Cellular secretion is an important mediator of cancer progression. Secreted molecules in glioma are key components of complex autocrine and paracrine pathways that mediate multiple 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. ©2018 AACR.

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 mediated by a heterogeneous array of molecules secreted into the extracellular space (2–15). The glioma secretome includes proteins, 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.

Table 1.

Glioma-secreted molecules and the hallmarks of cancer they affect

Secreted molecules functional in gliomaImpacted hallmark of cancer
Platelet-derived growth factor (2, 116), hepatocyte growth factor (56, 117), insulin-like growth factor (56, 118), transforming growth factor α (119), adrenomedullin (120), epidermal growth factor receptor variant III (121), sphingosine-1-phosphate (122) Sustaining proliferative signaling 
microRNA-17 (14, 123), microRNA-19 (14, 123), microRNA-21 (14, 123), microRNA-24 (123, 124), microRNA-26a (14, 123), microRNA-221/222 (123, 124) Evading growth suppression 
Transforming growth factor β2 (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), C-X-C motif chemokine ligand 12 (131, 132), gremlin 1 (133), sema 3C (134), periostin (135, 136), sphingosine-1-phosphate (122), telomerase reverse transcriptase transcript (14), transferrin (137) Enabling replicative immortality/ stemness 
Tumor necrosis factor α (138), interleukin-1β (138), interleukin-6 (15, 129), interleukin-8 (15, 139), glutamate (140) Tumor-promoting inflammation 
Transforming growth factor α (6, 119), hepatocyte growth factor (117), EGF (6), periostin (135, 136), osteopontin (128), C-X-C motif chemokine ligand 12 (131), glial cell–derived neurotrophic factor (141), urokinase-type plasminogen activator (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) Activating invasion and metastasis 
Vascular endothelial growth factor (14), TGFβ2 (125, 150), fibroblast growth factor (14, 150), hepatocyte growth factor (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) Inducing angiogenesis 
Kynurenine (4, 11), human endogenous retrovirus retrotransponson (3, 153), long interspersed nuclear element 1 retrotransponson (3, 154), arthrobacter luteus (Alu) retrotransponson (3, 155) Genome instability 
Vascular endothelial growth factor (14, 56), fibroblast growth factor (5, 14, 56), epidermal growth factor (6, 56), interleukin-6 (15, 129), Sema 3C (134), microRNA-21 (14, 123), microRNA-92 (14, 123) Resisting cell death 
Platelet derived growth factor (12, 116, 156), vascular endothelial growth factor (14, 156), fibroblast growth factor (14, 156), hepatocyte growth factor (117, 156), epidermal growth factor (6, 156) Deregulating cellular energetics 
Secreted molecules functional in gliomaImpacted hallmark of cancer
Platelet-derived growth factor (2, 116), hepatocyte growth factor (56, 117), insulin-like growth factor (56, 118), transforming growth factor α (119), adrenomedullin (120), epidermal growth factor receptor variant III (121), sphingosine-1-phosphate (122) Sustaining proliferative signaling 
microRNA-17 (14, 123), microRNA-19 (14, 123), microRNA-21 (14, 123), microRNA-24 (123, 124), microRNA-26a (14, 123), microRNA-221/222 (123, 124) Evading growth suppression 
Transforming growth factor β2 (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), C-X-C motif chemokine ligand 12 (131, 132), gremlin 1 (133), sema 3C (134), periostin (135, 136), sphingosine-1-phosphate (122), telomerase reverse transcriptase transcript (14), transferrin (137) Enabling replicative immortality/ stemness 
Tumor necrosis factor α (138), interleukin-1β (138), interleukin-6 (15, 129), interleukin-8 (15, 139), glutamate (140) Tumor-promoting inflammation 
Transforming growth factor α (6, 119), hepatocyte growth factor (117), EGF (6), periostin (135, 136), osteopontin (128), C-X-C motif chemokine ligand 12 (131), glial cell–derived neurotrophic factor (141), urokinase-type plasminogen activator (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) Activating invasion and metastasis 
Vascular endothelial growth factor (14), TGFβ2 (125, 150), fibroblast growth factor (14, 150), hepatocyte growth factor (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) Inducing angiogenesis 
Kynurenine (4, 11), human endogenous retrovirus retrotransponson (3, 153), long interspersed nuclear element 1 retrotransponson (3, 154), arthrobacter luteus (Alu) retrotransponson (3, 155) Genome instability 
Vascular endothelial growth factor (14, 56), fibroblast growth factor (5, 14, 56), epidermal growth factor (6, 56), interleukin-6 (15, 129), Sema 3C (134), microRNA-21 (14, 123), microRNA-92 (14, 123) Resisting cell death 
Platelet derived growth factor (12, 116, 156), vascular endothelial growth factor (14, 156), fibroblast growth factor (14, 156), hepatocyte growth factor (117, 156), epidermal growth factor (6, 156) Deregulating cellular energetics 
Figure 1.

Schematic representation of the impact of glioma secretion on the hallmarks of cancer. Pro-oncogenic molecules can be transported through the plasma membrane by classical secretory mechanisms, nonclassical secretory mechanisms (type I–IV; refs. 5, 15, 16, 19, 21, 25, 26, 29, 33, 72–81, 83), microvesicles, and exosomes (3, 8, 9, 14, 28, 32, 36). Molecules secreted by these mechanisms have been reported to contribute to each of the hallmarks of cancer (red arrows; refs. 2–15), as defined by Hanahan and Weinberg (114).

Figure 1.

Schematic representation of the impact of glioma secretion on the hallmarks of cancer. Pro-oncogenic molecules can be transported through the plasma membrane by classical secretory mechanisms, nonclassical secretory mechanisms (type I–IV; refs. 5, 15, 16, 19, 21, 25, 26, 29, 33, 72–81, 83), microvesicles, and exosomes (3, 8, 9, 14, 28, 32, 36). Molecules secreted by these mechanisms have been reported to contribute to each of the hallmarks of cancer (red arrows; refs. 2–15), as defined by Hanahan and Weinberg (114).

Close modal

Although the specific mechanisms regulating secretion in malignant cells remain to be fully characterized, there is significant 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 implications of targeting the tumor cell secretion (Table 1).

Glioma cells modify their microenvironment by introducing diverse molecules into the extracellular space (Table 1). To exemplify 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 IL1β, IL6, and IL8, create a state of chronic inflammation that promotes the malignant 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 invasion (2, 13, 15). It has also been shown that cytokines, like IL6, IL8, EGF, and TGFβ, 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 mechanism facilitating the emergence of drug resistance via the activation 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 characterized 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 stimulating endothelial cell migration and promoting endothelial cell proliferation (2). Consistent with these findings, disrupting PDGF signaling markedly reduces angiogenesis, tumor growth, and invasion in multiple mouse models of glioma (2, 10, 12, 13).

Metabolites

Malignant cells reprogram their metabolism to meet the bioenergetic and biosynthetic demands of tumor growth (57). A consequence of this altered metabolism is the aberrant production of metabolites that can have profound effects on tumor biology (57). Studies suggest that several metabolites, including well-known molecules like glutamate and 2-hydroxyglutarate, are involved in glioma progression (58, 59).

A recently described, secreted pro-oncogenic metabolite in glioma is kynurenine (4, 11). Kynurenine is an intermediate in l-tryptophan catabolism and an endogenous aryl hydrocarbon receptor (AhR) agonist (4, 11). At levels secreted by glioma cells, but not at levels secreted by normal cells, kynurenine promotes genomic instability of HGG-derived cells (4). AhR activation by secreted kynurenine upregulates the trans-lesion synthesis polymerase, hpol κ (4). The dysregulated overexpression of this polymerase, which normally mediates the DNA damage tolerance pathway, increases genomic instability and promotes tumorigenesis (4, 60). Such an autocrine pathway mediating increased genomic instability may contribute to the exceptionally high levels of genomic heterogeneity characterizing HGG (61).

