molecular biology of cancer

1. Molecularbiology
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Molecular Biology of Cancer
 Cell numbers are a product of the rates of cell division (mitosis) and cell death
(apoptosis).Cancer can arise as a result of gene mutations that affect the rate of mitosis
as well as apoptosis, thereby leading to the accumulation of extra cells.
 The cell cycle is controlled by proteins from inside & outside the cell.
o Intracellular Cyclins and Cyclin Dependent Kinases (CDKs) control the
checkpoints.
o Hormones or extracellular proteins from other cells (called Growth Factors) signal
target cell to divide.
Hormones (e.g. Growth Hormone) or Growth Factors bind to receptor proteins of target
cell membrane. This triggers a molecular signaling pathway. A series of linked proteins
activate Cyclin- CDKs which Allows Cells to Pass Cell Cycle Checkpoints & divide.
 Cancer is a group of diseases caused by the uncontrolled multiplication of abnormal cells
in the body, a process called neoplasia. Abnormal new tissues called neoplasms are
formed. Neoplasms usually form masses called tumors that may be benign (non-
cancerous) or malignant (cancerous). Malignant or cancerous tumors grow rapidly, are
invasive (to surrounding tissue) and metastatic (traveling via blood/lymph to invade
distant tissues).
 Cancer is the 2nd major killer in populations of developed countries & the leading cause
of death in children.
 Cancers are genetic disorders caused by accumulation of somatic mutations (gene &
chromosome) in a person’s cells. Inherited mutations give a predisposition for certain
cancers.
 Characteristics of Cancer Cells
o Cancer cells are genetically altered via gene or chromosome mutations so:
• Lack normal controls over cell division or apoptosis.
• may express inappropriate genes (e.g. For telomerase, enzyme that maintains
length of DNA for continued division
• are genetically unstable due to loss of DNA repair mechanisms (so are more
susceptible to radiation damage than normal cells
o Divide excessively (proliferate) & indefinitely producing neoplasms.
o Live indefinitely (do not show apoptosis
o Lose the normal attachment to other cells so become metastatic (travelling via
blood/lymph to invade distant sites.
o Secrete signals for angiogenesis (growth of blood vessels into tumor).
 Malignancies fall into one of five categories based on the tissue type they arise from:
• Carcinomas are associated with skin, nervous system, gut, and respiratory tract
tissue.
• Sarcomas are associated with connective tissue (such as muscle) and bone.
• Leukemias (related to sarcomas) are cancers of the blood.
• Lymphomas develop in glands that fight infection (lymph nodes and glands scattered
throughout the body.
• Myelomas start in the bone marrow.
 Pathogenesis of Metastasis
o Cells in a primary tumor develop the ability to escape and travel in the blood
o Tumor cells secrete enzymes to break down extracellular matrix & gain access to
blood vessels.
o In blood they can escape attack by immune cells by attaching to platelets.
o Tumor cells attach to capillary walls & secrete more enzymes to digest their way
out, & grow in a new location (metastasis) forming a secondary tumor.

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Causes of cancer
o Inherited mutations in genes that affect cell cycle, DNA repair, or apoptosis: these
mutations give a genetic predisposition for cancer.
o Somatic mutations to these same genes caused by:
• Exposure to risk factors such as environmental mutagens (carcinogenic chemicals,
radiation), hormones and Weakening of immune system (as in AIDS).
• Oncogenic (tumor) virus infections: eg Epstein Barr virus (causes Burkitt lymphoma
and Human Papilloma virus (causes cervical cancer).
Tumor viruses transform human cells into cancer cells by Introducing viral cancer -
causing oncogenes into host cell DNA or by Causing Translocation and
overexpression of host protooncogenes.
Carcinogens are cancer-causing agents. Mutagens are agents that change the genetic
code in a cell. Almost all carcinogens are mutagens.
 Mutations in 4 types of genes cause Cancer
o Proto - oncogenes: genes that code for normal proteins used in cell division
–Growth factors
–Membrane Receptors for Growth Factors
–Signaling Proteins (e.g. ras proto- oncogene mutates in 30% of cancer.)
o Tumor Suppressor genes: gene that code for proteins that help prevent uncontrolled
cell division by blocking key steps (e.g. DNA replication.)
-Retinoblastoma susceptibilty (RB) gene
-p53 gene mutates in >50% of cancers.
o DNA Repair genes
o Genes for Apoptosis
 Tumor Suppressor Proteins Inhibit Cell Division & Prevent Cancer
o Tumor suppressor proteins are proteins that bind to checkpoint proteins to stop the
cell cycle & prevent cell division if DNA is damaged.
o Tumor suppressor proteins stop division of mutated cells until mistakes in DNA are
repaired by enzymes.
o TS proteins keep most mutations from being passed on to daughter cells &
developing into cancer. If the genes for TS proteins mutate the brake on cell
division are removed cancers may result. Two important TS proteins are the p53
protein & the RB protein.

