Abstract 1428: Necessary contribution of wild-type stroma to prostate tumorigenesis

Introduction: A previously described mouse model, Tgfbr2-fspKO, with a conditional stromal knockout of the TGF-beta type II receptor (Tgfbr2), developed prostatic intra-epithelial neoplasia (PIN) lesions and subsequently progressed to prostate adenocarcinoma. Tissue recombination of wild-type (WT) prostatic organoids with 100% Tgfbr2-floxE2/floxE2 prostatic stroma resulted in grafts with normal prostatic glandular architecture, whereas recombination with 100% Tgfbr2-fspKO stroma resulted in grafts with PIN lesions. Interestingly, only grafts made with a mixture of WT and KO stroma resulted in prostatic adenocarcinoma. Furthermore, loss of stromal Tgfbr2 expression occurs in a proportion of human prostate cancer tissues. The objective of the study was to elucidate the mechanism(s) contributing to the cancer progression in the context of a mixed heterogeneous stroma. Method: Prostate stromal-epithelial interactions were described by a hybrid computational model involving a hypothesized 2-step mechanism (initial transformation followed by invasion), where these steps are controlled by stromal-derived paracrine morphogenic factors. Biological parameters for the candidate morphogens (Wnt3a and SDF-1/CXCL12) were assessed by qPCR and ELISA from stromal mixing co-culture experiments. Results: Modeling indicated that the expression of the initiating morphogen increases as a function of the % of Tgfbr2-KO stromal cells. The incidence of invasion promoted by the pro-invasive morphogen was biphasic with a 50/50 mixture of WT and Tgfbr2-KO stromal cells resulting in maximal cancer progression. Wnt3a is produced at 4-fold higher levels in Tgfbr2-KO vs WT stroma and antibody mediated depletion of Wnt3a from stromal conditioned media reduced the growth rate of LNCaP cells. SDF-1 is produced at nearly 4-fold higher levels in WT vs. Tgfbr2-KO stroma and SDF-1 mRNA expression is synergistically increased when WT and Tgfbr2-KO stroma are co-cultured. Additionally, CD90 expression is heterogeneously expressed by stromal tissues associated with primary human prostate cancer as compared to benign tissue as demonstrated by immunofluorescence staining. Conclusions: The model and data support the importance of stromal heterogeneity in the development of prostatic adenocarcinoma in two independent tumorigenic steps. Each step is facilitated by a different stromal component, so that stromal heterogeneity results in the maximal tumorigenesis. Tgfbr2-KO stromal cells produce an altered cytokine profile that drives the proliferation of the epithelial compartment and likely primes the WT stromal cells to produce additional cytokines, like SDF-1, that promote epithelial invasion and cancer progression. While most studies tend to focus on the altered stroma, this study suggests that the WT stroma cells play a necessary and important role required as a rate-limiting step for prostate cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1428.