scholarly journals Exosomal circEIF3K from cancer-associated fibroblast promotes colorectal cancer (CRC) progression via miR-214/PD-L1 axis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kaihua Yang ◽  
Jie Zhang ◽  
Chuanqing Bao
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tube Formation ◽  
Normal Tissues ◽  
Cancer Associated Fibroblast ◽  
Dataset Analysis ◽  
Tcga Dataset ◽  
Sw620 Cells ◽  
Hct116 Cells

Abstract Background Tumor microenvironment (e.g., cancer-associated fibroblast) plays a key role in cancer tumorigenesis and metastasis. However, the detailed mechanism of whether hypoxia promotes CRC progression via tumor microenvironment remains unclear. Methods In this study, circEIF3K exosome was examined by NanoSight Tracking Analysis and RT-qPCR. We used cell colony formation assay, transwell assay and tube formation assay to determine proliferation, invasion and metastasis of HCT116 or SW620 cells. Xenograft tumor assay was employed to show in vivo tumor growth of HCT116 cells. Results We found that hypoxia could induce secretion of circEIF3K exosome. Conditioned medium (CM) and exosome from circEIF3K knockdown CAF significantly attenuated proliferation, invasion and tube formation of HCT116 or SW620 cells, which could be reverted by miR-214 under hypoxia treatment. Besides, we observed that circEIF3K knockdown evidently impaired tumor growth in mice. TCGA dataset analysis showed that low expression of circEIF3K was observed in normal tissues and associated with prolonged survival time. Finally, PD-L1 was confirmed as important target for miR-214 in CRC. Conclusion In conclusion, our study reveals that a novel axis circEIF3K/miR-214/PD-L1 mediates hypoxia-induced CRC progression via CAF, providing the rationale for developing new targeted therapeutics to treat CRC.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

scholarly journals Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Mu-Su Pan ◽  
Hui Wang ◽  
Kamar Hasan Ansari ◽  
Xin-Ping Li ◽  
Wei Sun ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Gallbladder Cancer ◽  
Molecular Mechanism ◽  
Poor Prognosis ◽  
Vasculogenic Mimicry ◽  
Tube Formation ◽  
Signal Pathway ◽  
Cancer Associated Fibroblasts

Abstract Background Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism. Methods A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (−) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway. Conclusions GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

scholarly journals Targeting Tumor Microenvironment: Effects of Chinese Herbal Formulae on Macrophage-Mediated Lung Cancer in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Fei Xu ◽  
Wenqiang Cui ◽  
Zhengxiao Zhao ◽  
Weiyi Gong ◽  
Ying Wei ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Chronic Obstructive Lung Disease ◽  
Chronic Obstructive ◽  
Arginase 1 ◽  
Airway Diseases ◽  
Stat3 Signaling Pathway ◽  
Stat3 Phosphorylation

Our previous studies have shown that Qing-Re-Huo-Xue (QRHX) formulae had significant anti-inflammatory effects in chronic airway diseases such as asthma and chronic obstructive lung disease. Here, we examined the effects of QRHX on lung cancer cell invasion and the potential associated mechanism(s), mainly polarization of macrophages in the tumor microenvironment. In vivo, QRHX both inhibited tumor growth and decreased the number of tumor-associated macrophages (TAMs) in mice with lung cancer. Further study indicated that QRHX inhibited cancer-related inflammation in tumor by decreasing infiltration of TAMs and IL-6 and TNF-α production and meanwhile decreased arginase 1 (Arg-1) expression and increased inducible NO synthase (iNOS) expression. QRHX could markedly inhibit CD31 and VEGF protein expression. Additionally, CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were reduced in QRHX treatment group. Thus, we draw that QRHX played a more important role in inhibiting tumor growth by regulating TAMs in mice, which was found to be associated with the inhibition of inflammation and the CXCL12/CXCR4/JAK2/STAT3 signaling pathway.

scholarly journals Small Extracellular Vesicles Released from Glioma Cells Under Hypoxic Conditions Induce Pericyte-phenotype Transition of Glioma Stem Cells.

