scholarly journals SorCS3 Promotes the Internalization of p75NTR to Inhibit Glioma Progression

2021 ◽  
Author(s):  
Yanqiu Zhang ◽  
Yue Li ◽  
Yuhua Fan ◽  
Baoshan Zhao ◽  
Huan Liang ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Tissue Microarrays ◽  
Cell Receptor ◽  
Receptor Internalization ◽  
Cellular Signal ◽  
Proliferation And Metastasis ◽  
The Impact ◽  
Glioma Progression

Abstract Background: Glioma is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. SorCS3 is involved in nerve cell receptor internalization. However, the impact of SorCS3 on the biological processes involved in glioma has not yet been reported. Here, we highlight the potential of SorCS3-mediated regulation of signalling receptor internalization as a rational target for therapeutic intervention in glioma.Methods: SorCS3 expression was analysed in the TCGA and CGGA databases and in tissue microarrays. The effects of SorCS3 on the proliferation and metastasis of glioma cells were examined in vitro and in vivo with Transwell, wound healing, EdU incorporation and nude mouse tumorigenicity assays. Fluorescent 5-FAM, SE-labelled proteins were used to detect the internalization of SorCS3 in glioma cells. Immunofluorescence and Co-IP assays were conducted to investigate the downstream effector of SorCS3. Moreover, Dynasore and Ro 08-2750, inhibitors of internalization and NGF binding to p75NTR, respectively, were used to validate the biological functions of SorCS3 in glioma.Results: Our data demonstrated that SorCS3 was downregulated in glioma tissues and closely related to favourable prognosis. Overexpression of SorCS3 inhibited the proliferation and metastasis of glioma cells in vitro and in vivo, while silencing of SorCS3 exerted the opposite effects. Mechanistic investigations showed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibition of glioma progression.Conclusions: Our work suggests that SorSC3 is a marker of promising prognosis in glioma patients and suggests that SorCS3 regulates internalization, which plays an important role in inhibiting glioma progression.

Amplified LncRNA PVT1 promotes lung cancer proliferation and metastasis by facilitating VEGFC expression

2020 ◽  
Vol 98 (6) ◽  
pp. 676-682
Author(s):  
Yanming Pan ◽  
Lantao Liu ◽  
Yongxia Cheng ◽  
Jianbo Yu ◽  
Yukuan Feng
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Tumor Model ◽  
Cancer Proliferation ◽  
Survival Prognosis ◽  
Proliferation And Metastasis ◽  
Factor C ◽  
The Impact

Although the abundance of long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) in lung cancer has been well researched, the underlying mechanisms behind its effects were unknown. Here we investigated the molecular events regulating PVT1 in lung cancer. The pro-proliferative property of PVT1 was examined using a xenograft tumor model. Transwell chambers were used to analyze the impact of PVT1 expression on cell invasiveness and migration. In vivo metastasis was examined by tail-vein-injection in mice. Direct binding of miR-128 to PVT1 was investigated using a probe pulldown assay. The relative expression levels of miR-128 and PVT1 were quantified by real-time polymerase chain reaction and Western blotting. We show here that when PVT1 is amplified, there is a poor survival prognosis for patients with lung cancer. Elevated levels of PVT1 promoted lung cancer cell proliferation and metastasis, both in vitro and in vivo. Mechanistically, we found that PVT1 competes endogenously with miR-128 in the regulation of vascular endothelial growth factor C (VEGFC) expression, which is significantly associated with an unfavorable prognosis in lung cancer. We identified that copy number amplification significantly contributes to the high level of PVT1 transcripts in lung cancer, which promotes cell proliferation and metastatic behavior via modulating VEGFC expression by endogenous competition with miR-128.

