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Cancer Notes 2010
Cancer Notes 2010
Cancer Notes 2010
Objectives:
1n) Explain how uncontrolled cell division can result in cancer, and identify factors which can increase the chances of
cancerous growth (knowledge that dysregulation of checkpoints of cell division can lead to uncontrolled cell division and
cancer is required but details of mechanisms are not required).
CANCER
TUMOURS
• When a cell loses genetic control over cell growth
(due to mutations), it can result in a tumour.
• Tumour = a mass or lump of cells, with an inherited
capacity for autonomous, uncontrolled growth, resulting
from uncontrolled cell division.
• 2 types of tumours:
Benign tumours
o Surrounded by a connective tissue capsule
and thus isolated (eg, moles, warts).
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Malignant tumour
o Made up of cancer cells
o Connective tissue capsule breaks down and cancer cells send out signals for the
production of a new blood vessels (angiogenesis) at the tumour site.
This is because blood supply allows removal of metabolic waste and supply of
nutrients which allow for rapid growth.
Angiogenesis is also required for the spread of cancer.
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• Contain oncogenes (mutated version of proto-oncogenes; more details will be covered under
CANCER DEVELOPMENT)
• Exhibit abnormal cell growth and division
(cell proliferation).
• Do not undergo apoptosis i.e. programmed
cell death.
• Do not become specialized i.e. remain
undifferentiated.
• Can stimulate growth of blood vessels
towards itself (angiogenesis) (Figure showing angiogenesis)
• Can invade surrounding tissues or
metastasize to other tissues.
• Lack of control by cell cycle checkpoints.
• Do not show density-dependent inhibition and anchorage dependence.
DENSITY-DEPENDENT INHIBITION
• Phenomenon in which normal cells stop dividing because of insufficient nutrients
• When a normal cell population reaches a certain density, the availability of nutrients becomes
insufficient to allow continued cell growth and division.
• Cancer cells can divide well beyond a single layer to give a clump of overlapping cells.
ANCHORAGE DEPENDENCE
• In order for most animal cells to divide, they must be attached to a substratum e.g. extra-cellular
matrix
• Anchorage is signalled to the cell cycle control system via pathways involving plasma membrane
proteins and elements of the cytoskeleton linked to them.
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• Checkpoints are control points whereby stop and go-ahead signals can regulate the cell cycle.
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1) Age
• Chances of developing cancers increase with age. Cancer results from mutations in certain genes
and since each mutation is a rare event, most cancers develop later in life.
2) Genetic Factors
• Certain cancers run in families. Eg. colon cancer. Mutated genes may be passed from one
generation to the next.
3) Carcinogens
• Agents are capable of causing cancer, such as radiation and some types of chemicals.
• Examples are UV light (possible cause of skin cancer) and X-rays (cause of leukaemia and skin
cancer).
• X-rays cause ionisation of molecules and the highly reactive ions stimulate mitosis and destroy cells.
• Chemical carcinogens include cigarette smoke which contains 4000 different chemicals, many of
which are responsible for causing lung cancer.
4) Viruses
• Some viruses can cause genetic changes in cells, increasing their likelihood to become cancerous.
• Possible ways are
(i) the viral DNA integrates into the host cell DNA (cause the cells to proliferate),
(ii) changing the host cell’s surface interactions (loss of density-dependent inhibition),
(iii) switching on DNA replicating machinery of the host (continued host cell division)
(iv) providing oncogenes.
• Eg. The human papilloma virus causes cancer of the cervix and the Epstein-Barr virus is associated
with Burkitt’s lymphoma.
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• Cancer is a multistep process: develop in progressive steps from mildly aberrant cells (cells that
deviate from the norm) to increasingly tumourigenic and malignant (accumulation of mutations)
• Therefore a single mutation is not sufficient to transform a normal cell into a malignant cell.
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PROTO-ONCOGENES
• Proto-oncogenes are genes whose products promote cell growth and division, and have essential
function in normal cells.
• They do this by encoding:
1. transcription factors that stimulate expression of other genes
2. signal transduction molecules that stimulate cell division e.g. ras gene codes for Ras protein
3. cell cycle regulators that move the cell through the cell cycle
• Proto-oncogene products may be located in the plasma membrane, cytoplasm, or nucleus
• Activities of proto-oncogene products are controlled in various ways e.g. regulation in the
transcriptional, translational and protein modification levels.
• When cells become quiescent (non-dividing) and cease division, expression of most proto-
oncogene products are repressed.
ras PROTO-ONCOGENES
• The ras gene family encodes signal transduction molecules (Ras proteins) that are associated
with the cell membrane.
• Ras proteins normally transmit signals from the cell membrane to the nucleus, stimulating the cell
to divide in response to external growth factors; thus, regulate cell growth & division.
• Ras proteins cycle between an inactive and an active state by binding either GDP or GTP
respectively
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1. CHROMOSOMAL TRANSLOCATION
(i) Cancer cells are frequently found to contain
chromosomes that have broken and rejoined incorrectly.
(ii) If a translocated proto-oncogene ends up near an
especially active promoter, or other control element, its
transcription may increase, making it an oncogene.
(iii) Movement of transposable elements may also place a
more active promoter near a proto-oncogene hence
increasing its expression.
2. GENE AMPLIFICATION
(i) An abnormal increase in the copy number2 of a
proto-oncogene.
(ii) For example, the myc gene, which codes for a transcription factor, has been amplified in
human leukemias, breast, stomach, lung, and colon carcinomas3.
1
Constitutive – continually / at a constant rate
2
Copy number - number of copies of a gene within a cell's genome
3
Carcinoma – malignant cancer
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3. VIRAL INTEGRATION
When a virus integrates into the chromosome, it may enhance the expression of nearby proto-
oncogenes.
4. POINT MUTATION
(i) Within the control element: change in the nucleotide sequence in the promoter or enhancer
causing an increased expression of proto-oncogene or changes in the silencer resulting in the
inability to repress gene expression.
(ii) Within the gene: change in the coding sequence resulting in a protein that is more active or
more resistant to degradation than the normal protein (constitutively activated protein).
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• A primary role of the p53 protein is to determine if a cell has incurred DNA damage.
• DNA damage can be caused by several events:
- chemical damage to DNA
- double-stranded breaks in DNA induced by ionising radiation
- presence of DNA-repair intermediates generated by exposure of cells to ultraviolet
light
• DNA damage results in
- Increase in p53 protein phosphorylation and acetylation
High levels of activated p53
- Increase in p53 protein stability
• Hence, rapid increase in the nuclear levels of activated p53 protein
• Activated p53 protein initiates three different responses to DNA damage through activation of
genes:
1. Activate genes that promote DNA repair.
• To prevent accumulation of mutations that activates oncogenes or inactivate tumour
suppressor genes.
2. Activate genes that arrest cell division and may generally repress other genes that required for
cell division.
• To allow more time for the cell to repair its DNA.
• To avoid producing two mutant daughter cells.
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(iii) In many malignant tumours, the gene for telomerase is activated, preventing the shortening of
chromosome ends during DNA replication – number of times the cell can divide is unlimited.
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