Review Glioma Cell Secretion: A Driver of Tumor Progression and a Potential Therapeutic Target Damian A. Almiron Bonnin 1,2 , Matthew C. Havrda 1,2 , and Mark A. Israel 1,2,3 Abstract Cellular secretion is an important mediator of cancer progres- sion. Secreted molecules in glioma are key components of complex autocrine and paracrine pathways that mediate multi- ple oncogenic pathologies. In this review, we describe tumor cell secretion in high-grade glioma and highlight potential novel therapeutic opportunities. Cancer Res; 78(21); 6031–9. Ó2018 AACR. Introduction Glial cells in the central nervous system (CNS) provide trophic support for neurons (1). In glial tumors, this trophic support is dysregulated creating a pro-oncogenic microenvironment medi- ated by a heterogeneous array of molecules secreted into the extracellular space (2–15). The glioma secretome includes pro- teins, nucleic acids, and metabolites that are often overexpressed in malignant tissue and contribute to virtually every aspect of cancer pathology (Table 1; Fig. 1; refs. 2–15), providing a strong rationale to target the cancer cell–secretory mechanisms. Although the specific mechanisms regulating secretion in malignant cells remain to be fully characterized, there is signif- icant evidence that the secretory mechanisms themselves are altered during oncogenesis (8, 16–36). Well-known mediators of secretion, like the ADP-ribosylation factors (ARF) and the small Rab GTPase proteins (RAB) have been reported to be dysregulated in glioma and several other tumors (17, 20, 22, 28, 31, 32, 37–41). These proteins facilitate secretion of pro-oncogenic molecules (28, 42) and their inhibition diminishes multiple aspects of cancer pathology including cellular proliferation, survival, and invasion (20, 22, 28, 32, 37–39, 41, 42), while showing no signs of obvious toxicities in animal models (18, 19, 21, 26, 36, 43–46). This reliance of cancer cells on secretory pathways is exemplified by the unfolded protein response (UPR; ref. 18). UPR activation is thought to be crucial for oncogenic progression (18), and agents inhibiting the UPR have shown potent antitumorigenic effects in models of glioma, multiple myeloma, and pancreatic cancer (18). Tumor cell secretory "addiction" describes the dependence of tumor cells on secretory pathways like the UPR (18), and suggest a potential therapeutic window to target these pathways. The functional impact of secreted molecules and secretory pathways on glioma biology underscores the potential therapeutic implica- tions of targeting the tumor cell secretion (Table 1). Glioma-Secreted Molecules Impact Disease Progression Glioma cells modify their microenvironment by introducing diverse molecules into the extracellular space (Table 1). To exem- plify the pro-oncogenic role that secreted molecules can have on glioma pathology, we review the functional impact of specific cytokines, metabolites, and nucleic acids on glioma biology. By describing some of the potent antitumorigenic effects observed in preclinical therapeutic studies targeting tumor cell secretion, we also highlight how blocking secreted molecules might be of therapeutic impact in gliomas, as well as other tumors. Cytokines Cytokines are essential mediators of cellular signaling (2, 13, 15). In glioma, secreted cytokines, including IL1b, IL6, and IL8, create a state of chronic inflammation that promotes the malig- nant phenotype (15). These cytokines are associated with poor prognosis for patients with high-grade gliomas (HGG; refs. 2, 13, 15). Both in vitro and in vivo studies demonstrate that targeting these mediators of inflammation inhibits important aspects of glioma pathology including angiogenesis, proliferation, and inva- sion (2, 13, 15). It has also been shown that cytokines, like IL6, IL8, EGF, and TGFb, promote resistance to antineoplastic therapy in glioma (15, 24, 47, 48), breast (49), and prostate cancer (50). In melanoma, secretion has been identified as an important mech- anism facilitating the emergence of drug resistance via the acti- vation of the AKT pathway (51). Importantly, these cytokines also facilitate the maintenance of cancer stem cells (Table 1; ref. 15), which are largely refractory to therapy, and play an important role in cancer progression (52). Platelet-derived growth factor (PDGF), one of the best charac- terized cytokines in HGGs and other cancers (2, 13, 53–55), is the ideal example to illustrate the functional impact of cytokines on cancer biology. Autocrine PDGF signaling was determined to play an important role in malignant transformation (2), and mouse models of HGG demonstrate that PDGF signaling is sufficient for tumor initiation and progression (13, 54). Dysregulated PDGF signaling activates MAPK-ERK and PI3K-AKT, two nodal points critical for cell proliferation, resistance to apoptosis, and invasion (10, 12, 56). PDGF-mediated PI3K/AKT activation has also been shown to regulate glucose metabolism facilitating the Warburg effect in HGGs (12). In vitro and in vivo studies confirm PDGF's recognized function enhancing tumor angiogenesis by stimulat- ing endothelial cell migration and promoting endothelial cell 1 Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. 2 Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. 3 Departments of Medicine and Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Corresponding Author: Mark A. Israel, M.D., Norris Cotton Cancer Center at Dartmouth, One Medical Center Drive, Lebanon, NH 03756. Phone: 603-653- 3611; Fax: 603-653-9003; E-mail: Mark.A.Israel@Dartmouth.edu doi: 10.1158/0008-5472.CAN-18-0345 Ó2018 American Association for Cancer Research. Cancer Research www.aacrjournals.org 6031 on April 25, 2020. © 2018 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst October 17, 2018; DOI: 10.1158/0008-5472.CAN-18-0345