The power of the few

Chen, Ran; Pan, Yuan; Gutmann, David H.

doi:10.1101/gad.303453.117

Cited by 8 publications

(8 citation statements)

References 10 publications

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“…We also observed that FTY720 reduced MAPK-mediated release of IL-6 from microglia. This observation is in line with other studies that have established a role for MAPKs in the production of inflammatory cytokines and chemokines, which contribute to glioma growth, migration, and invasion (13,39,40). Several studies have shown that IL-6 is a crucial cytokine in glioma development and is important for glioma proliferation, invasion, and differentiation (15,28,41,42).…”

Section: Discussionsupporting

confidence: 90%

FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia

Xue

et al. 2020

Front. Immunol.

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Background: Glioblastoma (GBM) is one of the most malignant and aggressive primary brain tumors. The incurability of glioblastoma is heavily influenced by the glioma microenvironment. FTY720, a potent immunosuppressant, has been reported to exert anti-tumor effects in glioblastoma. However, the impact of FTY720 on the glioma microenvironment remains unclear. Methods:We examined the effects of FTY720 on the distribution and polarization of glioma-associated microglia and macrophages (GAMs) in glioma-bearing rats using immunofluorescence staining. qRT-PCR and Western blotting were used to detect the expressions of CXCR4 and MAPK pathway-related signal molecules on microglia in the coculture system. The levels of inflammatory factors were tested via ELISA. Wound healing assay and Matrigel invasion assay were used to determine the migration and invasion of C6 glioma cells. Results:We discovered that FTY720 could inhibit the growth, migration, and invasion of glioma by targeting GAMs to impede their effect on glioma cells. Simultaneously, FTY720 could block the chemoattraction of GAMs by inhibiting MAPK-mediated secretion of IL-6 through increased internalization of CXCR4. Moreover, microglia and macrophages are polarized from pro-glioma to an anti-tumor phenotype.Conclusion: These results provide novel insights into the inhibitory effects of FTY720 on glioma by targeting GAMs-glioma interaction in the tumor microenvironment.

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Section: Discussionsupporting

confidence: 90%

FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia

Xue

et al. 2020

Front. Immunol.

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“…e fact that EGFR vIII is not present in all GB cells in tumor mass may complicate the perception of this receptor as a perfect therapeutic target. However, if cells expressing EGFR vIII are cancer stem cells [164] or EGFR vIII -negative cells are somehow dependent on EGFR vIII -positive ones, then discussed targeted therapy may turn out to be effective (Figure 3(a)). Our research indicates that EGFR vIII -negative cells may be indeed dependent on EGFR vIII -positive population.…”

Section: Intratumoral Heterogeneity Of Glioblastoma In Terms Of Egfr mentioning

confidence: 99%

“…(a) One of the hypotheses states that EGFR vIII is expressed on the surface of cancer stem cells (CSCs). In such a case, EGFR vIII -positive CSCs should be also detected in recurrent GB tumors [164]. Nevertheless, failure to detect such cells may be due to the exposure of primary tumor to therapeutic compounds.…”

Section: Journal Of Oncologymentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

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Epidermal growth factor receptor variant III (EGFRvIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28–30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFRvIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFRvIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFRWT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFRvIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFRvIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFRvIII-targeting therapies. On the other hand, EGFRvIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

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“…It is composed of tumor cells, cells infiltrating the tumor microenvironment, tumor-associated immune cells, cells of the tumor neovasculature, and tumor-initiating cells [87][88][89] These variable and dynamic facets of the GBM microenvironment allow the tumor to initiate, grow, sustain, and eventually develop resistance to therapies. Essentially, the GBM microenvironment can be described as a dynamic tumor ecosystem [88][89][90][91]. It is evident that by targeting a single component within this complex GBM microenvironment, desired therapeutic effects cannot be achieved.…”

Section: Discussionmentioning

confidence: 99%

Drug Conjugates for Targeting Eph Receptors in Glioblastoma

et al. 2020

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Glioblastoma (GBM) is a complex and heterogeneous tumor that warrants a comprehensive therapeutic approach for treatment. Tumor-associated antigens offer an opportunity to selectively target various components of the GBM microenvironment while sparing the normal cells within the central nervous system. In this study, we conjugated a multivalent vector protein, QUAD 3.0, that can target four receptors: EphA3, EphA2, EphB2, and also IL-13RA2, spanning virtually 100% of the GBM microenvironment, to doxorubicin derivatives. The conjugates effectively bound to all four receptors, although to varying degrees, and delivered cytotoxic loads to both established and patient-derived GBM cell lines, with IC 50 values in the low nM range. The conjugates were also non-toxic to animals. We anticipate that the QUAD 3.0 Dox conjugates will be further used in preclinical models and possibly clinics in the foreseeable future.Pharmaceuticals 2020, 13, 77 2 of 17 in tumor cells and its microenvironment but not in their normal counterparts. The targeting of such receptors has been achieved in different ways. These include the use of ligand- [11-13], antibody-[14,15], and liposome/nanoparticles-based therapeutic agents [16,17]. Additionally, immunotherapy has utilized antigen-pulsed dendritic cells [18], chimeric antigen receptor T-cells (CAR T-cells) [19][20][21][22], and vaccines [23-25] to selectively target TAA in tumors. While immunotherapy has yet to show clinical benefit in GBM, it is considered a fourth pillar of cancer treatment and holds much promise [26].The Eph receptors represent the largest family of receptor tyrosine kinases. It comprises nine EphA receptors that bind to five ephrinA ligands, and five EphB receptors that bind to three ephrinB ligands. Receptors EphB2 and EphA4 can bind to ephrin ligands of different classes [27]. Their implications have been discovered in various developmental [28,29], physiological [30][31][32], and pathological phenomena [33][34][35]. Moreover, increasing indications of their involvement in tumor invasion, initiation [36], tumor immunity [37], and tumor angiogenesis [12,35] have been observed. Specifically, EphA2 and EphA3 have been shown to be expressed individually in 60% of GBM patients, including in regions of tumor neovasculature, tumor-associated immune cells, and tumor-infiltrating cells [12,35,38]. The increased expression of EphA2 and EphA3 in GBM patients is associated with poor patient prognosis and survival [39,40]. Similarly, the expression of EphB2 has been coupled with increased migration and invasion of GBM cells [41,42].The Eph receptors have been targeted using antibodies, kinase inhibitors, radionucides, and peptides that mimic the receptor ligand and carry a cytotoxic load [10]. The Eph receptors internalize once bound to their ligands and resurface later [12,13]. This allows ligand-based or ligand-mimicking peptide-based therapeutics to be administered in multiple doses given the re-expression of the receptors over time. Recently, an ephrinA5-based cytotoxin that c...

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The power of the few

Cited by 8 publications

References 10 publications

FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia

FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia

EGFR^vIII: An Oncogene with Ambiguous Role

Drug Conjugates for Targeting Eph Receptors in Glioblastoma

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The power of the few

Cited by 8 publications

References 10 publications

FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia

FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia

EGFRvIII: An Oncogene with Ambiguous Role

Drug Conjugates for Targeting Eph Receptors in Glioblastoma

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EGFR^vIII: An Oncogene with Ambiguous Role