Kynurenine also has been shown to have immunosuppressive effects, to enhance cellular motility and to promote survival of HGG cells (11). Inhibition of kynurenine secretion in glioma increases the lysis of glioma cells by alloreactive blood mononuclear cells, decreases cellular migration in vitro, and markedly decreases clonogenic survival of glioma cells (11). Consistent with these observations, kynurenine-secreting tumors grow significantly more rapidly and have a higher proliferation index than nonsecreting tumors in immunocompetent mice (11).

Nucleic acids

Secreted nucleic acids are commonly found in the blood of patients with cancer and they have been shown to be indicative of disease progression (62). In glioma and other tumors, nucleic acids can be secreted in extracellular vesicles (EV) and delivered to nearby cells (3, 7, 9, 14). EVs can carry mutated or amplified oncogene sequences, mRNA, transposable elements, or miRNAs (7, 9, 14). EVs from HGG contain an array of pro-oncogenic miRNAs such as miR-19b, miR-20, and miR-21 that promote HGG progression (14). Importantly, genetic material contained in these EVs, such as mRNA and miRNAs, can be delivered to nearby cells where they remain functional (7, 9, 14). Glioma-derived cells incubated in medium supplemented with EVs from patient-derived glioblastoma cells exhibit increased proliferation when compared with glioma cells incubated in normal, untreated growth medium (14). Although further experimentation is required to demonstrate specific effects of each nucleic acid carried within EVs, it is highly likely that they are, at least in part, responsible for these EV-mediated effects in glioma.

Studies have demonstrated that EVs derived from glioma cells can transform fibroblasts and epithelial cells (8). Consistent with these findings, targeting proteins required for EV biogenesis effectively blocks EV-induced oncogenic transformation (8). These findings suggest that DNA transfer in EVs could transform nearby cells contributing to the high degree of heterogeneity and polyclonality observed in human HGGs (61, 63).

Classical secretory pathway

Malignant cells utilize the classical secretory pathway. In this pathway, proteins with a signal peptide are recognized by the signal recognition particle and then inserted into the endoplasmic reticulum (ER; ref. 64). In the ER, translation is completed and the newly synthesized proteins are transported through the Golgi apparatus to the plasma membrane in a process mediated by numerous proteins including RABs and ARFs (64).

Accumulating evidence indicates that RABs and ARFs are of significant importance for cancer progression (17, 20, 28, 37, 65, 66). Aberrant expression of RAB proteins, a family of more than 70 members, is observed in glioma and other cancers (22, 28, 31, 32, 40, 67, 68). In HGG RAB3A, RAB34, and RAB27A expression levels correlate with survival and pathologic grade (22, 31, 40). RAB3A, which regulates vesicular transport in neurons (69), is associated with increased proliferation and chemo- and radioresistance of cultured glioma cells and tumor formation and glioma growth in nude mice (22). A recent study has identified RAB35 as a novel activator of PI3K in multiple cells from kidney, colon, prostate, and cervical cancer. Somatic RAB35 mutations found in human tumors were capable of transforming cells in vitro, and this oncogenic RAB35 was sufficient to drive vesicular transport in the absence of stimuli, suggesting that dysregulated vesicular trafficking can contribute to oncogenesis (70).

Like the RAB family of proteins, ARFs and their associated guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP) are emerging as novel mediators of disease progression in gliomas, as well as other tumors (17, 20, 36–39, 65, 66). Dysregulated ARF6 has been reported to be a key driver of tumor cell invasion in several cancer types including glioma (17, 20, 65, 66). A glioma study has shown that ARF6 knockdown by siRNA markedly decreases invasion of intracranial brain xenografts in nude mice (20). ARF6 has also been shown to orchestrate the activity of the oncogenic guanine nucleotide–binding protein G(q) subunit alpha (GNAQ) in uveal melanoma by mediating the vesicular transport of GNAQ and β-catenin (71). Consistent with this finding, targeting ARF6 with the small-molecule inhibitor, NAV-2729, reduces melanoma proliferation and tumorigenesis in vivo (71).

Nonclassical secretory pathway

A substantial proportion of cancer secretion is mediated by the nonclassical secretory pathway (29). This pathway is induced by cellular stress (72), a characteristic of transformed cells (18, 73). There are four types of nonclassical pathway secretion, which may play a role in cancer: type I or pore-mediated secretion, type II or ABC transporter-mediated secretion, type III or endosome/autophagosome-mediated secretion, and type IV or Golgi-bypass secretion (72).

Proteins secreted by the type I pathway rely on the formation of pores in the plasma membrane. The formation of these pores can be mediated by either the cytoplasmic protein to be secreted or by inflammation (72). Secretion of FGF2, a widely studied pro-oncogenic protein of importance in glioma (5), is a well-known example of the former mechanism (72). FGF2 binds to phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2) on the plasma membrane and oligomerizes promoting the formation of a lipidic pore through which secretion occurs (72). Alternatively, pore formation can be mediated by inflammation (72, 74), which characterizes the glioma microenvironment (75). During inflammation, gasdermin D, gasdermin A, and gasdermin A3 are cleaved by caspase-1 releasing the N-terminal half of these proteins: gasdermin-N, which binds PIP2 on the plasma membrane and forms 16-fold-symmetry in the pore (72, 74). These pores then mediate the secretion of IL1β (74), a cytokine known to promote further inflammation and drive glioma growth (75, 76). While a role for the gasdermin protein family in glioma has not been proposed, members of this family are aberrantly expressed in several tumor types (16) and promote brain metastasis of tumors from outside the CNS (77).

The type II nonclassical pathway relies on the ATP-binding cassette (ABC) transporters (72), which are well-described mediators of chemoresistance in glioma as well as other tumor types (27, 78). These transporters facilitate chemoresistance by mediating the efflux of chemotherapeutic agents from malignant cells (27, 78). Overexpression of the ABC transporter subfamily B member 1, which is also known as the multidrug resistance protein 1 (MDR1), mediates resistance to chemotherapeutic agents in aggressive gliomas (27, 78). Inhibiting MDR1, in vitro or in vivo, increases the sensitivity of HGG cells to vincristine and temozolomide, two antineoplastic agents commonly used in the management of patients with glioblastoma (78). Furthermore, MDR1 inhibitors have been shown to lead to increased concentrations of chemotherapy agents in the brain when used as adjuvants (19, 21). MDR1 is also expressed in endothelial cells of the blood–brain barrier (19), where it pumps metabolic waste products out of the CNS as well as enhancing the efflux of chemotherapy agents and decreasing their availability in brain tumors (19). Thus, clinical therapies that effectively inhibited these transporters could potentially have the added advantage of increasing the CNS availability of chemotherapy agents active in glioma (21), although to date, MDR1 inhibitors have not been useful in the clinic due to the side effects they cause (19). Multiple strategies to prevent such drug toxicities are currently under investigation (26).

The type III pathway of nonclassical secretion relies on autophagosomes (72), double-membraned vesicles that enclose cellular material destined to be degraded or secreted (25). Secretory autophagosomes carry cytokines including IL1β, and IL18 (25, 72), which are well-characterized mediators of glioma progression (15, 75, 76). The process of autophagosome formation is tightly controlled by highly conserved autophagy-related genes (ATG; refs. 25, 72). These genes, as well as the process of autophagy, can have pro-oncogenic or antioncogenic effects in HGG (30, 79, 80). For example, targeting ATG7 or ATG13 has been shown to result in markedly decreased KRAS-driven HGG growth in vivo (80), while inhibiting ATG5 enhances the resistance of cultured HGG cells to temozolomide, a drug routinely used in the treatment of glioblastoma (30). The mechanisms behind this dual role of ATGs in HGG remain to be elucidated (79).