Temozolomide, irradiation and hypoxia promote homing of hematopoietic progenitor cells towards gliomas

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 20044-20044
Author(s):  
W. Wick ◽  
G. Tabatabai ◽  
B. Frank ◽  
M. Weller
Keyword(s):  
Progenitor Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tumor Hypoxia ◽  
Glioma Cells ◽  
Signaling Cascade ◽  
Hematopoietic Stem ◽  
The Impact

20044 Background: Temozolomide and irradiation are essential parts of the standard therapy and hypoxia is a critical aspect of the microenvironment of gliomas. IN the present study, we aimed at investigating the impact of these stimuli on the previously defined transforming growth factor beta (TGF-β)- and stromal cell-derived factor-1/CXC chemokine ligand 12 (SDF-1α/CXCL12)-dependent migration of adult hematopoietic stem and progenitor cells (HPC) towards glioma cells in vitro and the homing to experimental gliomas in vivo. Hyperthermia served as control. Methods and Results: Cerebral irradiation of nude mice at 21 days after intracerebral implantation of LNT-229 glioma induces tumor satellite formation and enhances the glioma tropism of HPC in vivo. Supernatants of temozolomide-treated, irradiated or hypoxic LNT-229 glioma cells promote HPC migration in vitro. Reporter assays reveal that the CXCL12 promoter activity is enhanced in LNT-229 glioma cells at 24 h after irradiation at 8 Gy or after exposure to 1% oxygen for 12 h. The irradiation- and hypoxia-induced release of CXCL12 depends on hypoxia inducible factor-1 alpha (HIF-1α), but not on p53. Induction of transcriptional activity of HIF-1α by hypoxia and irradiation requires an intact signaling cascade of TGF-β. Conclusions: Thus, we delineate a novel stress signaling cascade in glioma cells involving TGF-β, HIF-1α and CXCL12. Stress stimuli can be temozolomide, irradiation and hypoxia but not hyperthermia. These data suggest that the use of HPC as cellular vectors in the treatment of glioblastoma may well be combined with anti-angiogenic therapies which induce tumor hypoxia. [Table: see text]

scholarly journals Tumor associated macrophages and its nanovesicles: Immunological insights in cerebral glioma

2020 ◽  
Vol 10 (1) ◽  
pp. 14
Author(s):  
Turano E ◽  
Farinazzo A ◽  
El Mously S ◽  
Calabria F ◽  
Jugerson I ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Annexin V ◽  
Low Grade ◽  
Cerebral Glioma ◽  
Tumor Associated Macrophages ◽  
Cellular Activation ◽  
Protein Assay ◽  
Glioma Progression

Purpose: The immune system has a key role in glioma progression, especially the tumor associated macrophages (TAMs). In-vivo, we aimed to study the total TAMs and differential M1 and M2 TAM infiltration in low grade (LGG) versus high grade gliomas (HGG). Also, we investigated the implication of total TAMs and differential M1 and M2 TAMs infiltration on glioma progression. In-vitro, we studied the effect of soluble factors present in nanovesicles (NV) released from M1 TAMs on the fate of glioma cells.Methods: In-vivo, we performed immunohistochemistry using iNOS and CD163 (markers for M1 and M2 respectively). In-vitro, we polarized the human monocytes U937 cell line into M1, we isolated the NV from the M1-conditioned medium (CM) by centrifugation and filtration; then, the protein content of the NV was quantified by the protein assay. We added M1-NV on U251 glioma cells and we studied the cellular activation of glioma cells using the MTT assay. To assess the apoptosis of U251, we used the flow-cytometry. Apoptotic cells were identified by annexin V and Propidium Iodide (markers for early and late apoptosis respectively).Results: in-vivo, there is an M1/M2 imbalance in early stages of glioma which is associated with earlier progression to high malignancy. Also, the higher M2 infiltration, the earlier is the progression. In-vitro, M1-NV had a more potent anti-tumor effect compared to its corresponding CM. We assume that our experimental results can be a future treatment for the cerebral glioma.

Follicular Dendrytic Cells Deliver Angiogenesis Signaling To Follicular Lymphoma Cells That Is Hampered By The Pan-PI3K Inhibitor NVP-BKM120

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3072-3072 ◽  
Author(s):  
Alba Matas-Céspedes ◽  
Vanina Rodriguez ◽  
Susana Kalko ◽  
Eva Gine ◽  
Elias Campo ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Follicular Lymphoma ◽  
Cell Signalling ◽  
Principal Component ◽  
Cell Receptor ◽  
Lymphoid Follicle ◽  
Pi3k Inhibitor ◽  
The Impact

