Involvement of heparanase in tumor metastasis and angiogenesis.
The capacity of various blood-borne cells, whether normal or malignant, to extravasate was found to correlate with heparanase-mediated degradation of HS in subendothelial ECM. This degradation was stimulated by proteases or plasminogen and inhibited by native heparin and by various modified nonanticoagulant species of heparin. These heparins also induced a marked reduction in tumor cell metastasis and autoimmune diseases in experimental animals. Heparanase-mediated degradation of HS in ECM also released EC growth factors that are stored in ECM, most likely by high affinity binding to HS. Such growth factors were extracted from subendothelial ECM synthesized in vitro and from basement membranes of the cornea in vivo, and are structurally and functionally related to bFGF;bFGF binds to ECM and is readily released by incubation with either HS, heparin or low MW heparin fragments as well as by various normal and malignant cells and by heparanase-mediated degradation of ECM HS. In contrast, there was little or no release of growth-promoting activity upon incubation of ECM with hyaluronic acid, chondroitin sulfate or chondroitinase ABC. A model is proposed suggesting that regulation of capillary growth and neovascular response may result from displacement of an angiogenic protein (bFGF) from its storage sites within basement membranes.
Vlodavsky
I
I
Sharett Institute of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Michaeli
R I
RI
Bar-Ner
M
M
Fridman
R
R
Horowitz
A T
AT
Fuks
Z
Z
Biran
S
S
D005109:Extracellular Matrix / Q000201:enzymology / Q000503:physiopathology; D005966:Glucuronidase; D006026:Glycoside Hydrolases / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000503:physiopathology; D000099175:Heparanase
D005966:Glucuronidase; D006026:Glycoside Hydrolases; D006133:Growth Substances; D000099175:Heparanase