Modeling Prostate Tumorigenesis
An intriguing set of experimental observations:
In a set of tissue recombination experiments,
different ratios of normal and cancer-associated stromal cells were grafted
on a mouse.
100% normal stromal cells resulted
in normal growth
100% altered stromal cells resulted
in precancerous lesions
…but only the 50-50% mix resulted in
Modeling is used to vet a two-step mechanism for tumorigenesis:
We hypothesized a two-step mechanism for tumorigenesis: in the first step, altered stromal cells
contribute to initiating epithelial
transformation and in the second step, normal stromal cells
contribute to the progression of initiated epithelia to an invasive
The mathematical model tested the viability of
proposed mechanism by simulating the diffusion of
factors between epithelial and stromal compartments.
Altered stromal cells, which are not responsive to TGFß, permit the first step (AàB) that
is usually suppressed by TGFß . Normal stromal cells then, counter-intuitively,
permit the second step and progression to cancer.
Spatial relationships of stromal and epithelial cells around prostate
ducts were incorporated within the model:
Epithelial cells line the prostate duct while
different types of stromal cells lie in the regions separating the ducts.
Cell positions within the computation model were informed from the
positions of cells within a 2D allograft cross-section.
The model indicated ranges for the relative production
of paracrine factors by each cell type and provided
bounds for the diffusive range of the molecules.
These model-generated parameters may be used to screen
potential stromal factors. For example, we found that
experimentally measured properties of Wnt-3a were
not consistent with the initializing factor in
Step 1 for such a mechanism, whereas properties of SDF-1
were consistent with the progressive factor in Step
M.A., R. Jackson 2nd, R., J. Banerjee, M. Kang, O. Franco, S.
Hayward, and N. Bhowmick, 2011. Role for Stromal Heterogeneity
in Prostate Tumorigenesis, Cancer Research, 71 3459-70.