Abstract Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for proliferation and survival. In the lymphoid follicle, FL cells are surrounded by follicular dendrytic cells (FDCs) that function as antigen presenting cells delivering survival and proliferation signaling. FDCs together with macrophages are associated to poor FL survival. Our aim was to uncover the signaling pathways underlying FL-FDC crosstalk and its validation as new targets for therapy using specific inhibitors. Global gene expression profiling of FL-FDC co-cultures yield a marked modulation of FL transcriptome by FDCs. The Principal Component Analysis (PCA) showed that HK-cocultured FL cells clustered together,independently of the patient origin. Then, pathways assignmentwas performed by DAVID and GSEA softwares, both of themuncovering an overrepresentation on genes related toangiogenesis. In the DAVID analysis, we found significant(False Discovery Rate (FDR)<5%,) angiogenesis–related GOterms such as, blood vessel development, blood vessel morphogenesis, VEGFR signaling pathway, sprouting angiogenesis, positive regulation of angiogenesis, patterning of blood vessels among others. In the GSEA analysis, our dataset was interrogated for enrichment of genesets belonging to C2 data base together with custom-derived ones. In accordance with DAVID results, genesets related to angiogenesis were enriched (FDR< 5%) in HK-cocultured FLcells, such as HumanAngiogenesis, Weston_VEGFA_targtes, PID_VEGFR1_2 and PID_lymphangiogenesis. As PI3K pathway is known to play a determinant role in angiogenesis, we explored if NVP-BKM120, a pan-PI3K inhibitor in clinical trials for solid tumors, could interfere with this signaling. First, by using Taqman Angiogenesis Array®containing 94 probes against genes related to angiogenesis, we analyzed if the modulation of genes in FL cells cocultured with HK could be inhibited by NVP-BKM120. Effectively, we found a group of genes that were positively regulated by HK and inhibited by NVP-BKM120, among them ANGPT1, CXCL12, EPHB2, VEGFA, VEGFC, ADAMST1, NRP1, NRP2, HSPG2,COL4A1, PDGFRA and PDGFRB. In addition, by ELISA analysis of cell culture supernatants, we found that NVP-BKM120 reduced VEGFA and VEGFC secretion of FL cells alone or co-cultured with HK. Then, we analyzed if this reduction of proangiogenic factors effectively reduced angiogenesis. To this aim we performed HUVEC tube formation assay with the supernatants of FL cells co-cultured or not with HK, in the presence or absence of the PI3K inhibitor. We demonstrated that, as expected, supernatants derived fromFL-HK-cocultures increased the number of tubes formed, and NVP-BKM120 reduced these numbers. Then, we investigated the impact of NVP-BKM120 treatment on FL cell signalling and proliferation. NVP-BKM120 efficiently blocks both constitutive activation of PI3K/AKT pathway in FL cells and that derived from B-cell receptor stimulation or HK co-culture, reducing cell proliferation of FL cells and inducing apoptosis in a portion of FL cell lines and primary cells. NVP-BKM120 also impedes signaling and migration induced by the chemokine SDF1α. In vivo, NVP-BKM120 significantly (p<0.05) reduces tumor outgrowth in subcutaneous and systemic FL mouse models. We isolated RNA from mouse tumors and run TaqmanAngiogenesis array as before. NVP-BKM120 downmodulated the expresion of genes related to angiogenesis already found in vitro such a VEGFA, HSPGB2, NRP2 ,PDGFRA and PDGFRB, but also novel genes, including SERPINC1, FST,PDGFB, TGFB1, TNF, VEGFB, COL18A1, ANGPT4 and PECAM(CD31). In addition, the reduction on VEGFA and CD31 was also validated by IHC in these tumors. These results warrant further investigation of pan-PI3K inhibitors for FL therapy in the context of microenvironment survival signaling inhibition. Disclosures: Lopez-Guillermo: Roche: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals In vitro and in vivo evidence for uncoupling of B-cell receptor internalization and signaling in chronic lymphocytic leukemia

Haematologica ◽  
2017 ◽  
Vol 103 (3) ◽  
pp. 497-505 ◽  
Author(s):  
Eve M. Coulter ◽  
Andrea Pepper ◽  
Silvia Mele ◽  
Najeem’deen Folarin ◽  
William Townsend ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Receptor Internalization

scholarly journals Repeated stimulation of CD4 effector T cells can limit their protective function

2005 ◽  
Vol 201 (7) ◽  
pp. 1101-1112 ◽  
Author(s):  
Dawn M. Jelley-Gibbs ◽  
John P. Dibble ◽  
Svetlana Filipson ◽  
Laura Haynes ◽  
Roslyn A. Kemp ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Primary Immune Response ◽  
Receptor Stimulation ◽  
Repeated Stimulation ◽  
The Impact

