Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z
Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Cancer Metastasis Rev. 1990 Nov;9(3):203-26. doi: 10.1007/BF00046361.
Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a solid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM produced in vitro and in basement membranes of the cornea and blood vessels in vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.
肿瘤细胞需要一个合适的细胞周围环境以及新的基质和血管形成，才能构成实体瘤。肿瘤进展还涉及各种细胞外基质（ECM）成分的降解。在本综述中，我们重点关注了ECM驻留生长因子和酶在新血管形成和细胞侵袭中的可能作用。我们证明，多能血管生成因子碱性成纤维细胞生长因子（bFGF）是支持细胞增殖和分化所需的一种ECM成分。碱性FGF已在体外产生的内皮下ECM以及体内角膜和血管的基底膜中被鉴定出来。尽管bFGF在正常组织中普遍存在，但这些组织中的内皮细胞（EC）增殖通常非常低，这表明bFGF在某种程度上与其作用位点分离。我们的结果表明，bFGF与ECM中的硫酸乙酰肝素（HS）结合，当ECM-HS被细胞型乙酰肝素酶降解时，以活性形式释放。我们提出，通过与ECM结合来限制bFGF的生物利用度及其释放的局部调节，为正常和病理情况下毛细血管生长的调节提供了一种新机制。乙酰肝素酶活性与各种肿瘤细胞的转移潜能相关，并且乙酰肝素酶抑制分子可显著降低实验动物的肺转移发生率。因此，乙酰肝素酶可能通过降解ECM-HS和动员ECM驻留的EC生长因子，参与肿瘤细胞侵袭和血管生成。内皮下ECM还含有组织型和尿激酶型纤溶酶原激活剂（PA），以及可能调节细胞侵袭和组织重塑的PA抑制剂。乙酰肝素酶和ECM驻留的PA协同参与ECM中HS蛋白聚糖的顺序降解。这些结果以及对其他ECM固定化酶和生长因子特性的类似观察结果表明，ECM为生物活性分子提供了一个储存库，从而使这些分子得以稳定和保护。与液相中的相同分子相比，这可能允许一种更局部、受调节和持久的作用方式。
