Abstract B2-53: The significance of stromal reactivity in shaping prostate cancer evolution and the prognosis: An integrated approach
Authors: Frankenstein Ziv , Basanta David , Franco Omar , Hayward Simon , Ayala Gustavo , Anderson Alexander 
Published: May 2016

Abstract
Prostate cancer (PCa) is ranks fourth in worldwide cancer incidence. Gleason (epithelial cancer marker) is the standard metric for defining prostate cancer aggressiveness. Still, PCa is difficult to predict using available prognostic data. Stromal-tumor crosstalk, through growth factors (GFs), is known to play a major role in tumor progression, where GFs facilitate stromal activation (reactivity) to repair tissue. Reactive stroma has been correlated with tumor progression in PCa as well as in lung, breast and skin cancers. However, this interplay remains unclear and the prognostic significance of pronounced reactive stroma in prostate biopsies remains uncertain.
Here, we investigate how the interplay between stroma and tumor heterogeneity drives tumor growth, evolution and invasiveness. We used an integrated approach combining 4800 in silico simulated PCa over 20 years, a large cohort of 870 PCa patients with 20 years of follow-up (recurrence and death) with 263 clinico-pathologic parameters and biomarkers, as well as in-vivo and in-vitro experimentation. We designed a multiscale computational model that incorporates, chemical and physical properties of the microenvironment that modulate the dynamic behavior of hundreds of thousands of cells. This model was simulated on an anatomically reconstructed tissue domain that represents a large segment of the prostate where cancer occurs most frequently (peripheral zone). Each simulated tumor was initiated by seeding a heterogeneous distribution of GF producing tumor cells along with different degrees of stromal reactivity. Clinical analysis included survival models to associate covariates and information criterion with predictive model comparisons. In addition, experiments were performed combining an initiated epithelial cell line with fibroblasts from patients with pathologically-defined degrees of stromagenesis.
Our findings reveal that the complex dialogue within and between tumor, stromal and reactive stromal cell populations regulates differential tumor growth, evolution, heterogeneity and invasion. Mechanistically, selection pressure for GF producing tumor cells can be balanced by different degrees of GF found in the microenvironment. That is due to the dynamic contributions from the reactive stroma and the evolving tumor cells phenotypes. We find that a limited availability of GF leads to an increased competition that drives decreased stromal activation, growth and invasion, whilst selecting for more aggressive and heterogeneous tumor cells. On the other hand, sufficient availability of GF leads to a complex cooperative behavior, that drives increased stromal reactivity, growth and invasion, whilst selecting for less aggressive and heterogeneous tumor cells. Key to this faster invasion is the ability of stromal cells to be reactive beyond the observed tumor margin. Clinically, we identified that Gleason (with the current prostate clinico-pathologic parameters) and Reactive Stromal Grading (RSG), when combined, significantly improve predictive power. In fact, the RSG significantly stratifies all of the recurrence and death risk categories as suggested by the current Gleason Grading system. These results suggest that for patients whose biopsy shows a high RSG, the risk should be considered higher than the standard Gleason assessment. Conversely, low RSG in a patient's biopsy would imply a lower risk than the standard Gleason assessment. We conclude that the stroma surrounding PCa appears to result in significant selection pressure driving differential tumor cell aggressiveness, evolution, heterogeneity, growth and invasiveness. We show that the degree of stromal reactivity, when integrated with the current clinical in use methodology (Gleason with clinico-pathologic parameters), significantly improves PCa prognosis.
Citation Format: Ziv Frankenstein, David Basanta, Omar Franco, Simon Hayward, Gustavo Ayala, Alexander Anderson. The significance of stromal reactivity in shaping prostate cancer evolution and the prognosis: An integrated approach. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-53.