Gingis-Velitski Svetlana, Ishai-Michaeli Rivka, Vlodavsky Israel, Ilan Neta
Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
FASEB J. 2007 Dec;21(14):3986-93. doi: 10.1096/fj.07-8866com. Epub 2007 Jul 12.
Heparanase is a mammalian endo-beta-D-glucuronidase capable of cleaving HS side chains at a limited number of sites, activity that is strongly implicated in tumor metastasis, neovascularization, inflammation, and autoimmunity. Clinically, up-regulation of heparanase mRNA and protein expression has been documented in a variety of primary human tumors, correlating with reduced postoperative survival and increased lymph node and distant metastasis, thus providing strong clinical support for the prometastatic feature of the enzyme and making it an attractive target for the development of anticancer and anti-inflammatory drugs. Screening a panel of monoclonal antibodies for their ability to inhibit heparanase enzymatic activity, we noted that one hybridoma, 6F8, exhibited the opposite effect and significantly enhanced heparanase activity. Here, we provide evidence that antibody 6F8 enhances the activity of recombinant and cellular heparanase, facilitates invasion of tumor-derived cells in vitro, and improves wound healing in a mouse punch model in vivo. These results support a role of heparanase in the course of wound healing and, moreover, suggest that monoclonal antibodies can be applied clinically for the enhancement, rather than inhibition, of certain enzymes.
乙酰肝素酶是一种哺乳动物内切β-D-葡萄糖醛酸酶，能够在有限数量的位点切割硫酸乙酰肝素（HS）侧链，该活性与肿瘤转移、新血管形成、炎症和自身免疫密切相关。临床上，已证实在多种原发性人类肿瘤中乙酰肝素酶mRNA和蛋白表达上调，这与术后生存率降低以及淋巴结和远处转移增加相关，从而为该酶的促转移特性提供了有力的临床支持，并使其成为开发抗癌和抗炎药物的一个有吸引力的靶点。在筛选一组单克隆抗体抑制乙酰肝素酶活性的能力时，我们注意到一种杂交瘤6F8表现出相反的效果，显著增强了乙酰肝素酶的活性。在此，我们提供证据表明抗体6F8增强重组和细胞乙酰肝素酶的活性，促进肿瘤来源细胞在体外的侵袭，并在体内小鼠打孔模型中改善伤口愈合。这些结果支持了乙酰肝素酶在伤口愈合过程中的作用，此外，还表明单克隆抗体可在临床上用于增强而非抑制某些酶。
