Deficient activity of von Willebrand's factor-cleaving protease in patients with disseminated malignancies.
An aberrant platelet immunorelated glycoprotein Ib (GPIb) receptor expressed by human tumor cells appears to participate in primary adhesive interactions required for the metastatic process. Hence, we questioned whether plasma von Willebrand's factor (vWf), its adhesive ligand, manifested comparable anomalies in patients with disseminated tumors. Plasma specimens from patients with disseminated metastases showed 68% (P < 0.013), 91% (P < 0.0009), and 207% (P < 0.0009) enhancements in FVIII:C activity, vWf-related antigen levels, and ristocetin co-factor activity, respectively, whereas their SDS-agarose electrophoretic analysis demonstrated a 165% (P < 0.001) increase in the highly polymeric forms of vWf compared to control preparations from patients with corresponding, localized solid tumors. Substantially reduced levels of vWf-cleaving protease activity were observed in study patient specimens, with no plasma inhibitors detectable. The clinical presence and absence of tumor metastases correlated significantly with vWf-cleaving enzyme activities of < or = 15% and > or = 88%, respectively (n = 20; P < 0.0001). Finally, with an in vitro model system, tumor-induced platelet aggregation was enhanced by 127% (P < 0.001) in study patient platelet-rich plasma (PRP) compared to control PRP and could be completely inhibited (P < 0.0009) when both tumor cells and their PRP substrates were incubated with monoclonal antibodies directed against the vWf binding epitope of GPIb alpha and against the GPIb binding epitope of plasma vWf, respectively. Unusually large vWf multimers observed in patients with disseminated tumors probably result from deficient vWf-cleaving protease activity and may represent a novel mechanism regulating primary platelet-tumor adhesive interactions involved in the metastatic process.
Oleksowicz
L
L
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. oleksowicz@sc3101.med.buffalo.edu
Bhagwati
N
N
DeLeon-Fernandez
M
M
D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001704:Biopolymers; D001777:Blood Coagulation / Q000187:drug effects; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D000939:Epitopes / Q000276:immunology; D005169:Factor VIII / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000378:metabolism; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000276:immunology; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000276:immunology; D014841:von Willebrand Factor / Q000032:analysis / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D001704:Biopolymers; D000939:Epitopes; D009363:Neoplasm Proteins; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D014841:von Willebrand Factor; C028254:von Willebrand factor receptor; D005169:Factor VIII; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human