Published OnlineFirst October 17, 2018; DOI: 10.1158/0008-5472.CAN-18-0345 Cancer Review Research Glioma Cell Secretion: A Driver of Tumor Progression and a Potential Therapeutic Target Damian A. Almiron Bonnin1,2, Matthew C. Havrda1,2, and Mark A. Israel1,2,3 Abstract Cellular secretion is an important mediator of cancer progres- ple oncogenic pathologies. In this review, we describe tumor cell sion. Secreted molecules in glioma are key components of secretion in high-grade glioma and highlight potential novel complex autocrine and paracrine pathways that mediate multi- therapeutic opportunities. Cancer Res; 78(21); 6031–9. Ó2018 AACR. Introduction Glioma-Secreted Molecules Impact Disease Glial cells in the central nervous system (CNS) provide trophic Progression support for neurons (1). In glial tumors, this trophic support is Glioma cells modify their microenvironment by introducing dysregulated creating a pro-oncogenic microenvironment medi- diverse molecules into the extracellular space (Table 1). To exem- ated by a heterogeneous array of molecules secreted into the plify the pro-oncogenic role that secreted molecules can have on – extracellular space (2 15). The glioma secretome includes pro- glioma pathology, we review the functional impact of specific teins, nucleic acids, and metabolites that are often overexpressed cytokines, metabolites, and nucleic acids on glioma biology. By in malignant tissue and contribute to virtually every aspect of describing some of the potent antitumorigenic effects observed in – cancer pathology (Table 1; Fig. 1; refs. 2 15), providing a strong preclinical therapeutic studies targeting tumor cell secretion, we – rationale to target the cancer cell secretory mechanisms. also highlight how blocking secreted molecules might be of fi Although the speci c mechanisms regulating secretion in therapeutic impact in gliomas, as well as other tumors. malignant cells remain to be fully characterized, there is signif- icant evidence that the secretory mechanisms themselves are Cytokines altered during oncogenesis (8, 16–36). Well-known mediators Cytokines are essential mediators of cellular signaling (2, 13, of secretion, like the ADP-ribosylation factors (ARF) and the small 15). In glioma, secreted cytokines, including IL1b, IL6, and IL8, Rab GTPase proteins (RAB) have been reported to be dysregulated create a state of chronic inflammation that promotes the malig- in glioma and several other tumors (17, 20, 22, 28, 31, 32, 37–41). nant phenotype (15). These cytokines are associated with poor These proteins facilitate secretion of pro-oncogenic molecules prognosis for patients with high-grade gliomas (HGG; refs. 2, 13, (28, 42) and their inhibition diminishes multiple aspects of 15). Both in vitro and in vivo studies demonstrate that targeting cancer pathology including cellular proliferation, survival, and these mediators of inflammation inhibits important aspects of invasion (20, 22, 28, 32, 37–39, 41, 42), while showing no signs glioma pathology including angiogenesis, proliferation, and inva- of obvious toxicities in animal models (18, 19, 21, 26, 36, 43–46). sion (2, 13, 15). It has also been shown that cytokines, like IL6, This reliance of cancer cells on secretory pathways is exemplified IL8, EGF, and TGFb, promote resistance to antineoplastic therapy by the unfolded protein response (UPR; ref. 18). UPR activation is in glioma (15, 24, 47, 48), breast (49), and prostate cancer (50). In thought to be crucial for oncogenic progression (18), and agents melanoma, secretion has been identified as an important mech- inhibiting the UPR have shown potent antitumorigenic effects in anism facilitating the emergence of drug resistance via the acti- models of glioma, multiple myeloma, and pancreatic cancer (18). vation of the AKT pathway (51). Importantly, these cytokines also Tumor cell secretory "addiction" describes the dependence of facilitate the maintenance of cancer stem cells (Table 1; ref. 15), tumor cells on secretory pathways like the UPR (18), and suggest which are largely refractory to therapy, and play an important role a potential therapeutic window to target these pathways. The in cancer progression (52). functional impact of secreted molecules and secretory pathways Platelet-derived growth factor (PDGF), one of the best charac- on glioma biology underscores the potential therapeutic implica- terized cytokines in HGGs and other cancers (2, 13, 53–55), is the tions of targeting the tumor cell secretion (Table 1). ideal example to illustrate the functional impact of cytokines on cancer biology. Autocrine PDGF signaling was determined to play 1Department of Molecular and Systems Biology, Geisel School of Medicine at an important role in malignant transformation (2), and mouse Dartmouth, Hanover, New Hampshire. 