Nem’s Notes…
MOLECULES, CELLS & TISSUES 3 (page 1 of 2)
Cell Division & Cancer
Cell Division
Phase 2 Year 3
co-author: Sabina Rashid
Cells have three options during their lifespan:
(a) Grow and divide
(b) Not grow but remain alive
(c) Die by apoptosis
The decision is dependent on external signals such as diffusable growth factors which
are transmitted into the cell via intramembrane receptors.
Growth Control Control of cell growth requires four classes of protein:
(a) A growth factor
(b) A growth factor receptor
(c) Intracellular transducers
(d) Transcription factors
Mutations in any of the genes encoding for these proteins can cause deregulation of
growth control and can cause uncontrolled cell division. These genes would be called
protooncogenes before the mutation and oncogenes after.
GF Signalling
Growth factors such as epidermal growth factor (EGF) attach to intramembrane
receptors to have an effect. A sequence of steps occurs within the cell following the
binding of the growth factor:
(a) Dimerisation and phosphorylation of the receptor
(b) Dimer unit is recognised by adaptor proteins (Grb-Sos)
(c) Grb-Sos interacts with Ras
(d) GDP converted to GTP activating the unit
(e) Ras becomes Raf which phosphorylates MAPKK to MAPK
(f) This activates transcription factors to transcribe DNA
Receptors can be turned off via a number of mechanisms:
(a) Internalisation of receptors
(b) Negative feedback (via MAPK)
(c) Phosphatases (inactivate MAPK)
(d) GTPase activating proteins (prevent step (d) above)
Control of
Mitosis
Mitosis can be controlled by TGFβ (transforming growth factor) since it acts as a CDK
inhibitor and stops the cell cycle in G1 preventing entry into S phase.
Integrins are a family of cell membrane receptors for extra-cellular matrix proteins
which augment growth factor signals. Binding triggers association of Focal Adhesion
Kinase (FAK) and other kinases which drive the cell cycle. However some integrins
inhibit mitosis and promote differentiation.
Contact
Inhibition
Cells do not overlap due to contact inhibition. This occurs via the action of cell
adhesion molecules (CAMs) such as E-cadherin. These generate an anti-growth
signal. Transformed cells such as cancerous cells lose contact inhibition.
more online at http://homepage.virgin.net/nemonique.sam/noteindx.htm page 1 of 2
Nem’s Notes…
MOLECULES, CELLS & TISSUES 3 (page 2 of 2)
Cell Division & Cancer
Cancer
Capabilities
Phase 2 Year 3
co-author: Sabina Rashid
Most cancers acquire the same set of functional capabilities and include:
(a) Self-sufficiency in growth signals
(b) Limitless replication potential
(c) Insensitivity to anti-growth signals
(d) Evasion of apoptosis
(e) Sustained angiogenesis (blood vessel formation)
(f) Tissue invasion and metastases
The spread of cancerous cells to form new colonies distant from the primary tumour is
called metastatic spread and is responsible for 90% of cancer deaths.
Metastases
For a cancer to become invasive or metastatic it must undergo certain changes:
(a) Loss of E-cadherin function (or other CAMs)
(b) Increased expression of extracellular proteases (breaks down ECM)
(c) Integrin profile changes in preference of ECM in the new site
Liver Cancer
Liver cancer is the fifth most common cancer worldwide and has poor prognosis and
high fatality. The most important risk factors are hepatitis B (HBV) infection and
exposure to aflatoxin.
HBV infection involves liver damage and the incorporation of viral genes into infected
cells. Genes affected include those for p53, cyclin D and other proteins involved in the
G1 phase of the cell cycle.
Aflatoxins are derived from the Aspergillus fungus which can affect various food crops
such as peanuts, maize and rice. The most potent form adducts to DNA leading to
mutations. One ‘hot-spot’ is the code of the p53 gene. They can also act
synergistically with HBV infection in causing liver cancer.
Liver cancer is thought to involve a ‘multi-hit’ mechanism of carcinogenesis where a
sequence of mutations must occur in order to establish full blown clinical cancer. At
least two mutation events are required (and maybe more) before the cancer can
develop. There are four main mutations that can cause this, involving the:
(a) response to DNA damage (p53)
(b) control of the cell cycle (RB, p16, cyclin D)
(c) growth inhibition (TGFβ, M6P/IGF2R)
(d) cell contact signalling (APC, β-catenin, E-cadherin)
The exact mechanism is poorly understood and the exact sequence in which events
occur is still to be determined.
more online at http://homepage.virgin.net/nemonique.sam/noteindx.htm page 2 of 2