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 cancer.

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 phenotype. The mathematical model tested the viability of this 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 2.

Kiskowski, 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.