2021 ◽  
Author(s):  
Yue Cheng ◽  
Shijie Li ◽  
Yongying Hou ◽  
Weijun Wang ◽  
Ke Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Antiangiogenic Therapy ◽  
Alternative Therapy ◽  
Tube Formation ◽  
Glioma Stem Cells ◽  
Phenotype Transition

Abstract Background:The prognosis of malignant glioblastoma (GBM) is dismal despite advances in surgery, radiation and chemotherapy treatments. Thus, alternative therapy strategies are urgently needed. Antiangiogenic therapy for cancer offers the possibility of universal efficacy. However, preclinical and clinical studies suggest that this therapy using anti-VEGF drug Avastin (Bevacizumab) may lead to a pro-migratory phenotype in therapy resistant GBM and thus actively promote tumor invasion and recurrent tumor growth. Methods: An ultracentrifugation strategy was used to isolate glioma-derived sEVs under hypoxic or normoxic conditions. Transmission electron microscopy (TEM), Western blotting, and nanoparticle tracking analysis (NTA) were used to characterize these isolated particles. Cytochalasin D was added to disrupt cellular sEVs uptake. A tube formation assay was used to evaluate angiogenic activity, while ELISAs and Western blotting were used to assess the activated TGF-β signaling pathway. The effects of sEVs on glioma stem cells (GSCs) in vivo were evaluated using subcutaneous xenografts model system in nude mice. Immunofluorescence and immunohistochemical staining were set out to evaluate the pericyte-phenotype transition of GSCs.Results: In this present study, we showed that hypoxia could promote the release of sEVs by glioblastoma cells and hypoxia-induced glioma-derived sEVs could be taken up by GSCs. This internalization of sEVs promoted tumor growth in mouse Xenografts through the pericyte-phenotype transition of GSCs. We also demonstrated hypoxia-derived sEVs can efficiently deliver TGF-β1 to GSCs. The activated TGF-β signaling pathway mediated this kind of phenotype transition. In addition, combination of Ibrutinib and Bevacizumab showed more effective in targeting GBM. Conclusion: This present study provides a new interpretation to the failure of antiangiogenesis therapy in noncurative surgical resection of GBM, and discovers promising brain-specific therapeutic targets for this damaging tumor.

scholarly journals Chemical and Functional Separation of Pro- and Antiangiogenic Components of Danhong Injection in Ischemic or Tumor Vascular Models

2021 ◽  
Author(s):  
Shuang He ◽  
Rongrong Chen ◽  
Li Peng ◽  
Zhenzuo Jiang ◽  
Haixin Liu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Lung Tumor ◽  
Tube Formation ◽  
Migration Ability ◽  
Migration Assay ◽  
Danhong Injection ◽  
Limb Perfusion ◽  
Inhibition Of Angiogenesis ◽  
And Migration

Abstract Objective: We aimed to investigate the chemical basis and mechanism of angiogenesis regulation by a multicomponent Chinese medicine Danhong injection (DHI). Methods: A chemical fraction library of DHI was screened and validated for angiogenesis activities by tube formation and migration assays. Mouse ischemic and tumor vascular models were used to verify the angiogenesis effects in vivo. Migration ability of the main monomers of proangiogenic component (PAC) and antiangiogenic component (AAC) in EA.hy926 cells were determined by migration assay. qPCR analyses were performed to access whether the main monomers of PAC or AAC could affect the expression of angiogenesis-related genes in ECs. Western blotting was used to verify the main monomers PAC and AAC effects on CXCR4 protein expression. Results: Two chemically-distinct fractions, including promotion and inhibition of angiogenesis, were identified in DHI. PAC enhanced angiogenesis and improved recovery of ischemic limb perfusion while AAC reduced Lewis lung tumor growth in vivo in VEGFR-2-Luc mice. CA and RA upregulated the expression of TSP1 and downregulated the expression of KDR and PECAM genes. CXCR4 expression was significantly decreased by CA and RA, but increased by PAI, consistent with their differential effects on EC migration. Conclusion: DHI is capable of bi-directional regulation of angiogenesis in a disease-specific manner. The proangiogenesis activity of DHI promotes ischemic vascular injury repair, whereas the anti-angiogenesis activity inhibits tumor growth. The best pro- and anti-angiogenesis activities are composed of unique chemical combinations that differentially regulate angiogenesis-related gene network.

