Mechanism of TNF‐α‐induced migration and hepatocyte growth factor production in human mesenchymal stem cells

Zhang, Aibin; Wang, Yan; Zhou, Ye; Xie, Haiyang; Zhou, Lin; Zheng, Shusen

doi:10.1002/jcb.22729

Cited by 48 publications

(42 citation statements)

References 28 publications

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“…Functionally, the C-domain of heparanase can mediate enhanced Akt phosphorylation (35). Interestingly, it was recently demonstrated that induction of Akt phosphorylation leads to enhanced HGF expression and secretion in human mesenchymal stem cells (36). However, heparanase did not alter levels of Akt phosphorylation in the myeloma cells studied here 4 indicating that the C-domain likely has functions that have not yet been uncovered.…”

Section: Discussionmentioning

confidence: 81%

Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity

Ramani¹,

Yang

Ren³

et al. 2011

Journal of Biological Chemistry

106

110

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Hepatocyte growth factor (HGF) is a heparin-binding cytokine that enhances growth, motility, and angiogenesis of many tumor types, including multiple myeloma where it is often highly expressed. However, little is known regarding what controls HGF level and activity in these tumors. Evaluation of bone marrow biopsies from myeloma patients revealed a strong positive correlation between the levels of HGF and heparanase, an endoglucuronidase known to promote aggressive tumor behavior. In vitro, addition of recombinant heparanase to myeloma cells or transfection of myeloma cell lines with the cDNA for heparanase significantly increased tumor cell expression and secretion of biologically active HGF. Shed syndecan-1, whose levels in myeloma are also enhanced by heparanase expression, binds to secreted HGF. This syndecan-1-HGF complex is active as shown by its ability to stimulate paracrine signaling via c-Met, the cell surface receptor for HGF. Surprisingly, heparanase enzyme activity was not required for up-regulation of HGF expression by the tumor cells. This is in contrast to the heparanase-mediated enhanced syndecan-1 shedding, which does require activity of the enzyme. This suggests that two different functional domains within the heparanase enzyme (the enzyme active site and a separate site) contribute to events leading to enhanced HGF signaling. These findings demonstrate a novel mechanism driving the HGF pathway whereby heparanase stimulates an increase in both HGF expression and syndecan-1 shedding to enhance HGF signaling. This work also provides further mechanistic insight into the dynamic role of heparanase in driving aggressive tumor progression.Heparanase, an endo-␤-D-glucuronidase capable of cleaving intact heparan sulfate chains from proteoglycans, is up-regulated in a wide variety of human cancers and has been associated with promoting an array of cellular events leading to enhanced tumor progression (1). In addition to its enzymatic glycosidase activity, various nonenzymatic roles of heparanase such as enhancement of AKT signaling have also been described (2). In multiple myeloma, data from in vitro and in vivo models coupled with analysis of clinical samples have identified heparanase as a promoter of tumor angiogenesis, growth, and metastasis (3-7). Together these findings indicate that heparanase is a key regulator of myeloma progression.Many of the pro-tumorigenic effects of heparanase in myeloma have been traced to heparanase-stimulated up-regulation of syndecan-1 expression and shedding (2, 4). Syndecan-1, a heparan sulfate proteoglycan, is expressed on most myeloma tumor cells and is a critical determinant of myeloma cell survival and growth (8). Heparanase stimulates the synthesis and shedding of syndecan-1 via increased expression of two sheddases, MMP-9 and uPA 3 (7). Syndecan-1 remains biologically active after it is shed from cells and can control the localization and availability of many heparin-binding growth factors (9). Using in vivo models of myeloma, our laboratory has demonstrated t...