The type IV nonclassical pathway mediates the secretion of proteins during ER stress that bypass the Golgi enroute to the plasma membrane following synthesis (72). The IRE1α protein of the UPR activates this pathway in response to ER stress (18, 81), which is provoked by many conditions common to malignant tissues including hypoxia, nutrient deprivation, increased metabolic activity, and high levels of proliferation (18, 73, 82). Human glioma cells expressing a nonfunctional mutant of IRE1α demonstrate markedly decreased intracranial tumor growth in nude mice (82). Golgi bypass in the type IV pathway is mediated by an ER-sorting machinery that includes heat shock proteins (HSP; ref. 72). The role of HSPs in HGGs has been well described (33, 83). For example, HSP70, which is upregulated in HGGs (33, 83), increases tumor formation, survival, and chemoresistance in glioblastoma (33, 83).

Extracellular vesicle formation and secretion

Many different terms are used in the literature to describe EVs including microvesicles, exosomes, oncosomes, microparticles, and ectosomes (84, 85). Even although there is considerable debate in the field as to the proper usage of these terms (84, 85), EVs can be broadly classified into two main groups based on their biogenesis: microvesicles and exosomes (36). Microvesicles are derived from the plasma membrane, while exosomes originate from multivesicular endosomal compartments (36). However, experimental procedures designed to isolate each of these vesicle types, including centrifugation protocols, commercial kits, and filters, are based on the size and weight of these vesicles, and not on their intracellular origin (86, 87). Consequently, material isolated by these experimental techniques contain a mixture of different types of EVs (86, 87), and thus it is important to consider investigational findings in the light of these experimental limitations.

In cancer, EVs transport proteins, lipids, and nucleic acid (36) and can promote multiple aspects of cancer progression (3, 9, 14, 32, 36, 66), and even induce malignant transformation (8, 88). The small Ras homolog gene family member A (RhoA) GTPase regulates EV biogenesis in glioma cells (8, 36). Studies demonstrate that RhoA facilitates the activation of Rho kinase (ROCK) and subsequently the Lim kinase (LIMK; refs. 8, 36). LIMK phosphorylates cofilin causing a reorganization of actin fibers and microvesicle shedding (8, 36). Inhibition of these proteins has been shown to markedly reduce microvesicle release in glioma-derived cells (8). Inhibition of the RhoA–ROCK–LIMK pathway reduces cellular proliferation and migration in glioma (8, 35). Pharmacologic inhibition of this pathway by the ROCK inhibitor, Y-27632, suppresses migration and proliferation of glioma-derived cells. Similarly, silencing of LIMK reduced growth of a breast cancer xenograft in nude mice (8). Consistent with these observations, RhoA, which mediates the activation of ROCK and LIMK as discussed previously (8, 36), is highly expressed in HGGs and its expression is correlated with pathologic grade (34). RAB and ARF family members, which were discussed in previous sections, have also been implicated in EV formation in gliomas as well as other types of cancer (32, 36, 66).

Targeting secretion in glioma

The concept of tumor cell–secretory addiction describes the reliance of cancer cells on secreted molecules and their secretory machinery (18). Studies described above demonstrate the significance of this concept in HGG (Table 1). By describing some of the essential functions of glioma-secreted molecules and the mechanisms facilitating their secretion in glioma pathology (Fig. 1), we have sought to underscore the potential therapeutic benefits of targeting secretion in HGGs. Targeting proteins of the secretory mechanism in glioma has been shown to inhibit key aspects of glioma biology including tumor cell proliferation and survival (Table 1; Fig. 1; refs. 8, 17–23, 26–28, 32, 34–36, 38, 39, 44–46, 89, 90). Furthermore, targeting secretion seems to selectively affect transformed cells, while sparing normal cells, as evidenced by the lack of toxicities reported in multiple animal experiments testing agents that inhibit secretion (18, 19, 21, 26, 36, 43–46). This suggests that targeting proteins of the secretory machinery to disturb the secretion of molecules that enhance tumor pathology may be a promising treatment strategy.

Brefeldin A, a known secretion inhibitor (23), and EHT-1864, which inhibits Rac1 (91), a known mediator of secretion (92, 93), dramatically reduce VEGF secretion, decrease GSC self-renewal, and inhibit tumor growth in a mouse model of HGG (54). The antitumorigenic effects of these agents also have been observed in several other cancer types (38, 39, 41). Multiple high-throughput drug screens have identified novel small-molecule inhibitors that effectively target mediators of cellular secretion (94). Two small-molecule inhibitors of secretion that have been studied in cancer are AMF-26 (37) and Eeyarestatin I (EI; ref. 44). Like Brefeldin A, AMF-26 targets the ARF1-guanine nucleotide exchange factor (GEF) interaction, which prevents the assembly of the vesicle coating protein complex I (COPI) assembly and consequently inhibits protein secretion (37). AMF-26 has potent antitumor activity (37). Oral administration of AMF-26 resulted in complete regression of human breast cancer xenografts in nude mice, and was nontoxic to animals (37) providing further evidence of the potential of such drugs to have an acceptable therapeutic index.

Early preclinical studies also suggest that other pharmacologic agents that result in the inhibition of ARF1-mediated COPI assembly, like Exo2 (8), LM11 (95), and Golgicide A (96), have significant antitumorigenic activity in breast and prostate cancer models (97–99). However, these agents, as well as other agents that block ER-to-Golgi vesicular transport, including Exo1 (100), LG186 (100), CI-976 (101), dispergo (102), and FLI-06 (103), have not been tested in glioblastoma and their clinical value for cancer therapeutics remains largely unexplored.

EI, which inhibits Sec61-mediated protein translocation in the classical secretory pathway (44), has potent antioncogenic activity (46, 89). Preclinical studies demonstrated that EI treatment causes a significant reduction of invasion and cellular proliferation of a non–small cell lung carcinoma–derived cell line, while increasing cell death by apoptosis (46, 89). In vivo, EI treatment resulted in reduced xenograft growth in nude mice with no signs of toxicity (46). Other Sec61 inhibitors, like apratoxin (104) and cotransins (105), have also been shown to have significant antitumorigenic activity in preclinical studies (106–108). However, these agents, as well as other Sec61 inhibitors, like decatransin (109) and mycolactone (110), remain to be studied in the context of HGG, and they have yet to be studied in clinical trials for any tumor type. These pharmacologic inhibitors of secretion represent a relatively unexplored therapeutic opportunity for tumors, like HGG, that rely on secretory pathways, as discussed above.

Another potential target to inhibit cancer-associated secretion is the UPR (18). Treatment of HGG cells with epigallocatechin gallate, which inhibits GRP78, significantly increases the cytotoxic effect of temozolomide on HGG (90). This drug is currently being evaluated as an adjuvant for treatment of colorectal cancer in a phase I clinical trial (111). Similarly, inhibition of the glucose-regulated protein 78 (GRP78), a key regulator of the UPR pathway, by the novel fusion protein EGF-SubA results in substantial growth reduction of HGG xenografts in nude mice (45).

Botulinum neurotoxin–based pharmacologic agents represent another promising strategy to inhibit secretion (112). These drugs, which are known as targeted secretion inhibitors (TSI), can target specific cells and cleave SNARE proteins (112). TSIs contain a targeting domain, a transport domain, and a blocking domain. The targeting domain can be engineered to bind classic glioblastoma markers, such as EGFR (113). The transport domain facilitates the entry of this agent into the cytosol, where the enzymatic blocking domain cleaves SNARE proteins to inhibit protein secretion (112). Even although TSIs have yet to be explored in the context of cancer, their characteristics discussed above make them well suited for cancer therapeutics.

Cancer cell secretion is a vital process contributing to glioma progression. Numerous studies have characterized the autocrine and paracrine pathways that facilitate many key aspects of tumor progression described as hallmarks of cancer by Hanahan and Weinberg (Table 1; Fig. 1; ref. 114). The capacity of cancer cells to secrete a wide range of different soluble factors with redundant functions (Table 1) could also explain cancer resistance to antineoplastic therapies. In HGG, studies have shown that when signaling from a specific secreted factor is blocked, an alternative secreted factor can maintain the oncogenic functions of the secreted factor that was blocked (54, 115). These secreted factors have also been observed to promote resistance to radiation and chemotherapy (15, 24, 47–51). Therefore, targeting the secretory mechanisms of cancer cells could potentially reduce simultaneously the levels of multiple pro-oncogenic secreted factors and consequently diminish cancer drug resistance and increase patient survival. However, despite accumulating evidence demonstrating the importance of these secretory mechanisms in glioma biology (8, 16–36), there are currently no clinically available therapies targeting these mechanisms.

