Local anti-angiogenic therapy by magnet-assisted downregulation of SHP2 phosphatase

Rieck, Sarah; Heun, Yvonn; Heidsieck, Alexandra; Mykhaylyk, Olga; Pfeifer, Alexander; Gleich, Bernhard; Mannell, Hanna; Wenzel, Daniela

doi:10.1016/j.jconrel.2019.05.031

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…The tyrosine phosphatase SHP-2 has been demonstrated by us to positively influence angiogenesis in vitro and in vivo [11,12,13] and may constitute an interesting future therapeutic target within this context. In an earlier study we demonstrated that SHP-2 is important for HIF-1α stabilisation and activity during hypoxia, resulting in enhanced hypoxia induced HIF-1α dependent revascularisation of wounds in vivo [12].…”

Section: Introductionmentioning

confidence: 99%

The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity

Heun

Groterhorst

Pogoda

et al. 2019

IJMS

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Vascular remodeling and angiogenesis are required to improve the perfusion of ischemic tissues. The hypoxic environment, induced by ischemia, is a potent stimulus for hypoxia inducible factor 1α (HIF-1α) upregulation and activation, which induce pro-angiogenic gene expression. We previously showed that the tyrosine phosphatase SHP-2 drives hypoxia mediated HIF-1α upregulation via inhibition of the proteasomal pathway, resulting in revascularization of wounds in vivo. However, it is still unknown if SHP-2 mediates HIF-1α upregulation by affecting 26S proteasome activity and how the proteasome is regulated upon hypoxia. Using a reporter construct containing the oxygen-dependent degradation (ODD) domain of HIF-1α and a fluorogenic proteasome substrate in combination with SHP-2 mutant constructs, we show that SHP-2 inhibits the 26S proteasome activity in endothelial cells under hypoxic conditions in vitro via Src kinase/p38 mitogen-activated protein kinase (MAPK) signalling. Moreover, the simultaneous expression of constitutively active SHP-2 (E76A) and inactive SHP-2 (CS) in separate hypoxic wounds in the mice dorsal skin fold chamber by localized magnetic nanoparticle-assisted lentiviral transduction showed specific regulation of proteasome activity in vivo. Thus, we identified a new additional mechanism of SHP-2 mediated HIF-1α upregulation and proteasome activity, being functionally important for revascularization of wounds in vivo. SHP-2 may therefore constitute a potential novel therapeutic target for the induction of angiogenesis in ischemic vascular disease.

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Section: Introductionmentioning

confidence: 99%

The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity

Heun

Groterhorst

Pogoda

et al. 2019

IJMS

Self Cite

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“…Experiments in vitro suggested that SHP2 regulates endothelial adhesive functions and migration stemming from SHP2 binding to the intracellular domain of endothelial platelet-derived growth factor receptor-b (PDGFR-b), VE-cadherin and PECAM-1 (47,48). The knockdown of SHP2 transiently reduced FGF2+VEGF-dependent endothelial cell viability in vitro and ex vivo (22), delayed vessel regeneration in a mouse skin wounding model (49) and increased endothelial monolayer permeability (21). Also, SHP2 promoted VEGF-dependent ERK1/2 signaling (50), consistent with the role of EphrinB2-SHP2 signaling as a key regulator of VEGFR2 internalization and ERK signaling (37,38).…”

Section: Discussionmentioning

confidence: 99%

Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

Wang

Salvucci

Ohnuki

et al. 2020

Preprint

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The tyrosine phosphatase SHP2 is oncogenic in cancers driven by receptor-tyrosine-kinases, and SHP2 inhibition reduces tumor growth. Here, we report that SHP2 is an essential promoter of endothelial cell survival and growth in the remodeling tumor vasculature. Using genetic and chemical approaches to inhibit SHP2 activity in endothelial cells, we show that SHP2 inhibits pro-apoptotic STAT3 and stimulates proliferative ERK1/2 signaling. Systemic SHP2 inhibition in mice bearing tumors selected for SHP2-independent tumor-cell growth, promotes degeneration of the tumor vasculature and blood extravasation; reduces tumor vascularity and blood perfusion; and increases tumor hypoxia and necrosis. Reduction of tumor growth ensues, independent of SHP2 targeting in the tumor cells, blocking immune checkpoints or recruiting anti-tumor macrophages. We also show that inhibiting the Angiopoietin/TIE2/AKT cascade magnifies the vascular and anti-tumor effects of SHP2 inhibition by blocking tumor endothelial AKT signaling, not a target of SHP2. Since the SHP2 and Ang2/TIE2 pathways are active in vascular endothelial cells of human melanoma and colon carcinoma, SHP2 inhibitors alone or with Ang2/Tie2 inhibitors hold promise to effectively target the tumor endothelium.

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“…Also, establishment of 3D cell culture arrays which enable cellular patterning for an assessment of the impact of fibroblasts and their infiltration properties are provided by magnetic fields (Shim and Hur, 2017). MNPs can be localized in particular parts of the body using magnetic fields which permit to selectively transmit distinct payload to immune cells depending on the phagocytic uptake to injured areas of the liver (Rieck et al, 2019). The spatial concentration of MNPs may also be regulated via MRI apparatuses (Pi et al, 2018).…”

Section: Magnetic Nanoparticles For Liver Fibrosis Theranosticsmentioning

confidence: 99%

The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics

et al. 2021

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Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic liver damage and leading to cirrhosis, liver cancer, and liver failure. To date, there is no effective and specific therapy for patients with hepatic fibrosis. As a result of their various advantages such as biocompatibility, imaging contrast ability, improved tissue penetration, and superparamagnetic properties, magnetic nanoparticles have a great potential for diagnosis and therapy in various liver diseases including fibrosis. In this review, we focus on the molecular mechanisms and important factors for hepatic fibrosis and on potential magnetic nanoparticles-based therapeutics. New strategies for the diagnosis of liver fibrosis are also discussed, with a summary of the challenges and perspectives in the translational application of magnetic nanoparticles from bench to bedside.

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Local anti-angiogenic therapy by magnet-assisted downregulation of SHP2 phosphatase

Cited by 10 publications

References 32 publications

The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity

The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity

Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics

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