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o The p53 tumor suppressor protein is activated when DNA is damaged. The p53
gene is called the “guardian angel of the genome”
o P53 protein activates genes for proteins that Prevent cell entering S phase
,Repair DNA and Cause apoptosis (if DNA is irreparable)
 Oncogenes Are Mutated Proto-oncogenes
o A cell can acquire a cancer - causing oncogene from virus or mutation in a proto-
oncogene.
o Proto-oncogenes form active oncogenes by
• being misplaced (e.g. by translocation) to a site where the gene is continually
expressed resulting in overproduction of a protein that stimulates cell division
(e.g. in Chronic Myeloid Leukemia)
• By mutating to a form that is over expressed.
o Mutations that turn a gene into an oncogene are typically gain-of-function
mutations that greatly increase the activity of the protein encoded by the gene. This
can be achieved in a number of ways:
(1) Through enhancing the stability of the protein
(2) Increasing the expression rate of the gene encoding this protein
(3) By altering the protein active site (if its an enzyme) such that it now functions at
an enhanced rate or by some other conformational change that results in a more active
protein.
Fig ( ) How Carcinogens Cause Cancer Fig ( )

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 Multiple Genetic Changes Cause Cancer .Cancers result from a series of genetic
changes in a cell lineage

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o Inherited (germline) cancers begin with an inherited cancer susceptibility mutation in
every cell that is passed on to offspring.
o Inherited cancers may follow a dominant pattern, e.g. Inherited Retinoblastoma
caused by a mutation in the Rb tumor supressor gene increases cancer risk 10,000 x.
o However, Inherited cancers need at least one more somatic mutation for cancer to
develop (“2 hit hypothesis for cancer causation”) .
o Sporadic cancers are caused solely by somatic mutations occurring in certain body
cells so are not passed on to offspring.
o Accumulation of somatic mutations in a cell over time eventually leads to uncontrolled
cell division and cancer.
o Therefore sporadic cancers tend to appear much later in life than inherited cancers.
Genetics of Breast Cancer: 5 - 20% of breast cancers are Familial. Most involve
mutations in 2 Tumor Suppressor genes involved in DNA repair so are used as genetic
markers. Both genes also increase the risk of ovarian cancer. Breast Cancer
Susceptibility Gene 1 (BRCA1) on chromosome 17 .Breast Cancer Susceptibility Gene 2
(BRCA2) on chromosome 13.

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 INHERITED SUSCEPTIBILITY TO CANCER
 It is thought that 5% to 10% of cancers may be largely due to inherited defects. Many
of the genes involved in this are poorly understood, but they may be divided into three
general categories.
 First, as we have already discussed, it is possible to inherit one defective copy of an
anti-oncogene. In this case every somatic cell starts life with one faulty copy and only
a single somatic mutation is needed to completely inactivate the pair of anti-
oncogenes. (Note: Inheriting two defective copies of an anti-oncogene is normally
lethal. Artificially engineered mice that are doubly negative for such genes generally
die before birth.)
 Secondly, mutations in certain special genes affect the rate at which further mutations
occur during cell division. Such genes are known as mutator genes. These include
genes involved in DNA synthesis, such as the genes encoding DNA polymerase.
Some mutator genes are more subtle and are involved in DNA repair. These have
been analyzed in detail in bacteria, although less is known for humans. Nonetheless, it
appears that certain inherited forms of colon cancer are due to defects in genes
involved in mismatch repair. This, in turn, increases the rate of mutation in all other
genes including the tumor-suppressor genes. Defects in mutator gene are generally
recessive, like those in other tumor-suppressor genes.
 Inherited defects in anti-oncogenes, components of DNA replication, and DNA repair
systems can also predispose a person to cancer. Some genetic differences make
people more susceptible to certain cancers.
 Steps that can be taken to reduce the risks of cancer
 Do not smoke. Cigarettes are full of chemicals that damage your DNA. Smoking doubles
your overall chance of getting cancer. You are 25 times more likely to get lung cancer
than someone who does not smoke. The only group of people among whom smoking is
getting more common is teenagers and young adults. Many experts expect that lung
cancer will soon kill more women in Britain each year than any other type of cancer.
 Do not drink alcohol. Alcohol is linked to approximately 3% of cancer incidence,
particularly in the mouth, larynx, esophagus and liver.
 Increase your daily intake of fruit, vegetables and fibre. It is estimated that dietary
changes could pre-vent about 30% of cancers, perhaps more. As yet we have no
concrete proof as to which elements of diet protect against cancer, but most researchers
agree that eating plenty of fruit and vegetables and cutting down on red meat and animal
fats is a good idea.
 Avoid excessive exposure to the sun. Rays from the sun can damage the DNA of your
skin and eye cells.
 Follow all the guidelines to reduce exposure to harmful chemicals. For example, hazards
such as asbestos are now being removed from public places and homes.
 See a doctor if you suffer from any unexplained changes in health that persist for longer
than 2 weeks.
 Women: undertake regular cervical smear tests and breast examinations.
 Passive smoking is the inhalation of smoke from other peoples’ tobacco. Many studies
suggest that passive smoking increases the risk of lung cancer. It is estimated that 10%
of lung cancer deaths in non-smokers may be attributed to passive smoking. In the UK,
this translates to about 300 deaths a year. Studies show that if your husband or wife
smokes, but you do not, your chances of developing lung cancer are increased by
around 25–30%.
 The earlier a cancer is detected, the easier it is to cure. Over half of cancer sufferers are
cured today, especially if the disease is found before it has spread around the body.