As pharmacologic agents targeting secretory mechanisms emerge, it will become important to cautiously consider their safety. Although several drugs targeting secretory mechanisms have been tested in animal models with no observable toxicities (18, 19, 21, 26, 36, 43–46), inhibiting such an essential cellular function as secretion poses obvious risks. Many cell types, and especially neurons, glial cells, and immune cells, require secretion to function properly. Much like current chemotherapeutic drugs, dose levels and dosing schedules are likely to require careful evaluation to target secretion from malignant cells, while sparing secretion from normal cells.

No potential conflicts of interest were disclosed.

Support was generously provided by the Theodora B. Betz Foundation (to M.A. Israel), the Jordan and Kyra Memorial Foundation (to M.A. Israel), and the Andrea Clark Nelson Medical Research Endowment (to M.A. Israel).

1.
Du
Y
,
Dreyfus
CF
. 
Oligodendrocytes as providers of growth factors
.
J Neurosci Res
2002
;
68
:
647
54
.
2.
Andrae
J
,
Gallini
R
,
Betsholtz
C
. 
Role of platelet-derived growth factors in physiology and medicine
.
Genes Dev
2008
;
22
:
1276
312
.
3.
Balaj
L
,
Lessard
R
,
Dai
L
,
Cho
Y-J
,
Pomeroy
SL
,
Breakefield
XO
, et al
Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences
.
Nat Commun
2011
;
2
:
180
.
4.
Bostian
AC
,
Maddukuri
L
,
Reed
MR
,
Savenka
T
,
Hartman
JH
,
Davis
L
, et al
Kynurenine signaling increases DNA polymerase kappa expression and promotes genomic instability in glioblastoma cells
.
Chem Res Toxicol
2016
;
29
:
101
8
.
5.
Haley
EM
,
Kim
Y
. 
The role of basic fibroblast growth factor in glioblastoma multiforme and glioblastoma stem cells and in their in vitro culture
.
Cancer Lett
2014
;
346
:
1
5
.
6.
Hoelzinger
DB
,
Demuth
T
,
Berens
ME
. 
Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment
.
J Natl Cancer Inst
2007
;
99
:
1583
93
.
7.
Katakowski
M
,
Buller
B
,
Wang
X
,
Rogers
T
,
Chopp
M
. 
Functional microRNA is transferred between glioma cells
.
Cancer Res
2010
;
70
:
8259
63
.
8.
Li
B
,
Antonyak
MA
,
Zhang
J
,
Cerione
RA
. 
RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells
.
Oncogene
2012
;
31
:
4740
9
.
9.
Li
CCY
,
Eaton
SA
,
Young
PE
,
Lee
M
,
Shuttleworth
R
,
Humphreys
DT
, et al
Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells
.
RNA Biol
2013
;
10
:
1333
44
.
10.
Lokker
N
,
Sullivan
C
,
Hollenbach
S
,
Israel
M
,
Giese
N
. 
Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors
.
Cancer Res
2002
;
62
:
3729
35
.
11.
Opitz
CA
,
Litzenburger
UM
,
Sahm
F
,
Ott
M
,
Tritschler
I
,
Trump
S
, et al
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor
.
Nature
2011
;
478
:
197
203
.
12.
Ran
C
,
Liu
H
,
Hitoshi
Y
,
Israel
M
. 
Proliferation-independent control of tumor glycolysis by PDGFR-mediated AKT activation
.
Cancer Res
2013
;
73
:
1831
43
.
13.
Shih
AH
,
Holland
EC
. 
Platelet-derived growth factor (PDGF) and glial tumorigenesis
.
Cancer Lett
2006
;
232
:
139
47
.
14.
Skog
J
,
Wurdinger
T
,
van Rijn
S
,
Meijer
D
,
Gainche
L
,
Sena-Esteves
M
, et al
Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers
.
Nat Cell Biol
2008
;
10
:
1470
6
.
15.
Yeung
YT
,
McDonald
KL
,
Grewal
T
,
Munoz
L
. 
Interleukins in glioblastoma pathophysiology: implications for therapy
.
Br J Pharmacol
2013
;
168
:
591
606
.
16.
Carl-McGrath
S
,
Schneider-Stock
R
,
Ebert
M
,
Röcken
C
. 
Differential expression and localisation of gasdermin-like (GSDML), a novel member of the cancer-associated GSDMDC protein family, in neoplastic and non-neoplastic gastric, hepatic, and colon tissues
.
Pathology
2008
;
40
:
13
24
.
17.
Casalou
C
,
Faustino
A
,
Barral
DC
. 
Arf proteins in cancer cell migration
.
Small GTPases
2016
;
7
:
270
82
.
18.
Dejeans
N
,
Manié
S
,
Hetz
C
,
Bard
F
,
Hupp
T
,
Agostinis
P
, et al
Addicted to secrete - novel concepts and targets in cancer therapy
.
Trends Mol Med
2013
;
20
:
242
50
.
19.
Gottesman
MM
,
Fojo
T
,
Bates
SE
. 
Multidrug resistance in cancer: role of ATP–dependent transporters
.
Nat Rev Cancer
2002
;
2
:
48
58
.
20.
Hu
B
,
Shi
B
,
Jarzynka
MJ
,
Yiin
JJ
,
D'Souza-Schorey
C
,
Cheng
SY
. 
ADP-ribosylation factor 6 regulates glioma cell invasion through the IQ-domain GTPase-activating protein 1-Rac1-mediated pathway
.
Cancer Res
2009
;
69
:
794
801
.
21.
Hubensack
M
,
Muller
C
,
Hocherl
P
,
Fellner
S
,
Spruss
T
,
Bernhardt
G
, et al
Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice
.
J Cancer Res Clin Oncol
2007
;
134
:
597
607
.
22.
Kim
JK
,
Lee
SY
,
Park
C
,
Park
SH
,
Yin
J
,
Kim
J
, et al
Rab3a promotes brain tumor initiation and progression
.
Mol Biol Rep
2014
;
41
:
5903
11
.
23.
Misumi
Y
,
Misumi
Y
,
Miki
K
,
Takatsuki
A
,
Tamura
G
,
Ikehara
Y
. 
Novel blockade by brefeldin A of intracellular transport of secretory proteins in cultured rat hepatocytes
.
J Biol Chem
1986
;
261
:
11398
403
.
24.
Munoz
JL
,
Rodriguez-Cruz
V
,
Greco
SJ
,
Nagula
V
,
Scotto
KW
,
Rameshwar
P
. 
Temozolomide induces the production of epidermal growth factor to regulate MDR1 expression in glioblastoma cells
.
Mol Cancer Ther
2014
;
13
:
2399
411
.
25.
Ponpuak
M
,
Mandell
M
,
Kimura
T
,
Chauhan
S
,
Cleyrat
C
,
Deretic
V
. 
Secretory autophagy
.
Curr Opin Cell Biol
2015
;
35
:
106
16
.
26.
Singh
MS
,
Tammam
SN
,
Shetab Boushehri
MA
,
Lamprecht
A
. 
MDR in cancer: addressing the underlying cellular alterations with the use of nanocarriers
.
Pharmacol Res
2017
;
126
:
2
30
.
27.
Tivnan
A
,
Zakaria
Z
,
O'Leary
C
,
Kögel
D
,
Pokorny
JL
,
Sarkaria
JN
, et al
Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme
.
Front Neurosci
2015
;
9
:
218
.
28.
Tzeng
H-T
,
Wang
Y-C
. 
