Role of heparanase in platelet and tumor cell interactions with the subendothelial extracellular matrix.
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.
Eldor
A
A
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.
Bar-Ner
M
M
Yahalom
J
J
Fuks
Z
Z
Vlodavsky
I
I
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D005966:Glucuronidase; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008223:Lymphoma / Q000201:enzymology*; D010960:Plasminogen Activators / Q000502:physiology; D000099175:Heparanase
D005966:Glucuronidase; D006026:Glycoside Hydrolases; D006493:Heparin; D010960:Plasminogen Activators; D000099175:Heparanase