt’s lymphoma, a cancer of B-

lymphocytes.

Gene amplification:

Several fold amplifications of certain DNA

sequences are observed in some cancers.

Administration of anticancer drugs

methotrexate (inhibitor of dihydrofolate

reductase) is associated with gene

amplification.

The drug becomes inactive due to gene

amplification resulting in a several fold

increase in the activity of dihydrofolate

reductase.

Point mutations:

The replacement of one base pair by another

results in point mutation.

Growth factors:

Cell proliferation is stimulated by growth factors.

Growth factor binds to protein receptor on the

plasma membrane.

This binding activates cytoplasmic protein kinases

leading to the phosphorylation of intracellular

target proteins.

The phosphorylated proteins act as intracellular

messengers to stimulate cell division.

Transforming growth factor (TGF-α) is a

protein synthesized & required for the

growth of epithelial cells.

TGF - α is produced in high concentration in

individuals suffering from psoriasis, a

disease characterized by excessive

proliferation of epidermal cells.

Some oncogenes encoding growth factor

receptors.

Overexpression and/or structural

alterations in growth factor receptors are

associated with carcinogenesis.

These are a group of signal transducing

proteins.

Guanosine triphosphate (GTP) – binding

proteins are found in 30% of human cancers.

Mutation of ras protooncogene is the single-

most dominant cause of many human tumors.

A special category of genes – cancer

suppressor genes or antioncogenes.

The products of these genes apply breaks &

regulate cell proliferation.

The loss of these suppressor genes removes

the growth control of cells & a key factor in

the development of several tumors. E.g.

retinoblastoma, carcinoma of lung.

Tumor markers are defined as bio chemical

substance (e.g. hormone, enzyme or

proteins) synthesized & released by cancer

cells or produced by the host in response to

cancerous substance.

Site:

In blood circulation, body fluids, cell

membranes, cell cytoplasm.

Tumor marker Associated cancer

Oncofetal antigens

Carcinoembryonic antigen (CEA)Cancer of colon, stomach, lung, pancreas & breast

Alpha fetoprotein (AFP) Cancer of liver & germ cells of testis

Cancer antigen 125 (CA-125) Ovarian cancer

Hormones

Human chorionic gonadotropin(hCG)

Choriocarcinoma

Calcitonin Carcinoma of medullary thyroid

Catecholamines & their metabolites

Neuroblastoma

Tumor marker Associated cancer

Enzymes

Prostatic acid phosphatase Prostate cancer

Neuron specific enolase Neuroblastoma

Specific proteins

Prostate specific antigen (PSA) Prostate cancer

Immunoglobulins Multiple myeloma

Carcinoembryonic antigen(CEA):

CEA is a glycoprotein.

Present in both carcinoma & embryonic tissue.

Normal range: <5.0 ng/ml.

Site: GI mucos, lungs & pancreas

CEA is a most useful marker in colorectal

cancer.

Also elevated in breast cancer, pancreatic

gastric & lung cancers.

Human chorionic gonadotropin (β-HCG):

It is a placental hormone.

Synthesized by syncytiotrophoblastic cells of

placental villi.

Normal range: 120,000mIU/mL.

It is a glycoprotein

It is a dimer, contain α-subunit & β-subunit.

Useful tumor marker for gestational tumors &

germ cell tumors of testis & ovary.

Alpha-Fetoprotein(AFP):

AFP is synthesized in liver, yolk sac & GIT in

fetal life.

It is a glycoprotein.

Normal range: <15 ng/ml.

Chemically related to albumin.

AFP is the most specific tumor marker for

primary carcinoma of liver.

CA 125:

It is a tumor marker for ovarian carcinoma.

Also elevated in breast carcinoma & colorectal

cancers.

Narmal range: <35 U/ml.

CA 15-3:

It is useful tumor marker in breast carcinoma.

It is more sensitive marker than CEA.

Normal range: <30 U/ml.

CA 19-9:

It is useful tumor marker in pancreatic cancer.

It is also elevated in colorectal

cancer(20%),hepatomas(20 to 50%)and gastric

cancer.

Normal range: <37 U/ml.

These are identified in breast cancer.

MCA (Mucin-like carcinoma associated

antigen)

It is a mucin glycoprotein.

MAM6:

It is a epithelial membrane antigen.

Present on ductal & alveolar epithelial cells.

MSA (mammary serum antigen):

It is marker of intraductal breast cancer.

More sensitive marker then CA 15-3.

MAP (Mitogen activated protein) kinase:

It is a new breast cancer marker.

MAP kinase levels are 5 to 20 times higher in

breast cancer as compared to normal breast

tissue.

Prostatic acid phosphatase (PAP):

It is a tumor marker for prostate cancer.

Normal range: <2.5ng/ml.

Prostate specific antigen (PSA):

It is an organ specific.

Localized to prostatic ductal cells.

Normal range: 4.5 µg/L

Neuron –specific Enolase (NSE):

It is a specific tumor marker of neuro-

endocrine origin.

It is useful marker in neuroblastomas & lung

cancer.

NSE:

Also elevated in small-cell carcinoma of lung

The upper reference limit: 12.5 µg/L

Textbook of Biochemistry – U Satyanarayana

Textbook of Biochemistry – DM Vasudevan

Textbook of Biochemistry – MN Chatterjea