Rab-mediated vesicle trafficking in cancer
.
J Biomed Sci
2016
;
23
:
70
.
29.
Villarreal
L
,
Méndez
O
,
Salvans
C
,
Gregori
J
,
Baselga
J
,
Villanueva
J
. 
Unconventional secretion is a major contributor of cancer cell line secretomes
.
Mol Cell Proteomics
2013
;
12
:
1046
60
.
30.
Voss
V
,
Senft
C
,
Lang
V
,
Ronellenfitsch
MW
,
Steinbach
JP
,
Seifert
V
, et al
The Pan-Bcl-2 inhibitor (−)-Gossypol triggers autophagic cell death in malignant glioma
.
Mol Cancer Res
2010
;
8
:
1002
16
.
31.
Wang
HJ
,
Gao
Y
,
Chen
L
,
Li
YL
,
Jiang
CL
. 
RAB34 was a progression- and prognosis-associated biomarker in gliomas
.
Tumour Biol
2014
;
36
:
1573
8
.
32.
Wang
T
,
Gilkes
DM
,
Takano
N
,
Xiang
L
,
Luo
W
,
Bishop
CJ
, et al
Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis
.
Proc Natl Acad Sci U S A
2014
;
111
:
E3234
42
.
33.
Wu
J
,
Liu
T
,
Rios
Z
,
Mei
Q
,
Lin
X
,
Cao
S
. 
Heat shock proteins and cancer
.
Trends Pharmacol Sci
2017
;
38
:
226
56
.
34.
Yan
B
,
Chour
HH
,
Peh
BK
,
Lim
C
,
Salto-Tellez
M
. 
RhoA protein expression correlates positively with degree of malignancy in astrocytomas
.
Neurosci Lett
2006
;
407
:
124
6
.
35.
Zohrabian
VM
,
Forzani
B
,
Chau
Z
,
Murali
RAJ
,
Jhanwar-Uniyal
M
. 
Rho/ROCK and MAPK signaling pathways are involved in glioblastoma cell migration and proliferation
.
Anticancer Res
2009
;
29
:
119
23
.
36.
van Niel
G
,
D'Angelo
G
,
Raposo
G
. 
Shedding light on the cell biology of extracellular vesicles
.
Nat Rev Mol Cell Biol
2018
;
19
:
213
28
.
37.
Ohashi
Y
,
Iijima
H
,
Yamaotsu
N
,
Yamazaki
K
,
Sato
S
,
Okamura
M
, et al
AMF-26, a novel inhibitor of the Golgi system, targeting ADP-ribosylation factor 1 (Arf1) with potential for cancer therapy
.
J Biol Chem
2011
;
287
:
3885
97
.
38.
Tseng
CN
,
Hong
YR
,
Chang
HW
,
Yu
TJ
,
Hung
TW
,
Hou
MF
, et al
Brefeldin A reduces anchorage-independent survival, cancer stem cell potential and migration of MDA-MB-231 human breast cancer cells
.
Molecules
2014
;
19
:
17464
77
.
39.
Tseng
CN
,
Huang
CF
,
Cho
CL
,
Chang
HW
,
Chiu
CC
,
Chang
YF
. 
Brefeldin a effectively inhibits cancer stem cell-like properties and MMP-9 activity in human colorectal cancer Colo 205 cells
.
Molecules
2013
;
18
:
10242
53
.
40.
Wang
H
,
Zhao
Y
,
Zhang
C
,
Li
M
,
Jiang
C
,
Li
Y
. 
Rab27a was identified as a prognostic biomaker by mRNA profiling, correlated with malignant progression and subtype preference in gliomas
.
PLoS One
2014
;
9
:
e89782
.
41.
Hampsch
RA
,
Shee
K
,
Bates
D
,
Lewis
LD
,
Désiré
L
,
Leblond
B
, et al
Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer
.
Oncotarget
2017
;
8
:
21806
17
.
42.
Nie
Z
,
Randazzo
PA
. 
Arf GAPs and membrane traffic
.
J Cell Sci
2006
;
119
:
1203
11
.
43.
Almiron Bonnin
DA
,
Havrda
MC
,
Lee
MC
,
Liu
H
,
Zhang
Z
,
Nguyen
LN
, et al
Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia
.
Oncogene
2017
;
37
:
1107
18
.
44.
Cross
BCS
,
McKibbin
C
,
Callan
AC
,
Roboti
P
,
Piacenti
M
,
Rabu
C
, et al
Eeyarestatin I inhibits Sec61-mediated protein translocation at the endoplasmic reticulum
.
J Cell Sci
2009
;
122
:
4393
400
.
45.
Prabhu
A
,
Sarcar
B
,
Kahali
S
,
Shan
Y
,
Chinnaiyan
P
. 
Targeting the unfolded protein response in glioblastoma cells with the fusion protein EGF-SubA
.
PLoS One
2012
;
7
:
e52265
.
46.
Valle
CW
,
Min
T
,
Bodas
M
,
Mazur
S
,
Begum
S
,
Tang
D
, et al
Critical Role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma
.
PLoS One
2011
;
6
:
e29073
.
47.
Dubost
JJ
,
Rolhion
C
,
Tchirkov
A
,
Bertrand
S
,
Chassagne
J
,
Dosgilbert
A
, et al
Interleukin-6-producing cells in a human glioblastoma cell line are not affected by ionizing radiation
.
J Neurooncol
2002
;
56
:
29
34
.
48.
Hardee
ME
,
Marciscano
AE
,
Medina-Ramirez
CM
,
Zagzag
D
,
Narayana
A
,
Lonning
SM
, et al
Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-beta
.
Cancer Res
2012
;
72
:
4119
29
.
49.
Conze
D
,
Weiss
L
,
Regen
PS
,
Bhushan
A
,
Weaver
D
,
Johnson
P
, et al
Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells
.
Cancer Res
2001
;
61
:
8851
8
.
50.
Liu
C
,
Zhu
Y
,
Lou
W
,
Cui
Y
,
Evans
CP
,
Gao
AC
. 
Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells
.
Prostate
2014
;
74
:
201
9
.
51.
Obenauf
AC
,
Zou
Y
,
Ji
AL
,
Vanharanta
S
,
Shu
W
,
Shi
H
, et al
Therapy-induced tumour secretomes promote resistance and tumour progression
.
Nature
2015
;
520
:
368
72
.
52.
Batlle
E
,
Clevers
H
. 
Cancer stem cells revisited
.
Nat Med
2017
;
23
:
1124
34
.
53.
Verhaak
RGW
,
Hoadley
KA
,
Purdom
E
,
Wang
V
,
Qi
Y
,
Wilkerson
MD
, et al
An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1
.
Cancer Cell
2010
;
17
:
98
110
.
54.
Almiron Bonnin
DA
,
Ran
C
,
Havrda
MC
,
Liu
H
,
Hitoshi
Y
,
Zhang
Z
, et al
Insulin-mediated signaling facilitates resistance to PDGFR inhibition in proneural hPDGFB-driven gliomas
.
Mol Cancer Ther
2017
;
16
:
705
16
.
55.
Kohler
N
,
Lipton
A
. 
Platelets as a source of fibroblast growth-promoting activity
.
Exp Cell Res
1974
;
87
:
297
301
.
56.
Lemmon
MA
,
Schlessinger
J
. 
Cell signaling by receptor tyrosine kinases
.
Cell
2010
;
141
:
1117
34
.
57.
DeBerardinis
RJ
,
Chandel
NS
. 
Fundamentals of cancer metabolism
.
Science Advances
2016
;
2
:
e1600200
.
58.
Huang
J
,
Weinstein
SJ
,
Kitahara
CM
,
Karoly
ED
,
Sampson
JN
,
Albanes
D
. 
A prospective study of serum metabolites and glioma risk
.
Oncotarget
2017
;
8
:
70366
77
.
59.
Maus
A
,
Peters
GJ
. 
Glutamate and α-ketoglutarate: key players in glioma metabolism
.
Amino Acids
2017
;
49
:
21
32
.
60.
Bavoux
C
,
Leopoldino
AM
,
Bergoglio
V
,
O-Wang
J
,
Ogi
T
,
Bieth
A
, et al
Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis
.
Cancer Res
2005
;
65
:
325
30
.
61.
Soeda
A
,
Hara
A
,
Kunisada
T
,
Yoshimura
