Abstract 405: The role of Stat3 in pre-metastatic niche formation: Examination in murine models and benign lymph nodes from prostate cancer patients

Abstract

Abstract Objectives: High-risk prostate cancer (PC) represents a heterogeneous disease, and metastatic potential varies within this subset of patients. The occurrence of metastasis involves both tumor cells and tumor-associated stromal cells. In the present study, murine models were used to examine the association between Stat3 activation and tumor-associated stromal cells. The latter may confer metastatic potential through the formation of pre-metastatic niches. These parameters were subsequently assessed in the benign lymph nodes of patients with high-risk PC. Methods: To induce pre-metastatic conditions, we injected tumor-conditioned media from murine tumor cell lines over-expressing the Stat3 activator, S1PR1, into C57BL/6 mice. Subsequently, mice were challenged with parental tumor cells via tail vein injection. For assessing a potential role of Stat3 in formation of the pre-metastatic niche, we analyzed mouse lung tissue by immunofluorescent staining and Western blot. We also increased and decreased myeloid cell Stat3 activity by retrovirus transduction and genetic ablation, respectively. For clinical correlation, paraffin-embedded lymph node tissue derived from 50 patients with high-risk PC was acquired. High-risk PC was defined by standard criteria as follows: (1) baseline prostate specific antigen (PSA) ≫ 20, (2) clinical stage T3a disease, or (3) Gleason score 8-10. Immunohistochemistry (IHC) staining was performed to assess pStat3 levels and CD68+ myeloid cell clustering. Results: In the murine models examined, increasing Stat3 activity in tumor cells by its newly identified activator, S1PR1, produced factors that activated Stat3 in lung tissue. This led to a dramatic increase in myeloid clustering and metastasis. Up-regulating Stat3 activity within myeloid cells enhanced the interaction between myeloid cells and endothelial cells in vivo, increased angiogenesis, and promoted subsequent formation of metastasis. In contrast, ablation of Stat3 in myeloid cells prevented the formation of pre-metastatic niches and metastasis. IHC staining of benign lymph node tissue in patients with high-risk PC yielded a spectrum of pStat3 levels. Higher levels of pStat3 were qualitatively associated with infiltration of CD68+ macrophages, appearing in distinct clusters. Conclusion: The current study indicates a critical role of Stat3 in promoting metastatic potential, possibly through mediating myeloid cell infiltration and formation of pre-metastatic niches. In the context of high-risk PC, differential levels of pStat3 and a potential association with myeloid cell clustering was observed. While correlation between these parameters and clinical outcome is ongoing, these preliminary findings suggest a putative role for Stat3 as a therapeutic target to prevent and/or reduce pre-metastatic niche formation and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 405. doi:10.1158/1538-7445.AM2011-405