Abstract B23: Further defining reactive stroma in prostate cancer

Abstract

Abstract Quiescent fibroblasts and smooth muscle make up the mesenchymally-derived component of normal human stroma and function to maintain tissue homeostasis by forming a reactive stroma phenotype in the presence of injury. Reactive stroma initiates early during the evolution of human prostate cancer, with foci being observed during premalignant prostatic intraepithelial neoplasia (PIN). This microenvironment response is characterized by an accumulation of vimentin positive cells that co-express several reactive stroma markers. Reactive stroma co-evolves with development of cancer foci and is typified by accumulation of myofibroblasts that express tenascin-C and pro-collagen I. Our previous studies have shown that the degree of reactive stroma is a significant predictor of biochemical recurrent disease (elevation of PSA) using either archival prostatectomy specimens or pre-operative needle biopsy material. Patients with grade 3 exhibit a significantly reduced time to biochemical recurrent disease. Moreover, we have shown significant differences in gene expression profiles in human reactive stroma grade 3 relative to normal human prostate stroma. Our previous studies have shown that reactive stroma is tumor-promoting in prostate cancer models. TGF-β has emerged as a key factor in mediating the microenvironment perturbations in a variety of cancers, however its corresponding role in reactive stroma initiation has not been examined. It is our hypothesis that prostate cancer reactive stroma is composed of myofibroblasts / CAFs and is induced from tissue-fixed and/or bone marrow derived cells (BMDCs) in a TGF-β dependent manner. Our data shows that foci of reactive stroma in human prostate cancer consist of CD34+/vimentin+ progenitor cells that are juxtaposed to the sub basal lamina surface at the stromal-epithelial junction. Bone marrow transplants with CFP reporter donors into athymic mice containing LNCaP xenografts shows a time dependent increase in recruited fibroblast-like cells of marrow origin. Mechanistic studies using a transgenic mouse overexpressing TGF-β in prostatic epithelium demonstrate foci of inflammation in nerve ganglia and vessel structures. These mice also display distinct stromal proliferative lesions reminiscent of changes seen in a subtype of human prostate cancer. These histopathological changes occur in an age-dependent manner and seem to become more prevalent after a year of age in transgenic mice. Further mechanistic studies examining TGF-β signaling and the role of BMDCs are underway to examine reactive stroma induction and progression in prostate cancer. We propose a model of reactive stroma potential, affected by activation of local progenitors and subsequent recruitment of circulating progenitors to initiate and sustain a reactive microenvironment adjacent to cancer foci. We also propose that this microenvironment is selective for more aggressive cancer phenotypes and therefore is a potential target of opportunity for more advanced prognostics and novel therapeutics. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B23