scholarly journals Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Christof Kaltenmeier ◽  
Hamza O. Yazdani ◽  
Kristin Morder ◽  
David A. Geller ◽  
Richard L. Simmons ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Metastasis ◽  
Neutrophil Extracellular Traps ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Extracellular Traps

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

scholarly journals Degradation of long non-coding RNA-CIR decelerates proliferation, invasion and migration, but promotes apoptosis of osteosarcoma cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Shiwei Liu ◽  
Jingchao Li ◽  
Liang Kang ◽  
Yueyang Tian ◽  
Yuan Xue
Keyword(s):  
Tumor Growth ◽  
Osteosarcoma Cell ◽  
Loss Of Function ◽  
Osteosarcoma Cells ◽  
Invasion And Migration ◽  
Normal Tissues ◽  
Novel Target ◽  
And Migration

Abstract Background Over the years, long non-coding RNAs (lncRNAs) have been clarified in malignancies, this research was focused on the role of lncRNA cartilage injury-related (lncRNA-CIR) in osteosarcoma cells. Methods LncRNA-CIR expression in osteosarcoma tissues and cells, and adjacent normal tissues and normal osteoblasts was determined, then the relations between lncRNA-CIR expression and the clinicopathological features, and between lncRNA-CIR expression and the prognosis of osteosarcoma patients were analyzed. Moreover, the MG63 and 143B cells were treated with silenced or overexpressed lncRNA-CIR, and then the proliferation, invasion, migration and apoptosis of the cells were evaluated by gain- and loss-of-function approaches. The tumor growth, and proliferation and apoptosis of osteosarcoma cells in vivo were observed by subcutaneous tumorigenesis in nude mice. Results We have found that lncRNA-CIR was up-regulated in osteosarcoma tissues and cells, which was respectively relative to adjacent normal tissues and normal osteoblasts. The expression of lncRNA-CIR was evidently correlated with disease stages, distant metastasis and differentiation of osteosarcoma patients, and the high expression of lncRNA-CIR indicated a poor prognosis. Furthermore, the reduction of lncRNA-CIR could restrict proliferation, invasion and migration, but promote apoptosis of osteosarcoma cells in vitro. Meanwhile, inhibited lncRNA-CIR also restrained tumor growth and osteosarcoma cell proliferation, whereas accelerated apoptosis of osteosarcoma cells in vivo. Conclusion We have found in this study that the inhibited lncRNA-CIR could decelerate proliferation, invasion and migration, but accelerate apoptosis of osteosarcoma cells, which may provide a novel target for osteosarcoma treatment.

scholarly journals IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi125-vi125
Author(s):  
Tyler Alban ◽  
Defne Bayik ◽  
Balint Otvos ◽  
Matthew Grabowski ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Signaling Axis ◽  
Immunosuppressive Microenvironment ◽  
And Function

Abstract The immunosuppressive microenvironment in glioblastoma (GBM) enables persistent tumor growth and evasion from tumoricidal immune cell recognition. Despite a large accumulation of immune cells in the GBM microenvironment, tumor growth continues, and evidence for potent immunosuppression via myeloid derived suppressor cells (MDSCs) is now emerging. In agreement with these observations, we have recently established that increased MDSCs over time correlates with poor prognosis in GBM, making these cells of interest for therapeutic targeting. In seeking to reduce MDSCs in GBM, we previously identified the cytokine macrophage migration inhibitory factor (MIF) as a possible activator of MDSC function in GBM. Here, using a novel in vitro co-culture system to reproducibly and rapidly create GBM-educated MDSCs, we observed that MIF was essential in the generation of MDSCs and that MDSCs generated via this approach express a repertoire of MIF receptors. CD74 was the primary MIF receptor in monocytic MDSCs (M-MDSC), which penetrate the tumor microenvironment in preclinical models and patient samples. A screen of MIF/CD74 interaction inhibitors revealed that MN-166, a clinically relevant blood brain barrier penetrant drug, which is currently fast tracked for FDA approval, reduced MDSC generation and function in vitro. This effect was specific to M-MDSC subsets expressing CD74, and appeared as reduced downstream pERK signaling and MCP-1 secretion. In vivo, MN-166 was able reduce tumor-infiltrating MDSCs, while conferring a significant increase in survival in the syngeneic glioma model GL261. These data provide proof of concept that M-MDSCs can be targeted in the tumor microenvironment via MN-166 to reduce tumor growth and provide a rationale for future clinical assessment of MN-166 to reduce M-MDSCs in the tumor microenvironment. Ongoing studies are assessing the effects of MDSC inhibition in combination with immune activating approaches, in order to inhibit immune suppression while simultaneously activating the immune system.

