Identification of MFG-E8 as a novel therapeutic target for diseases

Li, Baozhu; Zhang, Haiyan; Pan, Hai‐Feng; Ye, Dong-Qing

doi:10.1517/14728222.2013.829455

Cited by 34 publications

(29 citation statements)

References 71 publications

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“…While previous data revealed a significant correlation of MFG-E8 with the progression of multiple tumor types [9], no available data have been published regarding the tumorigenic activity of MFG-E8 in HCC. High levels of MFG-E8 expression have been correlated to tumor progression via…”

Section: Discussionmentioning

confidence: 91%

“…It has been demonstrated that MFG-E8 regulates cellular proliferation, differentiation, and migration under various pathophysiological conditions, including sepsis and age-related diseases [6,7]. We also showed that MFG-E8 is secreted from human umbilical cord mesenchymal stem cells and strongly inhibits the activation of hepatic stellate cells, reducing liver fibrosis both in vitro and in vivo [8].Recent studies have revealed that MFG-E8 is involved in the progression of a variety of tumors, including breast cancer, ovarian cancer, and colorectal cancer [9][10][11]. MFG-E8 expression is significantly upregulated in colorectal cancer, oral squamous cell carcinoma, and melanoma, compared with normal tissues [11][12][13].…”

mentioning

confidence: 77%

“…Recent studies have revealed that MFG-E8 is involved in the progression of a variety of tumors, including breast cancer, ovarian cancer, and colorectal cancer [9][10][11]. MFG-E8 expression is significantly upregulated in colorectal cancer, oral squamous cell carcinoma, and melanoma, compared with normal tissues [11][12][13].…”

mentioning

confidence: 99%

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Milk Fat Globule-EGF Factor 8 Contributes to Progression of Hepatocellular Carcinoma

Kim

Park

et al. 2020

Cancers

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Milk fat globule-EGF factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates a wide spectrum of pathophysiological processes. MFG-E8 has been studied as a key regulator of cancer cell invasion, migration, and proliferation in different tissues and organs. However, potential roles of MFG-E8 in the growth and progression of liver cancer have not been investigated to date. Here, we analyzed 33 human hepatocellular carcinoma (HCC) samples and found that levels of MFG-E8 expression were significantly higher in HCC cells than in normal liver tissues. In addition, our in vitro gain-of-function study in three different HCC cell lines revealed that overexpression of MFG-E8 promoted the proliferation and migration of HCC cells, as determined by RT-qPCR, MTT assays, and wound healing analyses. Conversely, an MFG-E8 loss-of function study showed that proliferation capacity was significantly reduced by MFG-E8 knockdown in HCC cells. Additionally, MFG-E8 activity-neutralizing antibodies profoundly inhibited both migration and proliferation of HCC cells, attenuating their tumorigenic properties. These reductions in migration and proliferation were rescued by treatment of HCC cells with recombinant MFG-E8 protein. Furthermore, an in vivo HCC xenograft study showed that the number of proliferating HCC cells and tumor volume/weight were all significantly increased by MFG-E8 overexpression, compared to control mice. These results clearly show that MFG-E8 plays an important role in HCC progression and may provide a basis for future mechanistic studies and new strategies for the treatment of liver cancer.Cancers 2020, 12, 403 2 of 16 underlying HCC tumorigenesis and identifying novel therapeutic targets are both of great significance in improving the overall prognosis of patients with HCC.Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein initially identified as a component of milk fat globules secreted from mammary epithelial cells [3]. Human MFG-E8 consists of an N-terminal EGF-like domain which contains an integrin-binding RGD motif, and two repeated C-terminal discoidin/F5/8C domains that bind phosphatidylserine [3]. Because phosphatidylserine is exposed on the surfaces of apoptotic cells, MFG-E8 has been studied as an opsonin that mediates clearance of dying cells via integrin-expressing phagocytes [4,5]. MFG-E8 is also expressed in many cell types, including mammary epithelial and myoepithelial cells, dendritic cells, endothelial cells, intestinal cells, and retinal epithelial cells. It has been demonstrated that MFG-E8 regulates cellular proliferation, differentiation, and migration under various pathophysiological conditions, including sepsis and age-related diseases [6,7]. We also showed that MFG-E8 is secreted from human umbilical cord mesenchymal stem cells and strongly inhibits the activation of hepatic stellate cells, reducing liver fibrosis both in vitro and in vivo [8].Recent studies have revealed that MFG-E8 is involved in the progression of a variety of tumors, including breast cancer, ovarian canc...