S-i
,
Iwama
T
,
Park
DM
. 
The evidence of glioblastoma heterogeneity
.
Sci Rep
2015
;
5
:
7979
.
62.
Schwarzenbach
H
,
Hoon
DSB
,
Pantel
K
. 
Cell-free nucleic acids as biomarkers in cancer patients
.
Nat Rev Cancer
2011
;
11
:
426
37
.
63.
Meyer
M
,
Reimand
J
,
Lan
X
,
Head
R
,
Zhu
X
,
Kushida
M
, et al
Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity
.
Proc Natl Acad Sci U S A
2015
;
112
:
851
6
.
64.
Viotti
C
. 
ER to Golgi-dependent protein secretion: the conventional pathway
.
Unconventional protein secretion: methods and protocols
; 
2016
.
Springer
. p.
3
29
.
65.
Marchesin
V
,
Castro-Castro
A
,
Lodillinsky
C
,
Castagnino
A
,
Cyrta
J
,
Bonsang-Kitzis
H
, et al
ARF6–JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion
.
J Cell Biol
2015
;
211
:
339
58
.
66.
Muralidharan-Chari
V
,
Clancy
J
,
Plou
C
,
Romao
M
,
Chavrier
P
,
Raposo
G
, et al
ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles
.
Curr Biol
2009
;
19
:
1875
85
.
67.
Qin
X
,
Wang
J
,
Wang
X
,
Liu
F
,
Jiang
B
,
Zhang
Y
. 
Targeting Rabs as a novel therapeutic strategy for cancer therapy
.
Drug Discov Today
2017
;
22
:
1139
47
.
68.
Cheng
KW
,
Lahad
JP
,
Gray
JW
,
Mills
GB
. 
Emerging Role of RAB GTPases in cancer and human disease
.
Cancer Res
2005
;
65
:
2516
9
.
69.
Geppert
M
,
Bolshakov
VY
,
Siegelbaum
SA
,
Takei
K
,
De Camilli
P
,
Hammer
RE
, et al
The role of Rab3A in neurotransmitter release
.
Nature
1994
;
369
:
493
7
.
70.
Wheeler
DB
,
Zoncu
R
,
Root
DE
,
Sabatini
DM
,
Sawyers
CL
. 
Identification of an oncogenic RAB protein
.
Science
2015
;
350
:
211
7
.
71.
Yoo
JH
,
Shi
DS
,
Grossmann
AH
,
Sorensen
LK
,
Tong
Z
,
Mleynek
TM
, et al
ARF6 is an actionable node that orchestrates oncogenic GNAQ signaling in uveal melanoma
.
Cancer Cell
2016
;
29
:
889
904
.
72.
Rabouille
C
. 
Pathways of unconventional protein secretion
.
Trends Cell Biol
2016
;
27
:
230
40
.
73.
Senft
D
,
Ronai
ZeA
. 
Adaptive stress responses during tumor metastasis and dormancy
.
Trends Cancer
2016
;
2
:
429
42
.
74.
Ding
J
,
Wang
K
,
Liu
W
,
She
Y
,
Sun
Q
,
Shi
J
, et al
Pore-forming activity and structural autoinhibition of the gasdermin family
.
Nature
2016
;
535
:
111
6
.
75.
Ha
ET
,
Antonios
JP
,
Soto
H
,
Prins
RM
,
Yang
I
,
Kasahara
N
, et al
Chronic inflammation drives glioma growth: cellular and molecular factors responsible for an immunosuppressive microenvironment
.
Neuroimmunology Neuroinflammation
2014
;
1
:
66
76
.
76.
Tarassishin
L
,
Casper
D
,
Lee
SC
. 
Aberrant expression of interleukin-1β and inflammasome activation in human malignant gliomas
.
PLoS One
2014
;
9
:
e103432
.
77.
Hergueta-Redondo
M
,
Sarrió
D
,
Molina-Crespo
Á
,
Megias
D
,
Mota
A
,
Rojo-Sebastian
A
, et al
Gasdermin-B promotes invasion and metastasis in breast cancer cells
.
PLoS One
2014
;
9
:
e90099
.
78.
Munoz
JL
,
Rodriguez-Cruz
V
,
Ramkissoon
SH
,
Ligon
KL
,
Greco
SJ
,
Rameshwar
P
. 
Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level
.
Oncotarget
2015
;
6
:
1190
201
.
79.
Jawhari
S
,
Ratinaud
MH
,
Verdier
M
. 
Glioblastoma, hypoxia and autophagy: a survival-prone ‘ménage-à-trois'
.
Cell Death Dis
2016
;
7
:
e2434
.
80.
Gammoh
N
,
Fraser
J
,
Puente
C
,
Syred
HM
,
Kang
H
,
Ozawa
T
, et al
Suppression of autophagy impedes glioblastoma development and induces senescence
.
Autophagy
2016
;
12
:
1431
9
.
81.
Gee Heon
Y
,
Noh Shin
H
,
Tang Bor
L
,
Kim Kyung
H
,
Lee Min
G
. 
Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway
.
Cell
2011
;
146
:
746
60
.
82.
Drogat
B
,
Auguste
P
,
Nguyen
DT
,
Bouchecareilh
M
,
Pineau
R
,
Nalbantoglu
J
, et al
IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo
.
Cancer Res
2007
;
67
:
6700
7
.
83.
Rajesh
Y
,
Biswas
A
,
Mandal
M
. 
Glioma progression through the prism of heat shock protein mediated extracellular matrix remodeling and epithelial to mesenchymal transition
.
Exp Cell Res
2017
;
359
:
299
311
.
84.
Gould
SJ
,
Raposo
G
. 
As we wait: coping with an imperfect nomenclature for extracellular vesicles
.
J Extracell Vesicles
2013
;
2
:
20389
.
85.
Meehan
B
,
Rak
J
,
Di Vizio
D
. 
Oncosomes – large and small: what are they, where they came from?
J Extracell Vesicles
2016
;
5
:
33109
.
86.
Lötvall
J
,
Hill
AF
,
Hochberg
F
,
Buzás
EI
,
Di Vizio
D
,
Gardiner
C
, et al
Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles
.
J Extracell Vesicles
2014
;
3
:
26913
.
87.
Witwer
KW
,
Soekmadji
C
,
Hill
AF
,
Wauben
MH
,
Buzás
EI
,
Di Vizio
D
, et al
Updating the MISEV minimal requirements for extracellular vesicle studies: building bridges to reproducibility
.
J Extracell Vesicles
2017
;
6
:
1396823
.
88.
Antonyak
MA
,
Li
B
,
Boroughs
LK
,
Johnson
JL
,
Druso
JE
,
Bryant
KL
, et al
Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells
.
Proc Natl Acad Sci U S A
2011
;
108
:
4852
7
.
89.
Brem
GJ
,
Mylonas
I
,
Bruning
A
. 
Eeyarestatin causes cervical cancer cell sensitization to bortezomib treatment by augmenting ER stress and CHOP expression
.
Gynecol Oncol
2013
;
128
:
383
90
.
90.
Pyrko
P
,
Schonthal
AH
,
Hofman
FM
,
Chen
TC
,
Lee
AS
. 
The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas
.
Cancer Res
2007
;
67
:
9809
16
.
91.
Shutes
A
,
Onesto
C
,
Picard
V
,
Leblond
B
,
Schweighoffer
F
,
Der
CJ
. 
Specificity and Mechanism of Action of EHT 1864, a novel small molecule inhibitor of rac family small GTPases
.
J Biol Chem
2007
;
282
:
35666
78
.
92.
Akbar
H
,
Kim
J
,
Funk
K
,
Cancelas
JA
,
Shang
X
,
Chen
L
, et al
Genetic and pharmacologic evidence that Rac1 GTPase is involved in regulation of platelet secretion and aggregation
.
J Thromb Haemost
2007
;
5
:
1747
55
.
93.
Li
Q
,
Ho
CS
,
Marinescu
V
,
Bhatti
H
,
Bokoch
GM
,
Ernst
SA
, et al