Chronic infections often result in CD8 T-cell deletion or functional nonresponsiveness. However, to date no definitive studies have attempted to determine the impact of repeated T cell receptor stimulation on CD4 effector T cell generation. We have determined that when antigen presentation is limited to 2 d, optimum in vitro CD4 effector generation is achieved. Alternatively, repeated stimulation results in decreased CD4 effector expansion, decreased cytokine production, and altered migration. Similarly, functionally impaired effectors develop in vivo when antigen-pulsed antigen-presenting cells are replenished every 24 h during a primary immune response. CD4 effectors that are generated with repeated stimulation provide no protection during influenza infection, and have an impaired ability to provide cognate help to B cells. These results suggest that duration of antigen presentation dictates CD4 effector function, and repeated T cell receptor stimulation in vitro and in vivo that exceeds an optimal threshold results in effectors with impaired function.

scholarly journals Targeting abundant survivin expression in liposarcoma: subtype dependent therapy responses to YM155 treatment

2021 ◽  
Author(s):  
Christian Vay ◽  
Philipp M. Schlünder ◽  
Levent Dizdar ◽  
Irene Esposito ◽  
Markus P. H. Ghadimi ◽  
...  
Keyword(s):  
Cell Viability ◽  
Therapeutic Potential ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Survivin Expression ◽  
Tissue Microarrays ◽  
In Vivo Models ◽  
The Impact

Abstract Purpose Liposarcoma (LPS) represent the largest group of malignant soft tissue tumours comprising a heterogeneous group of subtypes in which the degrees of chemoresistance and radiosensitivity strongly vary. Consequently, it is of utmost interest to establish novel therapeutic regimens based on molecular targets. Methods Immunohistochemical staining of survivin was performed in tissue microarrays comprising 49 primary LPS specimens. LPS cell lines were treated with survivin antagonist YM155 and doxorubicin or etoposide alone as well as in combination. Changes in cell viability were investigated and the synergistic effect of a combined therapy analysed. Results Immunohistochemistry revealed an abundant expression of survivin in LPS that significantly concurred with less-differentiated tumour subtypes and grading. In vitro, we demonstrated the impact of the survivin inhibitor YM155 on dedifferentiated LPS (DDLPS) and, even more imposing, pleomorphic LPS (PLS) tumour cell viability with a strong induction of apoptosis. A combined treatment of doxorubicin or etoposide with YM155 augmented the cytotoxic effects on DDLPS and PLS cells. Conclusion These findings support the significant role of survivin in the oncogenesis and progression of LPS subtypes providing a rationale to target survivin in eligible in-vivo models and to pioneer clinical applications of survivin-specific substances unfolding their therapeutic potential in LPS patients prospectively.

scholarly journals Gene Suppression of Transketolase-Like Protein 1 (TKTL1) Sensitizes Glioma Cells to Hypoxia and Ionizing Radiation

2018 ◽  
Vol 19 (8) ◽  
pp. 2168 ◽  
Author(s):  
Sonja Heller ◽  
Gabriele Maurer ◽  
Christina Wanka ◽  
Ute Hofmann ◽  
Anna-Luisa Luger ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Hypoxia Inducible Factor ◽  
Glioma Cells ◽  
In Vitro Study ◽  
Clonogenic Survival ◽  
Pentose Phosphate ◽  
Gene Suppression ◽  
The Impact

In several tumor entities, transketolase-like protein 1 (TKTL1) has been suggested to promote the nonoxidative part of the pentose phosphate pathway (PPP) and thereby to contribute to a malignant phenotype. However, its role in glioma biology has only been sparsely documented. In the present in vitro study using LNT-229 glioma cells, we analyzed the impact of TKTL1 gene suppression on basic metabolic parameters and on survival following oxygen restriction and ionizing radiation. TKTL1 was induced by hypoxia and by hypoxia-inducible factor-1α (HIF-1α). Knockdown of TKTL1 via shRNA increased the cells’ demand for glucose, decreased flux through the PPP and promoted cell death under hypoxic conditions. Following irradiation, suppression of TKTL1 expression resulted in elevated levels of reactive oxygen species (ROS) and reduced clonogenic survival. In summary, our results indicate a role of TKTL1 in the adaptation of tumor cells to oxygen deprivation and in the acquisition of radioresistance. Further studies are necessary to examine whether strategies that antagonize TKTL1 function will be able to restore the sensitivity of glioma cells towards irradiation and antiangiogenic therapies in the more complex in vivo environment.

