Abstract 2612: Tumor associated microvesicles confer neoplastic transformation of patient derived adipose stem cells .

Abstract

Abstract Background: Unraveling the underlying mechanisms of prostate tumor growth and metastasis is critical to developing curative therapies currently unavailable for castration-resistant prostate cancer (CRPC). Obesity has been linked to increased risks of PC progression. Emerging evidence suggests that adipose-derived stem cells (ASCs) are often recruited to and promote tumor growth via unknown mechanisms. Methods: Patient derived ASCs (pASCs) with tumor homing potential were enriched and treated with condition media (CM) or microvesicles (MVs) of PC (C4-2B, PC-3) or normal prostate epithelial (RWPE1) cells. CM or MV-primed pASCs were examined for their ability to form prostate tumors in vivo. Tumor formation was validated by histopathologic analysis, expression of neoplastic and vasculogenic markers, karyotyping and PC specific markers. LC/MS-MS, miRNA array, miRNA mimics and qRT-PCR analyses were employed to decipher the underling mechanistic roles of oncogenic RNAs and proteins of PC cell associated MVs in pASC tumor formation. Results: Herein, we report that PC cell microenvironment induces genotypic and phenotypic changes in pASCs and subverts them to undergo neoplastic transformation. Unlike normal counterparts, the pASCs primed with PC cell CM form neoplastic lesions in vivo and reproduce aggressive tumors in secondary recipients. The pASC tumors acquire cytogenetic aberrations and express epithelial, neoplastic and vasculogenic markers reminiscent of molecular features of PC tumor xenografts and mesenchymal-to-epithelial transition (MET). MVs derived from PC cell CM recapitulated prostate tumorigenic mimicry by pASCs in vivo. The oncogenic ‘reprogramming’ of pASCs is associated with PC cell-derived MVs transfer of oncomiRNAs (miR-125b, miR-130b, miR-155), H-Ras and K-Ras transcripts and Ras-related oncoproteins (RAB1A, RAB2A, RAB1B, RAB11A) and down-regulation of tumor suppressors Lats2 and PDCD4. Conclusion: Our findings establish previously uncharacterized mechanisms for tumor-derived MV-pASC axis in tumor formation, phenotypic variations in mesenchymal and epithelial states in tumor microenvironment, and in promoting tumor burden and metastasis in cancer patients. Citation Format: Zakaria Y. Abd Elmageed, Yijun Yang, Raju Thomas, Krishnarao Moparty, Manish Ranjan, Debasis Mondal, Krzysztof Moroz, Oliver Sartor, Asim B. Abdel-Mageed. Tumor associated microvesicles confer neoplastic transformation of patient derived adipose stem 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 2612. doi:10.1158/1538-7445.AM2013-2612