Facilitation of Ca(2+)-dependent exocytosis by Rac1-GTPase in bovine chromaffin cells
.
J Physiol
2003
;
550
:
431
45
.
94.
Ivanov
AI
. 
Pharmacological inhibitors of exocytosis and endocytosis: novel bullets for old targets
.
In:
Ivanov
AI
,
editor
.
Exocytosis and endocytosis
.
New York, NY
:
Springer
; 
2014
. p.
3
18
.
95.
Viaud
J
,
Zeghouf
M
,
Barelli
H
,
Zeeh
JC
,
Padilla
A
,
Guibert
B
, et al
Structure-based discovery of an inhibitor of Arf activation by Sec7 domains through targeting of protein-protein complexes
.
Proc Natl Acad Sci U S A
2007
;
104
:
10370
5
.
96.
Sáenz
JB
,
Sun
WJ
,
Chang
JW
,
Li
J
,
Bursulaya
B
,
Gray
NS
, et al
Golgicide A reveals essential roles for GBF1 in Golgi assembly and function
.
Nat Chem Biol
2009
;
5
:
157
65
.
97.
Lang
L
,
Shay
C
,
Zhao
X
,
Teng
Y
. 
Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics
.
J Exp Clin Cancer Res
2017
;
36
:
112
.
98.
Xie
X
,
Tang
SC
,
Cai
Y
,
Pi
W
,
Deng
L
,
Wu
G
, et al
Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1
.
Oncotarget
2016
;
7
:
58111
20
.
99.
Luchsinger
C
,
Aguilar
M
,
Burgos
PV
,
Ehrenfeld
P
,
Mardones
GA
. 
Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling
.
PLoS One
2018
;
13
:
e0195401
.
100.
Feng
Y
,
Yu
S
,
Lasell
TKR
,
Jadhav
AP
,
Macia
E
,
Chardin
P
, et al
Exo1: a new chemical inhibitor of the exocytic pathway
.
Proc Natl Acad Sci U S A
2003
;
100
:
6469
74
.
101.
Chambers
K
,
Judson
B
,
Brown
WJ
. 
A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways
.
J Cell Biol
2005
;
118
:
3061
71
.
102.
Lu
L
,
Hannoush
RN
,
Goess
BC
,
Varadarajan
S
,
Shair
MD
,
Kirchhausen
T
, et al
The small molecule dispergo tubulates the endoplasmic reticulum and inhibits export
.
Mol Biol Cell
2013
;
24
:
1020
9
.
103.
Yonemura
Y
,
Li
X
,
Müller
K
,
Krämer
A
,
Atigbire
P
,
Mentrup
T
, et al
Inhibition of cargo export at ER exit sites and the trans-Golgi network by the secretion inhibitor FLI-06
.
J Cell Sci
2016
;
129
:
3868
77
.
104.
Liu
Y
,
Law
BK
,
Luesch
H
. 
Apratoxin a reversibly inhibits the secretory pathway by preventing cotranslational translocation
.
Mol Pharmacol
2009
;
76
:
91
104
.
105.
Garrison
JL
,
Kunkel
EJ
,
Hegde
RS
,
Taunton
J
. 
A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum
.
Nature
2005
;
436
:
285
9
.
106.
Cai
W
,
Chen
QY
,
Dang
LH
,
Luesch
H
. 
Apratoxin S10, a dual inhibitor of angiogenesis and cancer cell growth to treat highly vascularized tumors
.
ACS Med Chem Lett
2017
;
8
:
1007
12
.
107.
Huang
K-C
,
Chen
Z
,
Jiang
Y
,
Akare
S
,
Kolber-Simonds
D
,
Condon
K
, et al
Apratoxin a shows novel pancreas-targeting activity through the binding of sec 61
.
Mol Cancer Ther
2016
;
15
:
1208
16
.
108.
Serrill
JD
,
Wan
X
,
Hau
AM
,
Jang
HS
,
Coleman
DJ
,
Indra
AK
, et al
Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts
.
Invest New Drugs
2016
;
34
:
24
40
.
109.
Junne
T
,
Wong
J
,
Studer
C
,
Aust
T
,
Bauer
BW
,
Beibel
M
, et al
Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon
.
J Cell Biol
2015
;
128
:
1217
29
.
110.
McKenna
M
,
Simmonds
RE
,
High
S
. 
Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone
.
J Cell Biol
2016
;
129
:
1404
15
.
111.
ClinicalTrials.gov
. 
Chemopreventive effects of epigallocatechin gallate (EGCG) in colorectal cancer (CRC) patients
. Available from: https://clinicaltrials.gov/ct2/show/NCT02891538.
112.
Keith
F
,
John
C
. 
Targeted secretion inhibitors—innovative protein therapeutics
.
Toxins
2010
;
2
:
2795
815
.
113.
Foster
KA
. 
Harnessing toxins
.
Manuf Chem
2006
:
23
6
.
114.
Hanahan
D
,
Weinberg Robert
A
. 
Hallmarks of cancer: the next generation
.
Cell
2011
;
144
:
646
74
.
115.
Akhavan
D
,
Pourzia
AL
,
Nourian
AA
,
Williams
KJ
,
Nathanson
D
,
Babic
I
, et al
De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients
.
Cancer Discov
2013
;
3
:
534
47
.
116.
Nistér
M
,
Heldin
CH
,
Wasteson
Å
,
Westermark
B
. 
A platelet-derived growth factor analog produced by a human clonal glioma cell line
.
Ann N Y Acad Sci
1982
;
397
:
25
33
.
117.
Chattopadhyay
N
,
Tfelt-Hansen
J
,
Brown
EM
. 
PKC, p42/44 MAPK and p38 MAPK regulate hepatocyte growth factor secretion from human astrocytoma cells
.
Brain Res Mol Brain Res
2002
;
102
:
73
82
.
118.
Ambrose
D
,
Resnicoff
M
,
Coppola
D
,
Sell
C
,
Miura
M
,
Jameson
S
, et al
Growth regulation of human glioblastoma t98g cells by insulin‐like growth factor‐1 and its receptor
.
J Cell Physiol
1994
;
159
:
92
100
.
119.
Tang
P
,
Steck
PA
,
Yung
WKA
. 
The autocrine loop of TGF-α/EGFR and brain tumors
.
J Neurooncol
1997
;
35
:
303
14
.
120.
Ouafik
L
,
Sauze
S
,
Boudouresque
F
,
Chinot
O
,
Delfino
C
,
Fina
F
, et al
Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo
2002
;
160
:
1279
92
.
121.
Al-Nedawi
K
,
Meehan
B
,
Micallef
J
,
Lhotak
V
,
May
L
,
Guha
A
, et al
Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells
2008
;
10
:
619
24
.
122.
Marfia
G
,
Campanella
R
,
Navone
SE
,
Di Vito
C
,
Riccitelli
E
,
Hadi
LA
, et al
Autocrine/paracrine sphingosine-1-phosphate fuels proliferative and stemness qualities of glioblastoma stem cells
.
Glia
2014
;
62
:
1968
81
.
123.
Shea
A
,
Harish
V
,
Afzal
Z
,
Chijioke
J
,
Kedir
H
,
Dusmatova
S
, et al
MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics
.
Cancer Med
2016
;
5
:
1917
46
.
124.
Wei
Z
,
Batagov
AO
,
Schinelli
S
,
Wang
J
,
Wang
Y
,
El Fatimy
R
, et al
Coding and noncoding landscape of extracellular RNA released by human glioma stem cells
.
Nat Commun
2017
;
8
:
1145
.
125.
Wrann
M
,
Bodmer
S
,
Siepl
C
,
Hofer-Warbinek
R
,
Frei
K
,
Hofer
E
, et al
T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta
.
EMBO J
1987
;
6
:
1633
6
.
126.
Hishii
M
,
Nitta
T
,
Ishida
H
,
Ebato
M
,
Kurosu
A
,
Yagita
H
, et al
