KEY

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CONCEPTS:
Changes that occur to allow cancers
DNA repair and mutation
Oncogenes and Tumour suppressor genes
Technologies and development.

CANCER:
Cancer is generally a disease of a healthy society as people need to
live long enough for it to develop. It is a multi-step process, although
when it is detected, it is usually many years after the first initiating events
occurred.
Cancer is initiated when a cell within a normal population obtains
a genetic mutation that increases its propensity to proliferate
when it would normally rest. The altered cell and its descendants
continue to look normal, but they reproduce too much
(hyperplasia). After years, one in a million of these cells suffers
another mutation that further loosens controls on cell growth. In
addition to proliferating excessively, the offspring of this cell appear
abnormal in shape and in orientation; the tissue is now said to
exhibit dysplasia. Again, after a period of time, a rare mutation
that alters cell behaviour occurs.
ALL CANCER ARISES BECAUSE OF CHANGES TO ESSENTIAL GENES THAT
CONTROL CELL GROWTH AND DIVISION
Causes of cancer:
External

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Chemical
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Diet/exercise
o
Hormonal
o
Radioactive
o
Viral
Internal

o
Genetic
Environment accounts for 60-85% of cancers, shown in various studies.
CANCER PROLIFERATIVES VIA Clonal evolution:
Clonal Evolution
The emergence of a cancer cell from a normal cell is thought to occur
through a process known as clonal evolution. First, one daughter
cell inherits or acquires a cancer-promoting mutation and passes
the defect to all future generations. At some point, one of the
descendants acquires a second mutation, and a later descendant
acquires a third, and so on. Eventually, some cell accumulates
enough mutations to cross the threshold to become cancer. Due
to this gradual progression and heavy involvement of chance, the
process requires a long time for mutations to be acquired, thus it is
difficult to develop.
Hallmark of cancerous cell 6 + 2 + 2 enabling features

Sustaining of proliferative signals

Evading growth suppression
Activation of invasion and metastasis
Proliferative immortality
Angiogenesis
Resistance to apoptosis
Resistance/evasion of immune response
Deregulation of cell energetics
Plasticity of DNA
Tumour-promoting inflammation

OUTLINE:
A NORMAL CELL:
Cell cycle in normal cell consists of 4 main stages

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G1
This is the growth stage, where the cell synthesises

materials needed for replication. Nucleotides as well as

other proteins are amassed in preparation for replication.
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S
DNA replication occurs

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G2
Preparation for mitosis and replication of organelles

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Mitosis
Cell replication

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Extra:
G0 - stage of rest/senescence

In this stage, cells are active but not doing

anything to initiate proliferation
What causes cells to enter mitosis?
Factors were discovered due to experiments where cells were fused

to each other
Cyclin and Cyclin dependent Kinase

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Together, the structure is known as MPF (Mitosis promoting
factor)
Cyclin is a protein, which levels vary during specific phases of the

cell cycle.
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It is controlled by growth factors and activating peptides.
CDK is omnipresent but can only bind to cyclin when it is available.

When it binds, it is able to phosphorylate other proteins which

continue the cell cycle.
There are other genes known as proto-oncogenes which act as

positive signals to the cell cycle.

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Usually they are switched on and off via signals to engage or
disengage with the cell cycle
o
If uncontrolled, they are known as oncogenes, and act as
permanent accelerators, altering growth factors, intracellular
transducers and transcription factors.
o
Example is K-Ras in colorectal cancer.
NOTE: there are specific cyclins and CDK for each stage of the cell cycle.

Activation pathway is as follows

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Initial growth factor activates synthesis of cyclin D, initiating
G1 through the binding of the CDK and phosphorylation of
proteins.
o
The proteins then complete g1 and activates production of
the next cyclin for the next phase.
o
Rinse and repeat.

What barriers/checkpoints are there to ensure no neoplastic cells

are formed?

Checkpoints:
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There are 3 checkpoints in the cell cycle
o
These ensure each stage is properly carried out before the
next stage begins
G1 checkpoint

Checks for cell size

Nutrients and growth factors

DNA damage
G2 Checkpoint

Checks for proper DNA replication

Cell size
Metaphase Checkpoint

Checks chromosomes are properly aligned and

attached to spindle fibres.
Tumour suppressor genes
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P53, Rb
These are like brakes in the replication process.

They suppress changes that lead to cancerous growth

They can sense cellular damage, activate repair

pathways, or signal for apoptosis of the cell.

Both copies of a tumour suppressor gene must

be inactivated or altered for it to lose its function.

o
RB
Works by continually being bound to transcription

factors, and is inactivated by phosphorylation by CDKs

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P53
Is able to detect cellular damage and signal for repair

pathways
Can also signal for apoptosis of cells

Is mutated in over 50% of all human cancers

Mutation results in more aggressive, metastatic and

fatal growths.
Technology developed based on our understanding of Cancer
and cells:
Gene expression assays
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Utilised to view genes that are expressed in cancer cells and
provides indications of the patient's prognosis with 90%
accuracy.

Can be used to determine whether chemotherapy is

needed.
Gleevec
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A synthetic anti-cancer drug, which was created to combat
the phildelphia chromosome.
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A section of chromosome migrated from one chromosome to
another.
That section was a proto-oncogene ABL, which was

adjacent to its controlling factor on the previous

chromosome.
When it moves, it is then unregulated and thus alters

the cell cycle of the cell.

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Gleevec binds to the ABL proto-oncogene (which is a kinase),
replacing ATP and impairs the substrate protein from being
phosphorylated and initiating aspects of the cell cycle.