Milk fat globule epidermal growth factor–8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms

Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2009; 206(6):1317-26. DOI: 10.1084/jem.20082614
Source: PubMed

ABSTRACT Carcinogenesis reflects the dynamic interplay of transformed cells and normal host elements, but cancer treatments typically target each compartment separately. Within the tumor microenvironment, the secreted protein milk fat globule epidermal growth factor-8 (MFG-E8) stimulates disease progression through coordinated alpha(v)beta(3) integrin signaling in tumor and host cells. MFG-E8 enhances tumor cell survival, invasion, and angiogenesis, and contributes to local immune suppression. We show that systemic MFG-E8 blockade cooperates with cytotoxic chemotherapy, molecularly targeted therapy, and radiation therapy to induce destruction of various types of established mouse tumors. The combination treatments evoke extensive tumor cell apoptosis that is coupled to efficient dendritic cell cross-presentation of dying tumor cells. This linkage engenders potent antitumor effector T cells but inhibits FoxP3(+) T reg cells, thereby achieving long-term protective immunity. Collectively, these findings suggest that systemic MFG-E8 blockade might intensify the antitumor activities of existing therapeutic regimens through coordinated cell-autonomous and immune-mediated mechanisms.

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Available from: Akira Kanamoto, Sep 26, 2015
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    • "In the mouse, Mfge8 promotes phagocytosis of apoptotic cells by macrophages [6], and skews them to secrete tolerogenic cytokines [7]. On some tumor cells themselves, MFGE8 was shown to induce epithelial to mesenchymal transition [8,9], and/or to increase resistance to drug-induced apoptosis [10,11]. "
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    ABSTRACT: Milk Fat Globule - EGF - factor VIII (MFGE8), also called lactadherin, is a secreted protein, which binds extracellularly to phosphatidylserine and to αvβ3 and αvβ5 integrins. On human and mouse cells expressing these integrins, such as endothelial cells, phagocytes and some tumors, MFGE8/lactadherin has been shown to promote survival, epithelial to mesenchymal transition and phagocytosis. A protumoral function of MFGE8 has consequently been documented for a few types of human cancers, including melanoma, a subtype of breast cancers, and bladder carcinoma. Inhibiting the functions of MFGE8 could thus represent a new type of therapy for human cancers. Here, we show by immunohistochemistry on a collection of human ovarian cancers that MFGE8 is overexpressed in 45% of these tumors, and we confirm that it is specifically overexpressed in the triple-negative subtype of human breast cancers. We have established new in vitro assays to measure the effect of MFGE8 on survival, adhesion and migration of human ovarian and triple-negative breast cancer cell lines. Using these assays, we could identify new MFGE8-specific monoclonal antibodies, which efficiently blocked these three tumor-promoting effects of MFGE8. Our results suggest future use of MFGE8-blocking antibodies as new anti-cancer therapeutics in subgroups of ovarian carcinoma, and triple-negative breast carcinoma patients.
    PLoS ONE 08/2013; 8(8):e72708. DOI:10.1371/journal.pone.0072708 · 3.23 Impact Factor
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    • "MFG-E8 promotes the uptake and processing of apoptotic cells by DC, which may promote Foxp3+ regulatory T cell differentiation and suppress antigen-specific adaptive immunity [6], [9]. Several lines of evidences have revealed the impact of apoptotic cell engulfment in maintaining immune homeostasis and preventing excess inflammation [5], [10]. "
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    ABSTRACT: Dendritic cells (DC) manipulate tissue homeostasis by recognizing dying cells and controlling immune functions. However, the precise mechanisms by which DC recognize different types of dying cells and devise distinct immunologic consequences remain largely obscure. Herein, we demonstrate that Milk-fat globule-EGF VIII (MFG-E8) is a critical mediator controlling DC immunogenicity in inflammatory microenvironments. MFG-E8 restrains DC-mediated uptake and recognition of necrotic cells. The MFG-E8-mediated suppression of necrotic cell uptake by DC resulted in the decreased proinflammatory cytokines production and activated signal components such as STAT3 and A20, which are critical to maintain tolerogenic properties of DC. Furthermore, the DC-derived MFG-E8 negatively regulates the cross-priming and effector functions of antigen-specific T cells upon recognition of necrotic cells. MFG-E8 deficiency enhances an ability of necrotic cell-primed DC to stimulate antitumor immune responses against established tumors. Our findings define what we believe to a novel mechanism whereby MFG-E8 regulates the immunogenicity of DC by modulating the modes of recognition of dying cells. Manipulating MFG-E8 levels in DC may serve as a useful strategy for controlling inflammatory microenvironments caused by various pathological conditions including cancer and autoimmunity.
    PLoS ONE 06/2012; 7(6):e39607. DOI:10.1371/journal.pone.0039607 · 3.23 Impact Factor
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    • "It is hence conceivable that the ER status per se is not sufficient to determine MFG-E8 function in breast carcinoma cells and that the overall effect of MFG-E8 signaling will depend on its interactions with other signaling pathways that may become deregulated during malignant progression. It has been shown that functionally blocking anti- MFG-E8 antibodies induced the regression of experimental breast cancers (Ceriani et al., 1987) and acted synergistically with conventional chemotherapy to reduce experimental colon carcinomas, melanomas and lymphomas (Jinushi et al., 2009); in addition, triple-negative breast cancer cells in which MFG-E8 expression was silenced were more sensitive to cisplatin treatment (Yang et al., 2011). Taken together with this published evidence, our present results support the idea that combinatorial therapies that include MFG-E8 blockade may be operative in the treatment of some breast cancer patients. "
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    ABSTRACT: Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein highly expressed in breast cancer that contributes to tumor progression through largely undefined mechanisms. By analyzing publicly available gene expression profiles of breast carcinomas, we found that MFG-E8 is highly expressed in primary and metastatic breast carcinomas, associated with absent estrogen receptor expression. Immunohistochemistry analysis of breast cancer biopsies revealed that MFG-E8 is expressed on the cell membrane as well as in the cytoplasm and nucleus. We also show that increased expression of MFG-E8 in mammary carcinoma cells increases their tumorigenicity in immunodeficient mice, and conversely, its downregulation reduces their in vivo growth. Moreover, expression of MFG-E8 in immortalized mammary epithelial cells promotes their growth and branching in three-dimensional collagen matrices and induces the expression of cyclins D1/D3 and N-cadherin. A mutant protein unable to bind integrins can in part exert these effects, indicating that MFG-E8 function is only partially dependent on integrin activation. We conclude that MFG-E8-dependent signaling stimulates cell proliferation and the acquisition of mesenchymal properties and contributes to mammary carcinoma development.
    Oncogene 08/2011; 31(12):1521-32. DOI:10.1038/onc.2011.356 · 8.46 Impact Factor
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