Department of Mathematics and Statistics, University of South Alabama, 307 North University Blvd # 2100, Mobile, AL.
Prostate cancer develops through a stochastic mechanism whereby pre-cancerous lesions on occasion progress to multifocal adenocarcinoma. Analysis of human benign and cancer prostate tissues revealed heterogeneous loss of TGF-ß signaling in the cancer associated stromal fibroblastic cell compartment. To test the hypothesis that prostate cancer progression is dependent on the heterogeneous TGF-ß responsive microenvironment, a tissue recombination experiment was designed where the ratio of TGF-ß responsive and nonresponsive stromal cells were varied. While 100% TGF-ß responsive stromal cells supported benign prostate growth and 100% TGF-ß non-responsive stromal cells resulted in pre-cancerous lesions, only the mixture of TGF-ß responsive and nonresponsive stromal cells resulted in adenocarcinoma. A computational model was used to resolve a mechanism of tumorigenic progression where proliferation and invasion occur in two independent steps mediated by distinct stromally derived paracrine signals produced by TGF-ß non-responsive and responsive stromal cells. Complex spatial relationships of stromal and epithelial cells were incorporated into the model based on 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. Since SDF-1 satisfied model predictions for an invasion promoting paracrine factor, a more focused computational model was subsequently used to investigate if 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 IL-1ß 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. Major FindingsA computational model was used to resolve a mechanism of prostate epithelial tumor initiation dictated by paracrine signaling. Model simulations and biological experiments supported fibroblast responsiveness to TGF-ß as an initial tumor suppressor and subsequent mediator of tumor progression. TGF-ß non-responsive stromal cells permitted the initial proliferative step. Cooperativity of both TGF-ß non-responsive and responsive stromal cells was required for the secondary invasion step. Thus, stromal heterogeneity in TGF-ß responsiveness enables a paracrine mediated tumorigenesis.
Kiskowski MA, Jackson RS 2nd, Banerjee J, Li X, Kang M, Iturregui JM, Franco OE, Hayward SW, Bhowmick NA. Are you the author?
Reference: Cancer Res. 2011 Mar 28. Epub ahead of print.