2Norris Cotton Cancer Center, Geisel models of HGG demonstrate that PDGF signaling is sufficient for School of Medicine at Dartmouth, Lebanon, New Hampshire. 3Departments of tumor initiation and progression (13, 54). Dysregulated PDGF Medicine and Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, New signaling activates MAPK-ERK and PI3K-AKT, two nodal points Hampshire. critical for cell proliferation, resistance to apoptosis, and invasion Corresponding Author: Mark A. Israel, M.D., Norris Cotton Cancer Center at (10, 12, 56). PDGF-mediated PI3K/AKT activation has also been Dartmouth, One Medical Center Drive, Lebanon, NH 03756. Phone: 603-653- shown to regulate glucose metabolism facilitating the Warburg 3611; Fax: 603-653-9003; E-mail: [email protected] effect in HGGs (12). In vitro and in vivo studies confirm PDGF's doi: 10.1158/0008-5472.CAN-18-0345 recognized function enhancing tumor angiogenesis by stimulat- Ó2018 American Association for Cancer Research. ing endothelial cell migration and promoting endothelial cell www.aacrjournals.org 6031 Downloaded from cancerres.aacrjournals.org on October 6, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 17, 2018; DOI: 10.1158/0008-5472.CAN-18-0345 Almiron Bonnin et al. Table 1. Glioma-secreted molecules and the hallmarks of cancer they affect Secreted molecules functional in glioma Impacted hallmark of cancer Platelet-derived growth factor (2, 116), hepatocyte growth factor (56, 117), insulin-like growth factor (56, 118), Sustaining proliferative transforming growth factor a (119), adrenomedullin (120), epidermal growth factor receptor variant III (121), signaling sphingosine-1-phosphate (122) microRNA-17 (14, 123), microRNA-19 (14, 123), microRNA-21 (14, 123), microRNA-24 (123, 124), microRNA-26a (14, 123), Evading growth suppression microRNA-221/222 (123, 124) Transforming growth factor b2 (125), interleukin-10 (126), kynurenine (11), lactate dehydrogenase (14, 127), osteopontin (128) Avoiding immune destruction Vascular endothelial growth factor (43), basic fibroblast growth factor (5, 14), interleukin-6 (15, 129), interleukin-8 (15, 130), Enabling replicative C-X-C motif chemokine ligand 12 (131, 132), gremlin 1 (133), sema 3C (134), periostin (135, 136), sphingosine-1-phosphate immortality/ stemness (122), telomerase reverse transcriptase transcript (14), transferrin (137) Tumor necrosis factor a (138), interleukin-1b (138), interleukin-6 (15, 129), interleukin-8 (15, 139), glutamate (140) Tumor-promoting inflammation Transforming growth factor a (6, 119), hepatocyte growth factor (117), EGF (6), periostin (135, 136), osteopontin (128), C-X-C Activating invasion and motif chemokine ligand 12 (131), glial cell–derived neurotrophic factor (141), urokinase-type plasminogen activator metastasis (142), protease nexin 1 (143), metalloproteinase 2 (144), metalloproteinase 9 (144), autotaxin (145), kynurenine (11), glutamate (146), versican (147), laminins (148), metastasis-associated lung adenocarcinoma noncoding RNA (14, 149), sphingosine-1-phosphate (6, 122), microRNA-20a (14, 123), microRNA-21 (14, 123) Vascular endothelial growth factor (14), TGFb2 (125, 150), fibroblast growth factor (14, 150), hepatocyte growth factor Inducing angiogenesis (117, 150), epidermal growth factor (6, 150), interleukin-6 (15, 129), interleukin-8 (15, 138), C-X-C motif chemokine ligand 12 (151), angiogenin (14, 152), platelet-derived growth factor (116, 150) Kynurenine (4, 11), human endogenous retrovirus retrotransponson (3, 153), long interspersed nuclear element 1 Genome instability retrotransponson (3, 154), arthrobacter luteus (Alu) retrotransponson (3, 155) Vascular endothelial growth factor (14, 56), fibroblast growth factor (5, 14, 56), epidermal growth factor (6, 56), interleukin-6 Resisting cell death (15, 129), Sema 3C (134), microRNA-21 (14, 123), microRNA-92 (14, 123) Platelet derived growth factor (12, 116, 156), vascular endothelial growth factor (14, 156), fibroblast growth factor (14, 156), Deregulating cellular energetics hepatocyte growth factor (117, 156), epidermal growth factor (6, 156) proliferation (2). Consistent with these findings, disrupting PDGF of disease progression (62). In glioma and other tumors, signaling markedly reduces angiogenesis, tumor growth, and nucleic acids can be secreted in extracellular vesicles (EV) and invasion in multiple mouse models of glioma (2, 10, 12, 13). deliveredtonearbycells(3,7,9, 14). EVs can carry mutated or amplified oncogene sequences, mRNA, transposable elements, Metabolites ormiRNAs(7,9,14).EVsfromHGGcontainanarrayofpro- Malignant cells reprogram their metabolism to meet the bio- oncogenic miRNAs such as miR-19b, miR-20, and miR-21 that energetic