Lecture 4 Flashcards
What causes cancer?
The cause of cancer is
multifactorial
A complex genetic basis with environmental triggers
(10% infectious agents)
“Causes/Risks of Cancer”
- Smoking and Lung Cancer, Radon gas and Lung cancer
- Viruses and other infectious agents
– HPV and cervical cancer
– Hepatitis C and Liver cancer.
– H. pylori is an important cause of gastric cancer and of
gastric mucosa-associated lymphoid tissue (MALT)
lymphoma. - Diet (Obesity)-Low grade inflammation-Colon cancer
- UV exposure eg Melanoma
- Environmental exposure (ionizing radiation-Leukemia, thyroid
cancer - Reproductive History (Breast Cancer)
- Genetic Background eg Li Fraumeni syndrome, retinoblastoma
etc
The Cell Division Cycle
–Maintenance: In the adult there is a constant loss of
cells (skin, gut epithelium) which needs to be
replaced
–Repair (wound healing etc)
Selective advantage e.g. Generation of immune
repertoire
–The Decision to Divide is governed by External and
Internal Factors eg growth factors can lead to ‘GO’
signals whereas detection of DNA damage directs
the cell to ‘STOP and Repair then divide or in some
cases die. The cell needs to integrate the incoming
signals both internally and externally
The Phases of
the Cell Cycle
Interphase includes G1 ,S and G2
phases of the cell cycle.
G1 (first Gap Phase)-make decisions
about growth versus quiescence
S Phase (synthesis) period of DNA
synthesis
G2 (second Gap Phase). Is all the DNA
replicated with fidelity?
M Phase (2 new cells-division of the
genetic material-mitosis (prophase,
prometaphase, metaphase, anaphase,
telophase) and cytokinesis.
G0-resting, nonproliferative state of
cells that have withdrawn from the
active cell cycle-cells can remain in Go
for days or even Years.
G0 and its characteristics:
G0 is a specialized arrested state in the cell cycle-
[But Reversible
ie can enter cell division cycle again-mitogens]
Characteristics
* Reduced Protein Synthesis (~20%)
* Reduced Growth
* Reduced levels of CDKs
* No G1 Cyclins
How is cell division controlled?
Not a simple Clock
There are control points (check points) in the cell
cycle where progression through the cycle can be
halted
Checkpoints have 2 important features:
Allow internal feedback control
Allow Control from external cues/stimuli
Cell Cycle Checkpoints
G1/S is the cell ready for division-Can DNA synthesis begin?
RB and p53 important regulators here. Absence DNA
damage-sufficient nutrients.
* Intra-S and G2/M- respond to DNA damage-prevent the
replication of damaged DNA until repaired-if not possible
then cell exits permanently from replication or is
eliminated.
* Spindle Checkpoint-Are all chromosomes aligned correctly
to spindle?-If not mitotic arrest don’t proceed to Anaphase.
Failure of these checkpoints promotes
GENETIC
INSTABILITY-ALLOWS CELLS WITH DAMAGED DNA TO
PROPAGATE.
The Growth of a NORMAL
mammalian cell depends on Nutrient
Availability and Growth Factor
signalling-leads to …
- Import nutrients
- Generation of building blocks for the synthesis of
macromolecules - Protein synthesis
- Biogenesis of key organelles
- Cell cycle regulation and stimulation of growth and division
G1 Phase of the Cell Cycle
‘Decision making Point’
During early and mid-G1 cells are responsive
to mitogenic (growth factors) as well as to
inhibitory signals such as TGFb. Progression
to S depends on the presence of growth
promoting signals in the G1 phase up until
the R or restriction point. After the cell has
progressed through the R point then
removal of growth factors from the
medium does not influence whether it will
go forward through S, G2 M.
At the R point a cell must make the decision
of whether to proceed to S or to enter Go
(resting). If a cell has made the decision to
proceed then there are other CHECKPOINTS
in place during the progression to final
division in S, G2 or M phases which can halt
the cell cycle (eg detection of DNA damage).
Deregulation of the R-point decision making
machinery is found in most cancers.
