New Blocking Antibodies Impede Adhesion, Migration and Survival of Ovarian Cancer Cells, Highlighting MFGE8 as a Potential Therapeutic Target of Human Ovarian Carcinoma

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.

乳脂球-表皮生长因子-因子VIII（Milk Fat Globule – EGF – factor VIII，缩写MFGE8，又称乳黏附素（lactadherin））是一种分泌型蛋白质，可在细胞外结合磷脂酰丝氨酸以及整合素αvβ3和αvβ5。在表达上述整合素的人源及小鼠细胞（如内皮细胞、吞噬细胞与部分肿瘤细胞）中，已有研究证实MFGE8/乳黏附素可促进细胞存活、上皮间质转化及吞噬作用。据此，MFGE8的促肿瘤功能已在黑色素瘤、某类乳腺癌亚型以及膀胱癌等少数人类癌症类型中得到验证。因此，抑制MFGE8的功能或可成为一类新型人类癌症治疗策略。本研究通过对一组人类卵巢癌样本开展免疫组织化学检测，发现45%的此类肿瘤中存在MFGE8过表达现象；同时本研究证实，MFGE8在人类三阴性乳腺癌亚型中呈现特异性过表达。我们已建立全新的体外实验体系，用于检测MFGE8对人卵巢癌及三阴性乳腺癌细胞系的存活、黏附与迁移能力的影响。利用该实验体系，我们成功筛选得到新型MFGE8特异性单克隆抗体，该抗体可有效阻断MFGE8的上述三种促肿瘤效应。本研究结果提示，靶向MFGE8的阻断抗体有望成为卵巢癌亚组及三阴性乳腺癌患者的新型抗肿瘤治疗药物。