Human glioma-derived interleukin-10 inhibits antitumor immune responses in vitro
.
Neurosurgery
1995
;
37
:
1160
7
.
127.
Crane
CA
,
Austgen
K
,
Haberthur
K
,
Hofmann
C
,
Moyes
KW
,
Avanesyan
L
, et al
Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients
.
Proc Natl Acad Sci U S A
2014
;
111
:
12823
8
.
128.
Ellert-Miklaszewska
A
,
Wisniewski
P
,
Kijewska
M
,
Gajdanowicz
P
,
Pszczolkowska
D
,
Przanowski
P
, et al
Tumour-processed osteopontin and lactadherin drive the protumorigenic reprogramming of microglia and glioma progression
.
Oncogene
2016
;
35
:
6366
77
.
129.
Van Meir
E
,
Sawamura
Y
,
Diserens
AC
,
Hamou
MF
,
de Tribolet
N
. 
Human glioblastoma cells release interleukin 6 in vivo and in vitro
.
Cancer Res
1990
;
50
:
6683
8
.
130.
Infanger
DW
,
Cho
Y
,
Lopez
BS
,
Mohanan
S
,
Liu
SC
,
Gursel
D
, et al
Glioblastoma stem cells are regulated by interleukin-8 signaling in a tumoral perivascular niche
.
Cancer Res
2013
;
73
:
7079
89
.
131.
Wang
S-C
,
Hong
J-H
,
Hsueh
C
,
Chiang
C-S
. 
Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model
.
Lab Invest
2011
;
92
:
151
62
.
132.
Ho
SY
,
Ling
TY
,
Lin
HY
,
Liou
JT
,
Liu
FC
,
Chen
IC
, et al
SDF-1/CXCR4 signaling maintains stemness signature in mouse neural stem/progenitor cells
.
Stem Cells Int
2017
;
2017
:
2493752
.
133.
Yan
K
,
Wu
Q
,
Yan
DH
,
Lee
CH
,
Rahim
N
,
Tritschler
I
, et al
Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy
.
Genes Dev
2014
;
28
:
1085
100
.
134.
Man
J
,
Shoemake
J
,
Zhou
W
,
Fang
X
,
Wu
Q
,
Rizzo
A
, et al
Sema3C Promotes the survival and tumorigenicity of glioma stem cells through rac1 activation
.
Cell Rep
2014
;
9
:
1812
26
.
135.
Zhou
W
,
Ke
SQ
,
Huang
Z
,
Flavahan
W
,
Fang
X
,
Paul
J
, et al
Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth
.
Nat Cell Biol
2015
;
17
:
170
82
.
136.
Liu
AY
,
Zheng
H
,
Ouyang
G
. 
Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments
.
Matrix Biol
2014
;
37
:
150
6
.
137.
Schonberg
DL
,
Miller
TE
,
Wu
Q
,
Flavahan
WA
,
Das
NK
,
Hale
JS
, et al
Preferential iron trafficking characterizes glioblastoma stem-like cells
.
Cancer Cell
2015
;
28
:
441
55
.
138.
Hwang
J-S
,
Jung
E-H
,
Kwon
M-Y
,
Han
I-O
. 
Glioma-secreted soluble factors stimulate microglial activation: The role of interleukin-1β and tumor necrosis factor-α
.
J Neuroimmunol
2016
;
298
:
165
71
.
139.
Dwyer
J
,
Hebda
JK
,
Le Guelte
A
,
Galan-Moya
E-M
,
Smith
SS
,
Azzi
S
, et al
Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2
.
PLoS One
2012
;
7
:
e45562
.
140.
Ye
ZC
,
Sontheimer
H
. 
Glioma cells release excitotoxic concentrations of glutamate
.
Cancer Res
1999
;
59
:
4383
91
.
141.
Song
H
,
Moon
A
. 
Glial cell-derived neurotrophic factor (GDNF) promotes low-grade Hs683 glioma cell migration through JNK, ERK-1/2 and p38 MAPK signaling pathways
.
Neurosci Res
2006
;
56
:
29
38
.
142.
Amos
S
,
Redpath
GT
,
diPierro
CG
,
Carpenter
JE
,
Hussaini
IM
. 
Epidermal growth factor receptor-mediated regulation of urokinase plasminogen activator expression and glioblastoma invasion via C-SRC/MAPK/AP-1 signaling pathways
.
J Neuropathol Exp Neurol
2010
;
69
:
582
92
.
143.
Lagriffoul
A
,
Charpentier
N
,
Carrette
J
,
Tougard
C
,
Bockaert
J
,
Homburger
V
. 
Secretion of protease nexin-1 by C6 glioma cells is under the control of a heterotrimeric G protein, Go1
.
J Biol Chem
1996
;
271
:
31508
16
.
144.
Rooprai
HK
,
Rucklidge
GJ
,
Panou
C
,
Pilkington
GJ
. 
The effects of exogenous growth factors on matrix metalloproteinase secretion by human brain tumour cells
.
Br J Cancer
1999
;
82
:
52
5
.
145.
Hoelzinger
DB
,
Nakada
M
,
Demuth
T
,
Rosenstee
T
,
Reavie
LB
,
Berens
ME
. 
Autotaxin: a secreted autocrine/paracrine factor that promotes glioma invasion
.
J Neurooncol
2008
;
86
:
297
309
.
146.
Lyons
SA
,
Chung
WJ
,
Weaver
AK
,
Ogunrinu
T
,
Sontheimer
H
. 
Autocrine glutamate signaling promotes glioma cell invasion
.
Cancer Res
2007
;
67
:
9463
71
.
147.
Hu
F
,
a Dzaye
OD
,
Hahn
A
,
Yu
Y
,
Scavetta
RJ
,
Dittmar
G
, et al
Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling
.
Neuro-oncol
2015
;
17
:
200
10
.
148.
Kawataki
T
,
Yamane
T
,
Naganuma
H
,
Rousselle
P
,
Anduren
I
,
Tryggvason
K
, et al
Laminin isoforms and their integrin receptors in glioma cell migration and invasiveness: Evidence for a role of alpha5-laminin(s) and alpha3beta1 integrin
.
Exp Cell Res
2007
;
313
:
3819
31
.
149.
Gutschner
T
,
Diederichs
S
. 
The hallmarks of cancer: a long non-coding RNA point of view
.
RNA Biol
2012
;
9
:
703
19
.
150.
Dunn
IF
,
Heese
O
,
Black
PM
. 
Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs
.
J Neurosurg
2000
;
50
:
121
37
.
151.
Aghi
M
,
Cohen
KS
,
Klein
RJ
,
Scadden
DT
,
Chiocca
EA
. 
Tumor Stromal-Derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes
.
Cancer Res
2006
;
66
:
9054
64
.
152.
Miyake
M
,
Goodison
S
,
Lawton
A
,
Gomes-Giacoia
E
,
Rosser
CJ
. 
Angiogenin promotes tumoral growth and angiogenesis by regulating matrix metallopeptidase-2 expression via the ERK1/2 pathway
.
Oncogene
2015
;
34
:
890
901
.
153.
Campbell
IM
,
Gambin
T
,
Dittwald
P
,
Beck
CR
,
Shuvarikov
A
,
Hixson
P
, et al
Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
.
BMC Biol
2014
;
12
:
74
.
154.
Kines
KJ
,
Sokolowski
M
,
deHaro
DL
,
Christian
CM
,
Belancio
VP
. 
Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci
.
Nucleic Acids Res
2014
;
42
:
10488
502
.
155.
Fazza
AC
,
Sabino
FC
,
de Setta
N
,
Bordin
NA
,
da Silva
EHT
,
Carareto
CMA
. 
Estimating genomic instability mediated by Alu retroelements in breast cancer
.
Genet Mol Biol
2009
;
32
:
25
31
.
156.
Soga
T
. 
Cancer metabolism: key players in metabolic reprogramming
.
Cancer Sci
2013
;
104
:
275
81
.