Immunoregulatory influence of abundant <scp>MFG</scp>‐E8 expression by esophageal cancer treated with chemotherapy

Kanemura, Takashi; Miyata, Hiroshi; Makino, Tomoki; Sugimura, Keijiro; Hamada‐Uematsu, Mika; Mizote, Yu; Uchida, Hiroaki; Miyazaki, Yasuhiro; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Yamasaki, Makoto; Wada, Hisashi; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro; Tahara, Hideaki

doi:10.1111/cas.13785

Cited by 16 publications

(24 citation statements)

References 45 publications

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“…MFG-E8 expression is significantly upregulated in colorectal cancer, oral squamous cell carcinoma, and melanoma, compared with normal tissues [11][12][13]. A previous study found that there was a significantly higher rate of high MFG-E8 expression in the esophageal tumor tissues of patients treated with neoadjuvant chemotherapy (NAC), compared to those not treated with NAC [14]. They also observed the increased expression of MFG-E8 in esophageal cancer cell lines after treatment with chemotherapeutic drugs.…”

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confidence: 95%

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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confidence: 95%

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

Kim

Park

et al. 2020

Cancers

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“…The implanted AS tumors grew into the dark reddish tumors, and the size of the tumor peaked at 3-4 days after implantation, then it gradually shrunk and disappeared, suggesting that antitumor immunity, including CD8 + T cells might be associated with the rejection of AS tumor in mice. Several studies showed the regulation of antitumor immunity by MFG-E8 [14,23,39]. Jinushi et al reported that MFG-E8 inhibited the vaccination activity of GM-CSF-secreting tumor cells through regulatory T cells (Treg) induction, and that the combination anti-MFG-E8 Ab and chemotherapy enhanced antitumor effector T cells and inhibited Treg [14,39].…”

Section: Discussionmentioning

confidence: 99%

“…A protumoral function of MFGE8 has been documented for severaral types of human cancers, including oral, esophageal, colorectal, breast, bladder, ovarian and prostate carcinoma and melanoma [22][23][24][25][26][27][28][29][30]. It has been reported that MFG-E8 expression increased significantly in colorectal cancer compared with normal mucosa tissues, and high MFG-E8 expression was correlated with lymph node metastasis and shortened overall survivals, suggesting that MFG-E8 could be a prognostic marker for colorectal cancer and overexpression of MFG-E8 might be involved in lymph node metastasis and angiogenesis of colorectal cancer [24,25].…”

Section: Introductionmentioning

confidence: 99%

The significance of tumor cells-derived MFG-E8 in tumor growth of angiosarcoma

Fujiwara

Motegi

Ohira

et al. 2019

Journal of Dermatological Science

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Background: Previous studies have indicated that MFG-E8 enhances tumor cell survival, invasion and angiogenesis. However, the role of MFG-E8 in angiosarcoma (AS) has not been clarified. Objective: Objective was to elucidate the mechanism of the regulation by MFG-E8 in AS and the association between MFG-E8 and clinicopathological features of AS. Methods: The effects of the depletion of MFG-E8 by siRNA on tube formation, migration and proliferation in murine AS cells were examined. The effect of administration of anti-MFG-E8 antibody (Ab) on tumor growth of AS in mice was examined. The associations of MFG-E8 expression and clinicopathological features of human AS were assessed. Results: The expressions of MFG-E8 in murine and human AS cells were significantly higher than those in melanoma cells, macrophages and endothelial cells. Depletion of MFG-E8 in murine AS cells by siRNA significantly inhibited the formation of capillary-like structures and migration, but not proliferation. Administration of anti-MFG-E8 Ab significantly inhibited tumor growth and decreased the number of tumor-associated macrophages (TAMs) in AS tumors. Tumor size and the number of TAMs in human AS with high expression of MFG-E8 were significantly increased compared to those of AS with low expression of MFG-E8. Progression-free survival and overall survival time of the patients of AS with high expression of MFG-E8 were significantly shorter than those of AS with low expression of MFG-E8. Conclusions: AS-derived MFG-E8 might enhance tumor growth via angiogenesis and the induction of TAMs in autocrine/paracrine manner, and administration of anti-MFG-E8 Ab could be a therapeutic potential for AS.

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“…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]. According to Yamada et al, MFG-E8 promotes angiogenesis by upregulating the expression of VEGF and endothelin (ET)-1 in bone marrow-derived mesenchymal stromal cells to trigger tumor progression in melanomas [86].…”

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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Immunoregulatory influence of abundant MFG‐E8 expression by esophageal cancer treated with chemotherapy

Cited by 16 publications

References 45 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

The significance of tumor cells-derived MFG-E8 in tumor growth of angiosarcoma

Regulation of efferocytosis as a novel cancer therapy

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