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 77%

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Milk Fat Globule-EGF Factor 8 Contributes to Progression of Hepatocellular Carcinoma

Kim

Park

et al. 2020

Cancers

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“…Expressed and secreted by activated mϕ and dendritic cells, MFG-E8 is versatile, and displays a wide array of functions in cell physiology (15, 54). The therapeutic potential of this multi-domain protein has been recognized in a multitude of diseased conditions such as cancers, sepsis and ischemia-reperfusion injury of the heart and DSS-induced colitis (54-56) MFG-E8 has anti-inflammatory properties primarily executed by its effects on mϕ cell biology (57-58). Non-resolving inflammation is a key factor that underlies chronic wounds such as diabetic ulcers (2).…”

Section: Discussionmentioning

confidence: 99%

Correction of MFG-E8 Resolves Inflammation and Promotes Cutaneous Wound Healing in Diabetes

Das

Ghatak

Sinha

et al. 2016

The Journal of Immunology

106

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Milk fat globule EGF factor 8 (MFG-E8) is a peripheral glycoprotein which acts as a bridging molecule between the macrophage and apoptotic cells thus executing a pivotal role in the scavenging of apoptotic cells from affected tissue. We have previously reported that apoptotic cell clearance activity or efferocytosis is compromised in diabetic wound macrophages. In this work we test the hypothesis that MFG-E8 helps resolve inflammation, supports angiogenesis and accelerates wound closure. MFG-E8−/− mice, displayed impaired efferocytosis associated with exaggerated inflammatory response, poor angiogenesis and wound closure. Wound macrophage-derived MFG-E8 was recognized as a critical driver of wound angiogenesis. Transplantation of MFG-E8−/− bone marrow to MFG-E8+/+ mice resulted in impaired wound closure and compromised wound vascularization. On the other hand, MFG-E8−/− mice that received wild-type bone marrow showed improved wound closure and improved wound vascularization. Hyperglycemia and exposure to advanced glycated end products inactivated MFG-E8 recognizing a key mechanism that complicates diabetic wound healing. Diabetic db/db mice suffered from impaired efferocytosis accompanied with persistent inflammation and slow wound closure. Topical rMFG-E8 induced resolution of wound inflammation, improvements in angiogenesis and acceleration of closure upholding the potential of MFG-E8 directed therapeutics in diabetic wound care.

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“…MFG-E8 bridges between PS and α v β 3 /α v β 5 integrins [39] and its expression is upregulated in tumors [80]. MFG-E8 attenuates inflammation and increases Treg cells, efferocytosis, angiogenesis, allograft tolerance, tumorigenicity, and cancer metastasis [81,82]. Moreover, overexpression of MFG-E8 is negatively associated with prognosis in various cancers including breast, colorectal and esophageal cancers [83][84][85].…”

Section: Bridging Moleculesmentioning

confidence: 99%

Regulation of efferocytosis as a novel cancer therapy

et al. 2020

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Efferocytosis is a physiologic phagocytic clearance of apoptotic cells, which modulates inflammatory responses and the immune environment and subsequently facilitates immune escape of cancer cells, thus promoting tumor development and progression. Efferocytosis is an equilibrium formed by perfect coordination among "find-me", "eat-me" and "don't-eat-me" signals. These signaling pathways not only affect the proliferation, invasion, metastasis, and angiogenesis of tumor cells but also regulate adaptive responses and drug resistance to antitumor therapies. Therefore, efferocytosis-related molecules and pathways are potential targets for antitumor therapy. Besides, supplementing conventional chemotherapy, radiotherapy and other immunotherapies with efferocytosis-targeted therapy could enhance the therapeutic efficacy, reduce off-target toxicity, and promote patient outcome.

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Identification of MFG-E8 as a novel therapeutic target for diseases

Abstract: Though the exact roles of MFG-E8 have not been fully elucidated in diseases. MFG-E8 may serve as a promising therapeutic strategy.

Cited by 34 publications

References 71 publications

Milk Fat Globule-EGF Factor 8 Contributes to Progression of Hepatocellular Carcinoma

Milk Fat Globule-EGF Factor 8 Contributes to Progression of Hepatocellular Carcinoma

Correction of MFG-E8 Resolves Inflammation and Promotes Cutaneous Wound Healing in Diabetes

Regulation of efferocytosis as a novel cancer therapy

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