Abstract A080: Caveolin-1 detected in tumor-derived exosomes induces cancer stem cell phenotypes in castration-resistant prostate cancer

Prostate cancer (PCa) is by far the most common male malignancy and the third leading cause of cancer-related death in the US. Regardless of a great response of hormonal therapy for metastatic PCa patients, eventually PCa relapses to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Although introducing newer androgen receptor (AR) pathway inhibitors is encouraging, treatment resistance in CRPC continues to remain a clinical problem. Clinical evidence of treatment resistant CRPC indicates carcinoma cell undergoing transdifferentiation. However, the mechanism as well as cell lineage are not fully characterized, which highlights an unmet clinical need to uncover potential therapeutic targets for targeted therapy to improve the overall survival of CRPC patients. Exosome is characterized as nano-grade small extracellular vesicle derived from the endosomal system from many kinds of cells. Therefore, exosome can carry many kinds of message molecules as a delivery vehicle in a paracrine or endocrine manner. Overall, tumor-derived exosomes (TDE) has been shown to play a critical role in promoting cancer progression or drug resistance. Our recent data have shown that TDE from PCa cells is able to induce neuroendocrine differentiation of CRPC, which leads us to further elucidate the role of PCa-derived exosome. Previously by using xenograft model, we have reported that elevated caveolin-1 (Cav-1) in LNCaP cell can accelerate its tumor growth but also increase the tumor incidence of low tumorigenic cells in a paracrine manner, implying that Cav-1 can be secreted extracellualrly. However, the functional role of secreted Cav-1 in PCa is still being debated. The expression of Cav-1 was considered to function as a suppressor of cell transformation and as preventing the development and metastases of mammary tumor; on the other hand, Cav-1 served as an oncogene that correlates with PCa progression. Furthermore, recent studies have shown that Cav-1 expression is associated with chemoresistance in multiple cancers as well as cancer stem cell (CSC) property in lung cancer. CSC theory has raised significant attention in recent years because of its self-renewal and quiescent nature, which underlies its role as a cancer-initiating cell population responsible for recurrent tumor with treatment resistance. In this study, we purified TDE from various PCa cell lines including either Cav-1 positive (Cav-1High) or negative (Cav-1low) cells using membrane-based affinity chromatography, and further characterized its size and number using Zetaview (Particle Matrix, Mebane, NC) and Exocet quantitation kit (SBI, Palo Alto, CA) separately. We found that TDE derived from metastatic PCa cells without AR expression is capable of inducing CSC phenotypes in AR-expressing recipient cells. Further analyses demonstrated that the high accumulation of Cav-1 in TDE appears to be a potential candidate. Indeed, Cav-1High cells or exogenous Cav-1-treated PCa cell lines can increase CSC phenotypes in vitro and in vivo. Mechanistically, the presence of Cav-1 is able to increase stem cell transcription Yamanaka factors, including KLF4, SOX2, OCT4, and Nanog. Furthermore, from microarray screening, we found RPC32 as another potential Cav-1 downstream effector, which is characterized as a subunit of RNA polymerase III (Pol III). RPC32 has two different isoforms (α and β), and only RPC32α is known to be highly regulated and expressed in stem cell and transformed cells. Therefore, we hypothesize that RPC32α is responsible for the elevated Yamanaka factors protein expression leading to CSC development. Nevertheless, we conclude that the presence of Cav-1 in PCa TDE plays an inductive role in the appearance of treatment-resistant CRPC in a paracrine manner, which provides a potential prognostic marker and therapeutic target. Citation Format: Chun-Jung Lin, Andrew Dang, Elizabeth Hernandez, Jer-Tsong Hsieh. Caveolin-1 detected in tumor-derived exosomes induces cancer stem cell phenotypes in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A080.