MFG‐E8 activates proliferation of vascular smooth muscle cells via integrin signaling

Wang, Mingyi; Fu, Zhang; Wu, James T.; Zhang, Jing; Jiang, Liqun; Khazan, Benjamin; Telljohann, Richard; Zhao, Mingming; Krug, Alexander W.; Pikilidou, Maria; Monticone, Robert E.; Wersto, Robert P.; Eyk, Jennifer E. Van; Lakatta, Edward G.

doi:10.1111/j.1474-9726.2012.00813.x

Cited by 90 publications

(141 citation statements)

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“…18 MFG-E8 also coordinates cell cycle molecules such MFG-E8 expression in oral squamous cell carcinoma M Yamazaki et al as proliferating cell nuclear antigen and cyclin-dependent kinase 4 to facilitate cell proliferation via integrin/ERK1/2 signaling in vascular smooth muscle cells. 36 Our present MFG-E8 knockdown experiment clearly indicated that MFG-E8 facilitates cell proliferation and acts as an anti-apoptotic factor in oral SCC. When MFG-E8 was suppressed in the present study, geminin þ cells, which were about to divide, decreased in number, while apoptotic cells, which were revealed by activation of caspase-3 and DNA fragmentation, increased in number.…”

Section: Discussionsupporting

confidence: 58%

MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells

Yamazaki

Maruyama

Abé

et al. 2014

Laboratory Investigation

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Milk fat globule-epidermal growth factor (EGF)-factor VIII (MFG-E8) is a secreted glycoprotein that promotes clearance of apoptotic cells by bridging phosphatidylserine on apoptotic cells and integrin avb3/5 on phagocytes. High expression of MFG-E8 has been reported in various types of cancer in humans. Apoptotic figures are frequently found in the surgical samples of oral squamous cell carcinoma (SCC) and carcinoma in situ, and we have often observed apoptotic carcinoma cells engulfed by macrophages or even by neighboring carcinoma cells. Thus we hypothesized that MFG-E8 might promote engulfment of apoptotic carcinoma cells by living carcinoma cells and that MFG-E8 expressed by carcinoma cells could contribute to tumor progression. The aim of this study was to elucidate the biological role of MFG-E8 in oral SCC. Fifty-three surgical specimens of oral SCC were used for immunohistochemistry for MFG-E8, and the expression profiles were correlated with clinicopathological properties. Also, we examined the MFG-E8 expression patterns and functions using three human oral SCC cell lines. Most of the cases had MFG-E8-positive SCC cells, and the expression of MFG-E8 was correlated with such clinicopathological features as tumor size, pathological stage, locoregional recurrence, scattering invasion pattern, and SCC cell figures engulfing apoptotic SCC cells. The MFG-E8 staining was enhanced in apoptotic SCC cells, some of which were apparently engulfed by the neighboring SCC cells. ZK-1 cells showed high MFG-E8 expression, and its localization was found in the cytoplasm and the cell surface. Transient MFG-E8 knockdown by siRNA in ZK-1 decreased cell proliferation and invasiveness and increased cell death. Thus we have demonstrated that MFG-E8 promotes tumor progression in oral SCC and that it might be involved in the clearance of apoptotic SCC cells by living SCC cells. Milk fat globule-epidermal growth factor (EGF)-factor VIII (MFG-E8), a secreted glycoprotein also termed lactadherin, was identified initially as a marker of human breast cancer 1 and later as a major component of milk fat globule membranes in the murine lactating mammary gland. 2 MFG-E8 is a multifunctional protein that has key roles in apoptotic cell clearance, 3 cellular adhesion between sperm and oocyte, 4 morphogenetic and homeostatic regulation in diverse tissues, 5-7 and angiogenesis. 8 Human MFG-E8 contains two repeats of an EGF-like domain on the N-terminal side and two repeated domains homologous to blood coagulation factor V/VIII on the C-terminal side. 9-11 On the removal of apoptotic cells, MFG-E8 secreted by phagocytes binds to phosphatidylserine on the apoptotic cell surface via the factor V/VIII-like domains, as well as to integrin avb3/5 on the plasma membrane of phagocytes via its RGD sequence within the EGF-like domain. 3 Impaired MFG-E8-mediated uptake of apoptotic cells results in autoimmune diseases in MFG-E8-deficient mice, 12 indicating that it is related to immune tolerance induction. 13 Apoptotic cells are cleared in MFG-E8-depend...

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Section: Discussionsupporting

confidence: 58%

MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells

Yamazaki

Maruyama

Abé

et al. 2014

Laboratory Investigation

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“…VSMC phenotypes can exhibit plasticity in response to modulation by the age‐associated alterations in the proinflammatory niche, characterized by a loss of contractility and abnormal proliferation and migration 7, 9, 27. These VSMC phenotypic shifts are driven by a coordinated repression/activation of contractile markers SM22α, α‐SMA, and myocardin 28, 29.…”

Section: Resultsmentioning

confidence: 99%

“…PDGF‐BB is not only a potent mitogen, but also a strong chemoattractant of VSMCs, creating a permissive tissue microenvironment for VSMC migration and invasion, promoting formation of a thickened intima in vivo 1, 2, 3, 8, 41, 42. Prior findings indicate that PDGF‐BB treatment induces invasion and migration of old VSMCs in vitro 8, 9. The capacity of VSMC to repopulate a damaged area in vitro, a model for the cellular process of thickening intimal or neointimal formation, is markedly increased after PDGF‐BB treatment 43, 44.…”

Section: Discussionmentioning

confidence: 98%

“…A wound healing assay was performed as previously described 9. Briefly, both AL and CR rat VSMCs were seeded into 12‐well plates and grown to confluence.…”

Section: Methodsmentioning

confidence: 99%

“…Increases in the local arterial wall proinflammatory molecules, platelet‐derived growth factor (PDGF), matrix metalloproteinase type II (MMP2) and transforming growth factor beta 1 (TGF‐β1), promote cellular and matrix phenotypic shifts that contribute to aortic wall thickening and stiffening that accompany advancing age in mammals, a prominent arterial phenotype of biological aging 4, 5, 6, 7, 8, 9. Interestingly, arterial proinflammatory conditions reduces the threshold or increases the susceptibility for pernicious inflammatory arterial events under hostile conditions such as hyperlipidemia 1, 10…”

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confidence: 99%

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Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype

Wang

Zhang

Zhu

et al. 2018

JAHA

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BackgroundAging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction (CR) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated.Methods and ResultsAortae were harvested from young (6‐month‐old) and old (24‐month‐old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age‐associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented an age‐associated increase in the density of platelet‐derived growth factor, matrix metalloproteinase type II activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho‐mothers against decapentaplegic homolog‐2/3 (p‐SMAD‐2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from AL and CR rat aortae, CR alleviated the age‐associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet‐derived growth factor.Conclusions CR reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet‐derived growth factor signaling. Thus, CR reduces the platelet‐derived growth factor–associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.

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Proteomics Approach to Assess the Potency of Dietary Grape Seed Proanthocyanidins and Dimeric Procyanidin B2

Gao

Cheng

et al. 2015

Genomics, Proteomics and Metabolomics in Nutraceuticals and Functional Foods

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MFG‐E8 activates proliferation of vascular smooth muscle cells via integrin signaling

Cited by 90 publications

References 44 publications

MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells

MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype

Proteomics Approach to Assess the Potency of Dietary Grape Seed Proanthocyanidins and Dimeric Procyanidin B2

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