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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.

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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