Dataset Information

PDGF/PDGFR effects in osteosarcoma and the "add-on" strategy.

ABSTRACT: New treatment options for advanced osteosarcoma have remained limited. The platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) pathway plays an important role in the development and metastasis of osteosarcoma, via either direct autocrine stimulation of tumor cells, or paracrine stimulation on tumor stromal cells. It promotes angiogenesis to overcome hypoxia in the tumor microenvironment, and modulates tumor interstitial fluid pressure to control the influx and efflux of other agents. Targeting the PDGF/PDGFR pathway is a promising therapeutic method to overcome drug resistance and improve patients' outcome in osteosarcoma. Further evidence is needed to define the detailed mechanism. Results from clinical trials using PDGF/PDGFR inhibitor as a single agent were disappointing, both in osteosarcoma and soft tissue sarcoma. However, when combined with other agents, named as "add-on" strategy, a synergistic antitumor effect has been confirmed in soft tissue sarcoma, and should be attempted in osteosarcoma.

SUBMITTER: Xu J

PROVIDER: S-EPMC6071404 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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PDGF/PDGFR effects in osteosarcoma and the "add-on" strategy.

Xu Jie J Xie Lu L Guo Wei W

Clinical sarcoma research 20180802

New treatment options for advanced osteosarcoma have remained limited. The platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) pathway plays an important role in the development and metastasis of osteosarcoma, via either direct autocrine stimulation of tumor cells, or paracrine stimulation on tumor stromal cells. It promotes angiogenesis to overcome hypoxia in the tumor microenvironment, and modulates tumor interstitial fluid pressure to control the influx and e ...[more]

PMID: 30083310

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Project description:Inflammation plays a key role in the pathophysiological processes after intracerebral hemorrhage (ICH). Post-ICH macrophages infiltrate the brain and release pro-inflammatory factors (tumor necrosis factor-?), amplifying microglial activation and neutrophil infiltration. Platelet-derived growth factor receptor-? (PDGFR-?) is expressed on macrophages and it's activation induces the recruitment of macrophages. Platelet-derived growth factor-D (PDGF-D) is an agonist with a significantly higher affinity to the PDGFR-? compared to another isoform of the receptor. In this study, we investigated the role of PDGF-D in the pro-inflammatory response after ICH in mice.A blood injection model of ICH was used in eight-week old male CD1 mice (weight 30g). Some mice received an injection of plasmin or PDGF-D. Gleevec, a PDGFR inhibitor, was administered at 1, 3 or 6h post-ICH. Plasmin was administered with or without PDGF-D siRNAs mixture or scramble siRNA. A plasmin-antagonist, ?-Aminocaproic acid (EACA), was co-administrated with the blood. The effects of ICH and treatment on the brain injury and post-ICH inflammation were investigated.ICH resulted in the overexpression of PDGF-D, associated with the infiltration of macrophages. PDGFR-inhibition decreased ICH-induced brain injury, attenuating macrophage and neutrophil infiltration, reducing microglial activation and TNF-? production. Administration of recombinant PDGF-D induced TNF-? production, and PDGFR-inhibition attenuated it. A plasmin-antagonist suppressed PDGFR-? activation and microglial activation. Plasmin increased PDGF-D expression, and PDGF-D inhibition reduced neutrophil infiltration.ICH-induced PDGF-D accumulation contributed to post-ICH inflammation via PDGFR activation and enhanced macrophage infiltration. The inhibition of PDGFR had an anti-inflammatory effect. Plasmin is a possible upstream effector of PDGF-D. The targeting of PDGF-D may provide a novel way to decrease brain injury after ICH.

Project description:The purpose of this study was to explore the effect of miR-34c on PDGF-BB-induced HAVSMCs phenotypic transformation and proliferation via PDGFR-β/SIRT1 pathway, so as to find a new method for early diagnosis and treatment of cardiovascular disease. HA-VSMCs were treated with platelet-derived growth factor-BB (PDGF-BB) at 0 h, 12 h, 24 h, 48 h or 36 h to explore the optimal time for phenotypic transformation of VSMCs. And then, PDGF-BB-induced HA-VSMCs were transfected with miR-34c mimics/mimics NC and pcDNA3.1-PDGFR-β/pcDNA3.1-NC to observe cell biological behaviour. CCK8 was used to detect cell proliferation activity. Transwell chamber assay was used to detect cell invasion. Early apoptosis was analyzed by flow cytometry. The expression of α-SMA and Smemb was detected by immunofluorescence staining. The expressions of PDGFR-β, IRF9, Acetyl-NF-κB/p65, Acetyl-p53 and CyclinD1 were analyzed by Western blot analysis. The expression of miR-34a, miR-34b and miR-34c was detected by RT-PCR, and the targeting relationship between miR-34c and PDGFR-β was detected by luciferase reporting assay. The results indicated the proliferation and migration of PDGF-BB-induced HA-VSMCs significantly increased, and apoptosis significantly decreased. Besides, α-SMA decreased significantly, while Smemb increased significantly. Furthermore, expressions of PDGFR-β, IRF9, Acetyl-NF-κB/p65, Acetyl-p53 and CyclinD1 increased significantly, and SIRT1 decreased significantly. Experimental results showed that, miR-34c mimics significantly inhibited cell proliferation and migration, and promoted cell apoptosis, and miR-34c inhibitor had the opposite effects. MiR-34c mimics significantly increased α-SMA expression and decreased Smemb expression, while the opposite effects were reflected after transfection with miR-34c inhibitor. Moreover, miR-34c mimics significantly decreased the expressions of PDGFR-β, IRF9, Acetyl-NF-κB/p65, Acetyl-p53 and CyclinD1, and significantly increased the expression of SIRT1, while miR-34c inhibitor had the opposite effects. Luciferase assay confirmed that PDGFR-β was a potential target of miR-34c. Subsequently, PDGF-BB-induced HA-VSMCs were co-transfected with miR-34c mimics and pcDNA3.1-PDGFR-β. The results indicated that PDGFR-β reversed the biological function of miR-34c mimic. The results revealed the potential application value of miR-34c as a marker molecule of phenotypic transformation, providing a potential target for improving phenotypic transformation.

Dataset Information

PDGF/PDGFR effects in osteosarcoma and the "add-on" strategy.

Publications

PDGF/PDGFR effects in osteosarcoma and the "add-on" strategy.

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