Survival and Proliferation of Neural Progenitor–Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism

Calinescu, Anda-Alexandra; Yadav, Viveka Nand; Carballo, Erica; Kadiyala, Padma; Tran, Dustin; Zamler, Daniel; Doherty, Robert; Srikanth, Maithreyi; Löwenstein, Pedro R.; Castro, María G.

doi:10.1158/1078-0432.ccr-15-2888

Cited by 48 publications

(47 citation statements)

References 64 publications

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“…4,5 We previously proved that blockade of CXCR4/SDF-1 axis by reducing the secretion of SDF-1 derived from cancer-associated fibroblasts could significantly suppress the proliferation, invasion and migration of cancer cells in vitro, 6 similar results were observed under suppression of CXCR4 activity either by shRNA or pharmacological inhibitor. 7,8 Increasing evidences show that CXCR4 participates in chemotherapy resistance in various cancers such as breast cancer, ovarian cancer, and nonsmall cell lung cancer. [9][10][11][12][13] However, its role in the cisplatin resistance of TSCC cells has seldom been studied.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 enhances cisplatin resistance of human tongue squamous cell carcinoma

Zhuang

Zhou

2018

J Oral Pathology Medicine

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Background The chemokine receptor 4 (CXCR4) plays an important role in tumor progression. Overexpressed CXCR4 is associated with a poor prognosis of patient with head and neck squamous cell carcinomas. However, the correlation between CXCR4 and chemotherapy resistance in tongue squamous cell carcinoma (TSCC) remains obscure. Methods Stable cisplatin‐resistant CAL27 CDDP and SCC25 CDDP cells were established and identified by CCK8 assay, and the CXCR4 expression was detected using qRT‐PCR and Western blot. CXCR4‐siRNA was transfected into TSCC CDDP cells, whose transfect efficiency was examined. Cisplatin sensitivity was further detected, as well as several proliferation and apoptosis‐related proteins. Results CAL27 CDDP and SCC25 CDDP cells were successfully established, which exhibited significantly higher cell viability and less apoptosis under cisplatin stimulation than that of parental cells. CXCR4 expression was increased in TSCC CDDP cells. After transfection of CXCR4‐siRNA, the expression of CXCR4 was reduced by 73% and 78% in CAL27 CDDP and SCC25 CDDP cells, respectively. CCK8 assay and flow cytometry assay revealed that the proliferative capacity under cisplatin stimulation significantly decreased after CXCR4 silencing. Moreover, increased TSCC CDDP cells were arrested in the G0/G1 phase after knockdown of CXCR4. Compared with negative control group, the expression of cyclin D1 and p‐AKT decreased, while that of p‐caspase‐3 and Bax significantly increased. Conclusions Silencing CXCR4 may evidently inhibit proliferation, induce apoptosis and enhance cisplatin sensitivity of TSCC CDDP cells by reduced cyclin D1 and p‐AKT, and increased p‐caspase‐3 and Bax.

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Section: Introductionmentioning

confidence: 99%

CXCR4 enhances cisplatin resistance of human tongue squamous cell carcinoma

Zhuang

Zhou

2018

J Oral Pathology Medicine

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“…We have shown earlier that in response to irradiation there is hypoxia associated with increased secretion of CXCL12 [42]. Since CXCL12 can increase tumor cell survival, knocking down CXCR4 would lead to an increase in glioma cell death.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study

et al. 2016

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Glioblastoma (GBM) is a highly invasive brain tumor. Perivascular invasion, autovascularization and vascular co-option occur throughout the disease and lead to tumor invasion and progression. The molecular basis for perivascular invasion, i.e., the interaction of glioma tumor cells with endothelial cells is not well characterized. Recent studies indicate that glioma cells have increased expression of CXCR4. We investigated the in-vivo role of CXCR4 in perivascular invasion of glioma cells using shRNA-mediated knock down of CXCR4. We show that primary cultures of human glioma stem cells HF2303 and mouse glioma GL26-Cit cells exhibit significant migration towards human (HBMVE) and mouse (MBVE) brain microvascular endothelial cells. Blocking CXCR4 on tumor cells with AMD3100 in-vitro, inhibits migration of GL26-Cit and HF2303 toward MBVE and HBMVE cells. Additionally, genetic down regulation of CXCR4 in mouse glioma GL26-Cit cells inhibits their in-vitro migration towards MBVE cells; in an in-vivo intracranial mouse model, these cells display reduced tumor growth and perivascular invasion, leading to increased survival. Quantitative analysis of brain sections showed that CXCR4 knockdown tumors are less invasive. Lastly, we tested the effects of radiation on CXCR4 knock down GL26-Cit cells in an orthotopic brain tumor model. Radiation treatment increased apoptosis of CXCR4 downregulated tumor cells and prolonged median survival. In summary, our data suggest that CXCR4 signaling is critical for perivascular invasion of GBM cells and targeting this receptor makes tumors less invasive and more sensitive to radiation therapy. Combination of CXCR4 knock down and radiation treatment might improve the efficacy of GBM therapy.

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“…Brains that were fixed in 4% paraformaldehyde were processed, embedded in paraffin and sectioned as described previously 16 . FYN antibody was conjugated with Alexa Fluor™ 488 Tyramide SuperBoost™ Kit - Goat Anti-Rabbit IgG (# B40922) following the manufacture instructions (Invitrogen- Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

Comba

Dunn

Argento

et al. 2019

Preprint

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BackgroundHigh grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYN’s role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion.MethodsWe evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME.ResultsWe demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8−/− and CD4−/− immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME.ConclusionsGliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies.Key pointsInhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity.Importance of the StudyFYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.

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Survival and Proliferation of Neural Progenitor–Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism

Cited by 48 publications

References 64 publications

CXCR4 enhances cisplatin resistance of human tongue squamous cell carcinoma

CXCR4 enhances cisplatin resistance of human tongue squamous cell carcinoma

CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

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