FGF-2 Induced by Interleukin-1β through the Action of Phosphatidylinositol 3-Kinase Mediates Endothelial Mesenchymal Transformation in Corneal Endothelial Cells

Lee, Hyung Taek; Lee, Jung Goo; Na, Moonseok; Kay, EunDuck P.

doi:10.1074/jbc.m405208200

Cited by 71 publications

(87 citation statements)

References 37 publications

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“…A growing body of evidence indicates that inflammatory cytokine IL-1b, which has an important role in acute and chronic inflammatory diseases, might mediate signaling between tumor and inflammatory cells. 21,41,42 IL-1b orchestrates the expression of a variety of factors including: growth factors, 43 chemoattractants 44 and matrix MMPs. 45,46 Our data suggest that IL-1b, which triggers the initial steps of Mycinduced angiogenesis, mediates production of MMP9 in the microenvironment of Myc;BclXl tumors.…”

Section: Discussionmentioning

confidence: 99%

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Shchors

Nozawa

et al. 2012

Oncogene

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Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1b-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumorassociated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials.Oncogene advance online publication, 5 March 2012; doi:10.1038/onc.2012.60Keywords: tumor; metalloproteinase; invasion; cathepsin; Myc; interleukin-1b INTRODUCTIONMatrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that contribute to development and tissue homeostasis, and modulate cancer progression by digesting a variety of substrates. Owing to the role of MMP in extracellular matrix (ECM) re-arrangement (also referred to as remodeling or degradation), and in the promotion of neoangiogenesis, it was anticipated that MMP inhibition in vivo would have an anti-tumorigenic effect. However, phase III clinical trials with an MMP inhibitor (MMPI), combined with standard-of-care chemotherapy, failed to demonstrate clinical benefit for late stage cancer patients and, remarkably, was in some cases worse than the chemotherapyonly control arm. For instance, the use of Bay 12-9566 in treating patients with pancreatic cancer reduced both median progressionfree survival and quality-of-life when compared with standard care gemcitabine.1 In another case, treatment of glioblastoma patients rendered no statistically significant survival benefits.2 Additionally, the clinical trials in small-cell lung carcinomas had to be terminated prematurely.3 This failure led to the early cessation of ongoing trials, and to reconsideration of the merit of a variety of MMPIs in clinical development by a number of pharmaceutical companies. 4 --6 The molecular mechanism behind this disappointing outc...

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Section: Discussionmentioning

confidence: 99%

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Shchors

Nozawa

et al. 2012

Oncogene

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“…Moreover, osmotic shock and shear stress induce the release of FGF2 from endothelial cells [209,210]. FGF2 production and release from endothelial cells are also triggered by IFN-a plus IL-2 [211], IL-1b [212], and nitric oxide (NO) [213]. NO is produced by vascular endothelium following stimulation by cytokines, bacterial endotoxins, inflammatory mediators, neuropeptides, and shear stress [214].…”

Section: Fgf-dependent Angiogenesis and Inflammationmentioning

confidence: 99%

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

1,120

870

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Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization. #

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“…Indeed, FGF2 is known to inhibit EndMT in macrovascular endothelial cells, whereas it induces EndMT is some microvascular endothelial cell types (Lee et al, 2004;Lee and Kay, 2006). Whether this difference in EndMT induction is dependent on the organ-of-origin, as not all microvascular endothelial cells undergo EndMT following FGF2 stimulation (Ichise et al, 2014), …”

Section: (B-e) Light Microscopy Images Of Endothelial Cells (B) Untrmentioning

confidence: 99%

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

Correia

Moonen

Brinker

et al. 2016

Journal of Cell Science

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Endothelial-to-mesenchymal transition (EndMT) is characterized by the loss of endothelial cell markers and functions, and coincides with de novo expression of mesenchymal markers. EndMT is induced by TGFβ1 and changes endothelial microRNA expression. We found that miR-20a is decreased during EndMT, and that ectopic expression of miR-20a inhibits EndMT induction. TGFβ1 induces cellular hypertrophy in human umbilical vein endothelial cells and abrogates VE-cadherin expression, reduces endothelial sprouting capacity and induces the expression of the mesenchymal marker SM22α (also known as TAGLN). We identified ALK5 (also known as TGFBR1), TGFBR2 and SARA (also known as ZFYVE9) as direct miR-20a targets. Expression of miR-20a mimics abrogate the endothelial responsiveness to TGFβ1, by decreasing ALK5, TGFBR2 and SARA, and inhibit EndMT, as indicated by the maintenance of VE-cadherin expression, the ability of the cells to sprout and the absence of SM22α expression. FGF2 increases miR-20a expression and inhibits EndMT in TGFβ1-stimulated endothelial cells. In summary, FGF2 controls endothelial TGFβ1 signaling by regulating ALK5, TGFBR2 and SARA expression through miR-20a. Loss of FGF2 signaling combined with a TGFβ1 challenge reduces miR-20a levels and increases endothelial responsiveness to TGFβ1 through elevated receptor complex levels and activation of Smad2 and Smad3, which culminates in EndMT.

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FGF-2 Induced by Interleukin-1β through the Action of Phosphatidylinositol 3-Kinase Mediates Endothelial Mesenchymal Transformation in Corneal Endothelial Cells

Cited by 71 publications

References 37 publications

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

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