Abstract 5068: Differential regulation of tissue inhibitor of metalloproteinase (TIMP-1) expression in primary stromal fibroblast cells by androgen sensitive and resistant prostate cancer cells.

Abstract

Abstract Background: The tissue inhibitor of metalloproteinase 1 (TIMP-1) regulates matrix metalloproteinases (MMPs) activities and is involved in cancer invasion and metastasis. TIMP-1 level is significantly elevated in prostate cancer patient blood and the elevated plasma TIMP-1 level predicts decreased survival of metastatic castration-resistant prostate cancer (mCRPC) patients. Methods and findings: In this study, we examined serum TIMP-1 levels in 114 prostate cancer patient samples by ELISA and found mCRPC patients have significantly higher serum TIMP-1 (mean value of 373.5 ng/ml) than patients with recurrent hormone-sensitive disease (mean value of 304.8 ng/ml) (p<0.001). Then we examined TIMP-1 expression in androgen-sensitive (AS) and androgen resistant (AR) prostate cancer cell lines (LNCaP, VCaP, LAPC-4, 22RV1, DU145, PC-3 and PC-3M) and primary prostate stromal fibroblast cells (HPrF) by realtime PCR and ELISA. Our results showed that AS and AR cells regulate TIMP-1 expression differently. AS cells barely expressed any TIMP-1, whereas AR prostate cancer cells not only expressed moderate amount of TIMP-1, but also induced stromal fibroblast cells to secrete more TIMP-1. But overall, fibroblast cells secreted at least 10 times more TIMP-1 than AR prostate cancer cells, indicating that stromal fibroblasts are the major source of TIMP-1 in prostate cancer. To identify the soluble factors secreted by AR cells to induce TIMP-1 expression in HPrF, we analyzed cytokine and growth factor profiles of AR and AS cell condition medium (CM) by RayBio cytokine and growth factor arrays and found that multiple cytokines and growth factors were upregulated in AR cell line condition medium including IL-6, IL-10, GM-SCF, GRO alpha and etc. More investigation is underway to verify the roles of the cytokines and growth factors in TIMP-1 regulation in prostate cancer. In addition, using pharmaceutical inhibitors, we showed that AZD6244 (a MEK inhibitor) and BAY11-7082 (an NF-kB inhibitor) completely blocked prostate cancer cell line CM-induced TIMP-1 expression in stromal fibroblasts. Conclusion: Our studies have demonstrated that androgen resistance is associated with TIMP-1 overproduction in prostate cancer and suggested that we can potentially inhibit TIMP-1 overexpression in prostate cancer patients with MEK and NF-kB inhibitors. Citation Format: Yixuan Gong, Lan He, Matthew Galsky, William Oh. Differential regulation of tissue inhibitor of metalloproteinase (TIMP-1) expression in primary stromal fibroblast cells by androgen sensitive and resistant prostate cancer cells. [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 5068. doi:10.1158/1538-7445.AM2013-5068 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.