Abstract 4805: The role of exosomes in fibrosarcoma progression (2017)

Abstract Among pediatric cancers, sarcomas, especially those with large tumor burdens and metastatic disease, often result in poor outcome. Thus, new treatments are urgently needed to inhibit tumor progression, prevent metastasis, and improve overall survival. To understand the mechanisms driving sarcoma progression, we employed two mouse fibrosarcoma cell lines that display different growth phenotypes when transplanted into syngeneic immune competent mice. Progressor fibrosarcomas evade detection by the immune system and develop large tumor burdens, while regressor fibrosarcomas regress shortly after a period of limited tumor growth. This difference in the growth phenotype is mediated in part by immune cells, but the mechanisms by which progressor and regressor cells influence immune cell activity are not fully elucidated. Our research has focused on exosomes, 50-100 nm secreted nanovesicles, that contain bioactive cargoes and have emerged as mediators of intercellular communication between various cells. Here, we hypothesize that fibrosarcoma exosomes determine the aggressiveness of the disease by either educating tumor cells themselves or altering interactions with host cells. To investigate the role of fibrosarcoma exosomes, we first educated regressor tumor cells with progressor exosomes for 3 weeks in vitro, and vice versa. Upon in vivo inoculation, progressor cells conditioned with regressor cell-derived exosomes grew significantly slower compared to untreated progressor cells. In contrast, regressor cells educated with progressor exosomes did not regress and overgrew significantly compared to untreated regressor cells. These results indicate that exosomes have an ability to reprogram a tumor phenotype. To determine if fibrosarcoma exosomes specifically impact the host, we evaluated whether conditioning naïve mice with progressor exosomes alters in vivo growth of regressor tumor cells injected after three weeks of education. Twenty percent of regressor tumors continued to grow following progressor exosome education, while all tumors regressed in the control PBS group. These data suggest that exosomes also play an important role in the interaction with the host cells influencing tumor growth and disease progression. Next, to determine which exosomal cargo may mediate these effects, we sought to characterize the proteome of exosomes from progressor and regressor cells using mass spectrometry. We found basigin, also known as CD147, a transmembrane embryonic glycoprotein reported to regulate cell proliferation, tumor migration and metastasis as one of the candidate proteins highly expressed in progressor-derived exosomes. We conclude that exosomes derived from fibrosarcoma progresssors and regressors can alter the tumor phenotype both directly and indirectly. Exosomal cargo, such as basigin, may mediate the aggressive behavior of tumor cells, making it a potential therapeutic target to inhibit fibrosarcoma progression. Citation Format: Miho Nakajima, Stephen C. Searles, Ayuko Hoshino, Katherine M. Offer, Candia M. Kenific, Jack D. Bui, David C. Lyden. The role of exosomes in fibrosarcoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4805. doi:10.1158/1538-7445.AM2017-4805