Zetser Anna, Bashenko Yulia, Miao Hua-Quan, Vlodavsky Israel, Ilan Neta
Vascular and Tumor Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Cancer Res. 2003 Nov 15;63(22):7733-41.
Heparanase is an endo-beta-glucuronidase responsible for the cleavage of heparan sulfate, participating in extracellular matrix degradation and remodeling. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase up-regulation was detected in essentially all human tumors examined, correlating, in some cases, with poor postoperative survival and increased tumor vascularity. The role of heparanase in primary tumor progression is, however, poorly understood. Here, we overexpressed the human heparanase gene in a human glioma cell line, U87. We found that heparanase overexpression induces cell invasion, as might be expected. Surprisingly, elevated heparanase expression levels correlated with decreased proliferation rates and increased cell spreading and formation of a tight monolayer rather than large cell aggregates. This phenotypic appearance was accompanied by beta1-integrin activation, FAK and Akt phosphorylation, and Rac activation. In a xenograft tumor model, relatively moderate heparanase expression levels significantly enhanced tumor development and tumor vascularity, whereas high heparanase expression levels inhibited tumor growth. These results indicate that heparanase activates signal transduction pathways and, depending on its expression levels, may modulate tumor progression.
乙酰肝素酶是一种内切-β-葡萄糖醛酸酶，负责硫酸乙酰肝素的裂解，参与细胞外基质的降解和重塑。传统上，乙酰肝素酶活性与大量肿瘤来源细胞类型的转移潜能密切相关。最近，在几乎所有检测的人类肿瘤中都检测到乙酰肝素酶上调，在某些情况下，这与术后生存率低和肿瘤血管生成增加相关。然而，乙酰肝素酶在原发性肿瘤进展中的作用仍知之甚少。在此，我们在人胶质瘤细胞系U87中过表达人乙酰肝素酶基因。我们发现，正如预期的那样，乙酰肝素酶过表达诱导细胞侵袭。令人惊讶的是，乙酰肝素酶表达水平升高与增殖率降低、细胞铺展增加以及形成紧密的单层而非大的细胞聚集体相关。这种表型表现伴随着β1整合素激活、FAK和Akt磷酸化以及Rac激活。在异种移植肿瘤模型中，相对适度的乙酰肝素酶表达水平显著增强肿瘤发展和肿瘤血管生成，而高乙酰肝素酶表达水平则抑制肿瘤生长。这些结果表明，乙酰肝素酶激活信号转导通路，并根据其表达水平可能调节肿瘤进展。