scholarly journals FKBP10 promotes proliferation of glioma cells via activating AKT-CREB-PCNA axis

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Hong-Qing Cai ◽  
Min-Jie Zhang ◽  
Zhi-Jian Cheng ◽  
Jing Yu ◽  
Qing Yuan ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Xenograft Model ◽  
Glioma Cells ◽  
Tissue Microarrays ◽  
Xenograft Tumor ◽  
Confocal Immunofluorescence ◽  
Glioma Cell Proliferation ◽  
Proliferation Ability

Abstract Background Although the availability of therapeutic options including temozolomide, radiotherapy and some target agents following neurosurgery, the prognosis of glioma patients remains poor. Thus, there is an urgent need to explore possible targets for clinical treatment of this disease. Methods Tissue microarrays and immunohistochemistry were used to detect FKBP10, Hsp47, p-AKT (Ser473), p-CREB (Ser133) and PCNA expression in glioma tissues and xenografts. CCK-8 tests, colony formation assays and xenograft model were performed to test proliferation ability of FKBP10 in glioma cells in vitro and in vivo. Quantitative reverse transcriptase-PCR, western-blotting, GST-pull down, co-immunoprecipitation and confocal-immunofluorescence staining assay were used to explore the molecular mechanism underlying the functions of overexpressed FKBP10 in glioma cells. Results FKBP10 was highly expressed in glioma tissues and its expression was positively correlates with grade, poor prognosis. FKBP10-knockdown suppressed glioma cell proliferation in vitro and subcutaneous/orthotopic xenograft tumor growth in vivo. Silencing of FKBP10 reduced p-AKT (Ser473), p-CREB (Ser133), PCNA mRNA and PCNA protein expression in glioma cells. FKBP10 interacting with Hsp47 enhanced the proliferation ability of glioma cells via AKT-CREB-PCNA cascade. In addition, correlation between these molecules were also found in xenograft tumor and glioma tissues. Conclusions We showed for the first time that FKBP10 is overexpressed in glioma and involved in proliferation of glioma cells by interacting with Hsp47 and activating AKT-CREB-PCNA signaling pathways. Our findings suggest that inhibition of FKBP10 related signaling might offer a potential therapeutic option for glioma patients.

scholarly journals IL-33/ST2 axis promotes glioblastoma cell invasion by accumulating tenascin-C

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jian-fei Zhang ◽  
Tao Tao ◽  
Kang Wang ◽  
Guo-xiang Zhang ◽  
Yujin Yan ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Cell Invasion ◽  
Glioma Cells ◽  
Nuclear Factor Κb ◽  
Signalling Pathway ◽  
Control Treatment ◽  
Tenascin C ◽  
The Impact

AbstractTenascin-C (TNC), a very large multimeric glycoprotein, is overexpressed in human glioblastomas, leading to a highly motile and invasive phenotype of glioma cells. However, the regulation of TNC expression in glioma has remained unclear until now. Our data suggest that interleukin-33 (IL-33) may promote the accumulation of TNC protein by autocrine or paracrine modes of action in glioma. In the present study, the expression levels of TNC, IL-33, and ST2 were measured in glioma tissue specimens, and the impact of altered IL-33 expression on TNC was investigated in vitro and in vivo. In contrast with control treatment, IL-33 treatment increased TNC expression, and knockdown of IL-33 attenuated TNC expression in glioma cells. Furthermore, IL-33 induced the activation of nuclear factor κB (NF-κB) and increased the expression of TNC in U251 cells. In addition, blockage of the IL-33-ST2-NFκB pathway resulted in downregulation of TNC production. IL-33 promoted glioma cell invasion by stimulating the secretion of TNC. Similarly, knockdown of TNC inhibited the invasiveness of glioma cells. These findings provide a novel perspective on the role of the IL-33/NF-κB/TNC signalling pathway in supporting cancer progression. Thus, targeting the IL-33/NF-κB/TNC signalling pathway may be a useful therapeutic approach in glioma.

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