ABNORMAL CELLFATE REGULATION Cancer

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(23 October 2006 )
MBI Journal Club on Models of Cell-Fate Regulation
ABNORMAL CELL-FATE REGULATION (Cancer)
Part Five
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colorectal cancer
American Cancer Society website
http//www.cancer.org/docroot/CRI/CRI_2_1x.asp?rna
vcriovdt10
Wikipedia
http//en.wikipedia.org/wiki/Colorectal_cancer
polyp
http//upload.wikimedia.org/wikipedia/en/thumb /f/
fd/Polyp.jpeg/190px-Polyp.jpeg
colon cancer
http//www.cancer.org/common/images/type8/body1.gi
f
http//upload.wikimedia.org/wikipedia/en/thumb/c/c
8/ Colorectal_cancer_endo_2.jpg/ 200px-Colorectal_
cancer_endo_2.jpg
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Integrative Biology website (includes overview
of multiscale modeling of colorectal cancer)
http//www.maths.nottingham.ac.uk/personal/pmzivl/
crc.html
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Computer program starts with an initial
distribution of na, f.
na, f density of cells in cell-cycle phase f
and age a.
f
tf time duration of cell-cycle phase f
dt x Nf
where dt is the time step for the discrete cell
cycle model, Nf is the maximum number of time
steps in phase f.
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Evolution of cell densities na, f
where
(Darcys Law)
Pa,f cell density (net) proliferation term in
phase f at age a retrieved from the
cell cycle model.
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CELL CYCLE PHASES f G1, S, G2M, G0,
Apoptosis
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EXAMPLE
PNG1,G1 (rate from a NG1-1)
(rate to a 1, f S)
(rate from a NG1-1) (rate to a 1, f
Go)
or
Pa,f
(rate from a NG1-1) (rate to a 1, f
apoptosis)
or
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Cell cycle phase transitions (cellular level)
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Molecular mechanisms (gene/protein level)
Oxygen concentration
(C lt Tho) and SMAD
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Molecular mechanisms (gene/protein level)
(?n gt Tht) and APC
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Molecular mechanisms (gene/protein level)
ndsb Rfd
Thr
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Boolean gene/protein network
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Numerical procedure for solving equation (8)
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RESULTS
APCSMAD/RAS mutated
APC mutated
normal
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APC-dependent growth regulation overpopulation
leads to APC activation
and then to
quiescence
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APC-dependent growth regulation overpopulation
leads to APC activation
and then to
quiescence
early oscillations
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SMAD/RAS-dependent growth regulation (of
APC-mutated cells)
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Spatial coverage of overpopulation hypoxia
signals
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Evolution of spatial distribution of quiescent
mitotic cells
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number of cells in the apoptotic phase
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Total cell number
Apoptotic cell number
left
Right
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Mitotic cell number (fraction)
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Most critical parameters
Rf
Recall
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Effect of changing Rf
Total cell number
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uniform vs random initial cell distributions
(evolution of the overpopulation signal)