Abstract 4092: Identifying the role of TGFβ in osteogenic prostate cancer to bone metastases; an integrated biological/mathematical modeling study.
Authors: Cook Leah M. , Araujo Arturo , Basanta David , Lynch Conor C. 
Published: August 2014

Approximately 90% of patients that succumb to prostate cancer will have evidence of bone metastasis. Prostate to bone metastases are incurable with patients often experiencing intense pain. In bone, prostate cancer cells derive factors necessary for growth and survival by manipulating bone forming osteoblasts and bone resorbing osteoclasts, resulting in areas of excessive bone formation/osteogenesis and osteolysis, respectively. Our group and others have defined transforming growth factor beta (TGFβ) as being a key factor in the progression of bone metastases. Therapeutic inhibition of TGFβ however, presents a dilemma since TGFβ can have differential effects on various cell types in the tumor-bone microenvironment. Furthermore, the straightforward nature of current biological assays does not accurately reflect the complexity of a heterogeneous tumor and the potential impact that TGFβ inhibition may have on other cellular components, either individually or in tandem. Our in vitro experimental results show that prostate cancer-derived conditioned media promotes osteoblast migration in a TGFβ-dependent manner and also stimulates osteoblast proliferation, suggesting that TGFβ may play a role in prostate tumor-induced osteogenesis. Using an osteogenic intratibial PAIII model, we have observed that inhibition of TGFβ prevented prostate cancer progression in bone. To determine the mechanism, an integrated approach where experimental results inform a predictive mathematical model, allowing for exploration of complex interactions mediated by TGFβ. Our model is based on the evolutionary game theory (EGT) paradigm where the interactions between key cell types and their role on the evolutionary dynamics of the tumor can be studied. We consider a heterogeneous tumor made of three subpopulations: TGFβ ligand- and receptor-producing cells, TGFβ receptor producing, and TGFβ independent, and also incorporates resident stromal cells – osteoblasts and osteoclasts. Crucially, the fitness of each of cell type as mediated by TGFβ can readily be explored. This model suggests that TGFβ inhibition can hinder tumor growth but, in some instances, can lead to tumors that become less reliant on TGFβ. However, TGFβ inhibition may prevent prostate cancer-induced osteogenesis/osteolysis by regulation of osteoblast/osteoclast precursor recruitment. Histological analyses will determine the robustness of the mathematical approach and the impact of TGFβ inhibition on the tumor-bone microenvironment. The goal of these studies is to develop a method to predict the efficacy of therapeutically targeting TGFβ in prostate to cancer bone metastases.

Citation Format: Leah M. Cook, Arturo Araujo, David Basanta, Conor C. Lynch. Identifying the role of TGFβ in osteogenic prostate cancer to bone metastases; an integrated biological/mathematical modeling study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4092. doi:10.1158/1538-7445.AM2013-4092