Expression of gremlin 1 correlates with increased angiogenesis and progression-free survival in patients with pancreatic neuroendocrine tumors

Chen, Ming-Huang; Yeh, Yi‐Chen; Shyr, Yi‐Ming; Jan, Yi-Hua; Chao, Yee; Li, Chung–Pin; Wang, Shin‐E; Tzeng, Cheng‐Hwai; Chang, Peter Mu‐Hsin; Liu, Chunyu; Chen, Ming‐Han; Hsiao, Michael; Huang, Chi-Ying F.

doi:10.1007/s00535-012-0614-z

Cited by 31 publications

(41 citation statements)

References 18 publications

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“…Others have shown that GREM1 expression was associated with angiogenesis and was inversely correlated with survival in cancer. 39 The robust angiogenic response to GREM1 in SJL mice, despite the lack of significant up-regulation of Vegf, along with the lack of suppression of angiogenesis in GREM1 mice treated with 1D11 despite the reduction in Vegf with this therapy, suggest that GREM1 may have direct angiogenic properties not requiring VEGF or TGF-b. This hypothesis is supported by recent evidence that GREM1 may directly bind the VEGF receptor.…”

Section: Discussionmentioning

confidence: 95%

Gremlin Promotes Peritoneal Membrane Injury in an Experimental Mouse Model and Is Associated with Increased Solute Transport in Peritoneal Dialysis Patients

Siddique

Curran

Ghayur

et al. 2014

The American Journal of Pathology

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The peritoneal membrane becomes damaged in patients on peritoneal dialysis (PD). Gremlin 1 (GREM1) inhibits bone morphogenic proteins (BMPs) and plays a role in kidney development and fibrosis. We evaluated the role of gremlin in peritoneal fibrosis and angiogenesis. In a cohort of 32 stable PD patients, GREM1 concentration in the peritoneal effluent correlated with measures of peritoneal membrane damage. AdGrem1, an adenovirus to overexpress gremlin in the mouse peritoneum, induced submesothelial thickening, fibrosis, and angiogenesis in C57BL/6 mice, which was associated with decreased expression of BMP4 and BMP7. There was evidence of mesothelial cell transition to a mesenchymal phenotype with increased α smooth muscle actin expression and suppression of E-cadherin. Some of the GREM1 effects may be reversed with recombinant BMP7 or a pan-specific transforming growth factor β (TGF-β) antibody. Neovascularization was not inhibited with a TGF-β antibody, suggesting a TGF-β-independent angiogenic mechanism. Swiss/Jackson Laboratory (SJL) mice, which are resistant to TGF-β-induced peritoneal fibrosis, responded in a similar fashion to AdGrem1 as did C57BL/6 mice with fibrosis, angiogenesis, and mesothelial-to-mesenchymal transition. GREM1 was associated with up-regulated TGF-β expression in both SJL and C57BL/6 mice, but SJL mice demonstrated a defective TGF-β-induced GREM1 expression. In summary, GREM1 induces fibrosis and angiogenesis in mouse peritoneum and is associated with increased solute transport in these PD patients.

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Section: Discussionmentioning

confidence: 95%

Gremlin Promotes Peritoneal Membrane Injury in an Experimental Mouse Model and Is Associated with Increased Solute Transport in Peritoneal Dialysis Patients

Siddique

Curran

Ghayur

et al. 2014

The American Journal of Pathology

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“…Expression of α-SMA, Desmin (DES), CD248, NG2, CD146 and platelet derived growth factor receptor-beta (PDGFRB) genes (Chen et al, [34]) was analyzed in cultured HBVPs and HUVECs growing on plastic. All markers were highly expressed in HBVPs.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro

et al. 2014

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BackgroundEribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a tubulin-binding drug and approved in many countries worldwide for treatment of certain patients with advanced breast cancer. Here we investigated antiproliferative and antiangiogenic effects of eribulin on vascular cells, human umbilical vein endothelial cells (HUVECs) and human brain vascular pericytes (HBVPs), in vitro in comparison with another tubulin-binding drug, paclitaxel.MethodsHUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated. Global gene expression profiling changes caused by drug treatments were studied using Affymetrix microarray platform and custom TaqMan Low Density Cards. To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs.ResultsBoth eribulin and paclitaxel showed potent activities in in vitro proliferation of HUVECs and HBVPs, with the half-maximal inhibitory concentrations (IC50) in low- to sub-nmol/L concentrations. When gene expression changes were assessed in HUVECs, the majority of affected genes overlapped for both treatments (59%), while in HBVPs, altered gene signatures were drug-dependent and the overlap was limited to just 12%. In HBVPs, eribulin selectively affected 11 pathways (p < 0.01) such as Cell Cycle Control of Chromosomal Replication. In contrast, paclitaxel was tended to regulate 27 pathways such as PI3K/AKT. Only 5 pathways were commonly affected by both treatments. In in vitro pericyte-driven angiogenesis model, paclitaxel showed limited activity while eribulin shortened the formed capillary networks of HUVECs driven by HBVPs at low nmol/L concentrations starting at day 3 after treatments.ConclusionsOur findings suggest that pericytes, but not endothelial cells, responded differently, to two mechanistically-distinct tubulin-binding drugs, eribulin and paclitaxel. While eribulin and paclitaxel induced similar changes in gene expression in endothelial cells, in pericytes their altered gene expression was unique and drug-specific. In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

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“…GREM1 is a novel proangiogenic factor as demonstrated by several studies (2,7). In a study by Chen et al (7) on tumorrelated angiogenesis, expression of GREM1 was shown to be correlated with increased angiogenesis in patients with pancreatic neuroendocrine tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Considering that COL15A1 also serves as an endothelial marker, microvessels stained with COL15A1 were counted under light microscopy at a magnification of x 400 in 5 fields with a clear view of the lumen in randomly selected tumor tissues and normal tissues (7).…”

Section: Microvascular Densitymentioning

confidence: 99%

Investigation of GREMLIN 1, COL15A1 immunoreactivity and the relationship between microvessel density and GREMLIN 1 in papillary renal cell carcinoma and chromophobe renal cell carcinoma

Kara¹,

Karakök

2016

Med Sci and Discov

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Expression of gremlin 1 correlates with increased angiogenesis and progression-free survival in patients with pancreatic neuroendocrine tumors

Abstract: GREM1 expression was correlated with tumor-associated angiogenesis and was found to be a novel prognostic marker in pancreatic NETS. Our data support a tumor suppressor role of GREM1 in pancreatic NETs.

Cited by 31 publications

References 18 publications

Gremlin Promotes Peritoneal Membrane Injury in an Experimental Mouse Model and Is Associated with Increased Solute Transport in Peritoneal Dialysis Patients

Gremlin Promotes Peritoneal Membrane Injury in an Experimental Mouse Model and Is Associated with Increased Solute Transport in Peritoneal Dialysis Patients

Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro

Investigation of GREMLIN 1, COL15A1 immunoreactivity and the relationship between microvessel density and GREMLIN 1 in papillary renal cell carcinoma and chromophobe renal cell carcinoma

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