LAUSR

Tumor progression is a multifaceted process in which, complex interactions between tumor and different types of stromal cells and extracellular matrix components, actively contribute to its phenotypic heterogeneity. Among extracellular matrix proteins, secreted protein acidic and rich in cysteine (SPARC) has been deeply studied since conflicting reports have described its expression to be either increased or decreased in different cancer settings, also depending on whether it is produced by the neoplasm or by the neighboring stroma. Nevertheless, the different contribution of tumor- or stromal-derived SPARC in prostate tumor microenvironment has not been addressed at least for tumor tissue histotype. Given this evidence, we aimed at providing new insights into the mechanism by which SPARC modulation influences prostate cancer development and progression. We modeled human disease using TRAMP mice, which spontaneously develop autochthonous prostate tumors following the onset of puberty. Crossing TRAMP mice with Sparc -/- mice, we found the appearance of focal areas of neuroendocrine differentiation within adenocarcinoma. In patients this phenomenon commonly results after androgen ablation therapy and correlates with poor prognosis. Interestingly, areas of neuroendocrine differentiation in Sparc -/- TRAMP mice were both positive for cytokeratin 8 and synaptophysin (usually expressed by luminal proliferating cells within adenocarcinoma or neuroendocrine cells, respectively), further suggesting a differentiation of adenocarcinoma cells to a neuroendocrine-like phenotype. Moreover, immunohistochemistry showed SPARC positivity not only in scattered tumor cells but also in fibroblasts and myeloid cells infiltrating TRAMP prostate. Accordingly, in vitro experiments suggested that stromal-derived SPARC limits neuroendocrine differentiation of prostate cancer cells, while they excluded a role of endogenous SPARC in this phenomenon. Indeed, prostate cancer cell lines co-cultured in presence of Sparc-deficient fibroblasts increased or acquired neuroendocrine features. This likely occurs through the effect of IL-6, a cytokine recently discovered to induce neuroendocrine differentiation, and that we found to be released by Sparc-deficient, but not sufficient, fibroblasts. Data collected so far indicate that stromal SPARC deficiency skews prostate carcinogenesis toward neuroendocrine differentiation. A deeper understanding of the molecular mechanisms governing the balance between prostate adenocarcinoma and neuroendocrine tumors according to extracellular matrix composition will provide important insights for the development of new prognostic and therapeutic strategies. Citation Format: Claudia Enriquez, Valeria Cancila, Ivano Arioli, Claudio Tripodo, Mario Paolo Colombo, Elena Jachetti. Stromal SPARC deficiency skews prostate cancer toward neuroendocrine differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2141.