Role for Stromal Heterogeneity in Prostate Tumorigenesis

Prostate cancer develops through a stochastic mechanism whereby precancerous lesions on occasion progress to multifocal adenocarcinoma. Analysis of human benign and cancer prostate tissues revealed heterogeneous loss of TGF-beta signaling in the cancer-associated stromal fibroblastic cell compartment. To test the hypothesis that prostate cancer progression is dependent on the heterogeneous TGF-beta responsive microenvironment, a tissue recombination experiment was designed in which the ratio of TGF-beta responsive and nonresponsive stromal cells was varied. Although 100% TGF-beta responsive stromal cells supported benign prostate growth and 100% TGF-beta nonresponsive stromal cells resulted in precancerous lesions, only the mixture of TGF-beta responsive and nonresponsive stromal cells resulted in adenocarcinoma. A computational model was used to resolve a mechanism of tumorigenic progression in which proliferation and invasion occur in two independent steps mediated by distinct stromally derived paracrine signals produced by TGF-beta nonresponsive and responsive stromal cells. Complex spatial relationships of stromal and epithelial cells were incorporated into the model on the basis of experimental data. Informed by incorporation of experimentally derived spatial parameters for complex stromal-epithelial relationships, the computational model indicated ranges for the relative production of paracrine factors by each cell type and provided bounds for the diffusive range of the molecules. Because SDF-1 satisfied model predictions for an invasion-promoting paracrine factor, a more focused computational model was subsequently used to investigate whether SDF-1 was the invasion signal. Simulations replicating SDF-1 expression data revealed the requirement for cooperative SDF-1 expression, a prediction supported biologically by heterotypic stromal interleukin-1 beta signaling between fibroblastic cell populations. The cancer stromal field effect supports a functional role for the unaltered fibroblasts as a cooperative mediator of cancer progression. Cancer Res; 71(10); 3459-70. (C) 2011 AACR.