Eldor A, Bar-Ner M, Yahalom J, Fuks Z, Vlodavsky I
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.
Semin Thromb Hemost. 1987 Oct;13(4):475-88. doi: 10.1055/s-2007-1003524.
Dissemination of neoplastic cells within the body involves invasion of blood vessels by tumor cells. Since platelets have been shown to contribute to this process, we studied the interaction in vitro of platelets and malignant cells with the vascular endothelium and its underlying basement membrane-like ECM. A metastatic subline (ESb) of the methylcholanthrene-induced DBA/2 T-lymphoma invaded the vascular endothelium at a higher rate than its parental nonmetastatic (Eb) subline. ESb cells also exhibited a much higher ability to degrade the proteoglycan scaffold of the ECM by means of a specific HS degrading endoglycosidase (heparanase). The interaction of platelets with this ECM was associated with platelet activation, aggregation, and degradation of HS by means of the platelet heparanase. Degradation of ECM-HS was facilitated by proteolytic activity that produced a more accessible substrate for further cleavage by heparanase. A similar enhancement was exerted by plasminogen via the activity of the tumor cells or ECM associated PAs. Heparin and chemically modified heparins that lack anticoagulant activity inhibited degradation of the ECM-HS by heparanase. Interaction of platelets and lymphoma cells with ECM covered with vascular endothelial cells was investigated by SEM and by determination of ECM-HS degradation products. SEM studies demonstrated that platelets may adhere to minor gaps between adjacent endothelial cells and degrade the ECM-HS. Platelets were also shown to recruit lymphoma cells into these interendothelial gaps, suggesting that by binding to ECM and release of heparanase, platelets may play an active role in tumor cell invasion and metastasis. Our observation that nonanticoagulant heparins may interfere with heparanase-mediated degradation of ECM-HS suggests a potential therapeutic use for such heparins in neoplastic disorders.
肿瘤细胞在体内的播散涉及肿瘤细胞对血管的侵袭。由于血小板已被证明参与这一过程，我们研究了血小板和恶性细胞与血管内皮及其下方类似基底膜的细胞外基质（ECM）在体外的相互作用。甲基胆蒽诱导的DBA/2 T淋巴瘤的转移亚系（ESb）侵袭血管内皮的速率高于其亲代非转移亚系（Eb）。ESb细胞还表现出通过一种特异性的硫酸乙酰肝素（HS）降解内切糖苷酶（乙酰肝素酶）降解ECM蛋白聚糖支架的能力更强。血小板与这种ECM的相互作用与血小板活化、聚集以及通过血小板乙酰肝素酶降解HS有关。ECM-HS的降解通过蛋白水解活性得以促进，这种活性产生了一个更易被乙酰肝素酶进一步切割的底物。纤溶酶原通过肿瘤细胞或与ECM相关的纤溶酶原激活物（PAs）的活性也发挥了类似的增强作用。缺乏抗凝活性的肝素和化学修饰肝素抑制了乙酰肝素酶对ECM-HS的降解。通过扫描电子显微镜（SEM）和测定ECM-HS降解产物，研究了血小板和淋巴瘤细胞与覆盖有血管内皮细胞的ECM的相互作用。SEM研究表明，血小板可能黏附于相邻内皮细胞之间的微小间隙并降解ECM-HS。还显示血小板将淋巴瘤细胞募集到这些内皮细胞间隙中，这表明通过与ECM结合并释放乙酰肝素酶，血小板可能在肿瘤细胞侵袭和转移中发挥积极作用。我们观察到非抗凝肝素可能干扰乙酰肝素酶介导的ECM-HS降解，这表明此类肝素在肿瘤性疾病中具有潜在的治疗用途。