Abstract 453: Engineering the tumor microenvironment: Hemin conditioning in vivo impairs tumor growth and reprograms the immune-modulatory response in prostate cancer

2015 ◽  
Author(s):  
Felipe M. Jaworski ◽  
Geraldine G. Gueron ◽  
Lucas D. Gentilini ◽  
Daiana B. Leonardi ◽  
Ignacio González Pérez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Tumor Growth

μ Opioid Receptor Stimulates a Growth Promoting and Pro-Angiogenic Tumor Microenvironment by Transactivating VEGF Receptor-2/Flk-1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3687-3687
Author(s):  
Elliot J. Stephenson ◽  
Humberto J. Martinez-Suarez ◽  
Mariya Farooqui ◽  
Debabrata Mukhopadhyay ◽  
Deborah A. Hughes ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Opioid Receptor ◽  
Calcium Release ◽  
Small Gtpase ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Growth Promoting ◽  
Stimulation Of

Abstract Like VEGF, morphine stimulates MAPK/ERK and Akt, leading to the promotion of angiogenesis via NO dependent signaling (Cancer Res62: 4491, 2002). Morphine acts via pertussis toxin (PT)-dependent G-protein coupled receptors (GPCRS), while VEGF acts via receptor tyrosine kinases (RTKs). We showed that PT-dependent GPCRs transactivate VEGF receptor-2/Flk1 via small GTPase RhoA (JBC277: 4679, 2002; JBC278:20738, 2003). Therefore, we hypothesized that morphine via the mu opioid receptor (MOR) transactivates Flk1 and promotes a pro-angiogenic microenvironment. Morphine-induced proliferation of human umbilical vein endothelial cells (HUVEC) was completely abrogated by Y-27632 (100 μM), a highly selective and potent inhibitor of Rho-associated protein kinases, suggesting the activation of Rho signaling by morphine. Addition of 1 μM morphine potentiated VEGF-induced (10 ng/ml) proliferation of HUVEC by 25%. We observed a 30% increase in intracellular calcium release after VEGF stimulation of HUVEC pre-incubated with morphine as compared to HUVEC pre-incubated with PBS, detected by a change in the fluorescence ratio of the Fura-2 AM dye. These findings show that morphine, via MOR and Rho signaling, transactivates Flk1 leading to the stimulation of calcium signaling and endothelial cell proliferation. To functionally corroborate our hypothesis, we used MOR knockout (MOR-KO) mice and injected them with MOR-replete T241 fibrosarcoma cells. T241 fibrosarcoma tumor growth in vivo showed appearance of palpable and measurable tumors 2 days earlier in wild type (wt) as compared to MOR-KO mice. Tumor growth and angiogenesis were decreased by 20–35% in MOR-KO mice as compared to wt littermates during 3 weeks of tumor growth. None of the MOR-KO showed signs of lung metastasis versus 40% wt mice with metastasis. Morphine (1.42 for the first 2 wks and 2.14 mg/Kg/day later, respectively) stimulated 20–35% tumor growth in wt, but not in MOR-KO mice. Western immunoblotting showed a 10-fold increase in the expression of phospho-Flk1 in morphine treated wt tumors as compared to PBS-treated wt mice. Morphine did not stimulate phospho-Flk1 expression in MOR-KO mice. Western analysis of immunoprecipitates obtained with α-MOR antibody showed the expression of Flk1 and phospho-Flk1 in wt, but were not expressed in MOR-KO tumors. Thus, MOR stimulates the transactivation of Flk1 in wt mice but not in MOR-KO. These in vitro and in vivo data using MOR-KO mice and the MOR agonist, morphine, show that MOR stimulates endothelial proliferation, angiogenesis and promotes tumor growth and metastasis directly as well as by transactivating Flk1 phosphorylation. We speculate that MOR is a critical component of the ‘angiogenic switch’, which regulates the pro-angiogenic and growth promoting tumor microenvironment. Thus, MOR provides a novel target for developing anti-angiogenic therapies.

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