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Section: Discussionmentioning

confidence: 81%

Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity

Ramani¹,

Yang

Ren³

et al. 2011

Journal of Biological Chemistry

106

110

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“…MSC accumulation was significantly decreased through parthenolide inhibition of NF-kB activity. Although several studies have shown that mitogen-activated protein kinase (MAPK) phosphorylation by growth factors are involved in MSC migration (16,17), parthenolide did not inhibit MAPK phosphorylation (data not shown). Therefore, at least parthenolide treatment did not affect in migration ability of MSCs toward growth factors from tumors in this experimental settings.…”

Section: Discussionmentioning

confidence: 88%

NF-κB Activity Regulates Mesenchymal Stem Cell Accumulation at Tumor Sites

et al. 2013

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Mesenchymal stem cells (MSC) accumulate at tumor sites when injected into tumor-bearing mice, perhaps offering cellular vectors for cancer-targeted gene therapy. However, the molecular mechanisms involved in MSC targeting the tumors are presently little understood. We focused on MSC-endothelial cell (EC) adhesion following TNF-a stimulation in an attempt to elucidate these mechanisms. Interestingly, stimulation of MSCs with TNF-a enhanced the adhesion of MSCs to endothelial cells in vitro. This adhesion was partially inhibited by blocking antibodies against vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4). It is well known that TNF-a induces VCAM-1 expression via the NF-kB signaling pathway. Parthenolide has an anti-inflammatory activity and suppressed NF-kB activity by inhibition of IkBa phosphorylation after TNF-a stimulation and strongly inhibited TNF-a-induced VCAM-1 expression on MSCs. In vivo imaging using luciferase-expressing MSCs revealed that the bioluminescent signal gradually increased at tumor sites in mice injected with untreated MSCs. In contrast, we observed very weak signals at tumor sites in mice injected with parthenolide-treated MSCs. Our results suggest that NF-kB activity regulates MSC accumulation at tumors, by inducing VCAM-1 and thereby its interaction with tumor vessel endothelial cells. These findings have implications for the ongoing development of efficient MSC-based gene therapies for cancer treatment. Cancer Res; 73(1); 364-72. Ó2012 AACR.

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“…The factors that lead to up-regulation of HGF expression in the setting of bleomycin-induced lung injury are beyond the scope of this project, but a variety of proteases and inflammatory cytokines, such as interleukin (IL)-6, IL-1a, IL-1b and TNF-a, have been shown to increase HGF mRNA and protein expression [26][27][28][29][30]. Other data [7] provide an additional variable in persistent HGF production that involves previous exposure to endogenous apoptotic cells or cell debris in lung injury lesions since the phagocytic indexes in BAL alveolar macrophages increased following bacterial infections.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Lee

Moon²,

Lee³

et al. 2012

Eur Respir J

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Apoptotic cell clearance by macrophages and neighbouring tissue cells induces hepatocyte growth factor (HGF) secretion. HGF plays a key role in alveolar epithelial regeneration and reconstruction after lung injury. Direct in vivo exposure to apoptotic cells enhances HGF production, resulting in attenuation of pulmonary injury.We investigated the direct effect of in vivo exposure to apoptotic cells in bleomycin-stimulated lungs (2 days old) on HGF induction. Furthermore, sequential changes of bleomycin-induced HGF production following apoptotic cell instillation related to the changes in inflammatory and fibrotic responses were assessed.At 2 h after apoptotic cell instillation into bleomycin-stimulated lungs, the levels of HGF mRNA and protein production, and apoptotic cell clearance by alveolar macrophages were enhanced. Furthermore, HGF induction persistently increased following apoptotic cell instillation up to 21 days after bleomycin treatment. Apoptotic cell instillation attenuated bleomycin-induced proinflammatory mediator production, inflammatory cell recruitment and total protein levels. Apoptotic cell instillation also induced antiapoptotic and antifibrotic effects. These antiinflammatory and antiapoptotic effects could be reversed by co-administration of HGFneutralising antibody.These findings indicate that in vivo exposure to apoptotic cells enhances transcriptional HGF production in bleomycin-stimulated lungs, resulting in attenuation of lung injury and fibrosis.

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Mechanism of TNF‐α‐induced migration and hepatocyte growth factor production in human mesenchymal stem cells

Cited by 48 publications

References 28 publications

Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity

Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity

NF-κB Activity Regulates Mesenchymal Stem Cell Accumulation at Tumor Sites

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

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