Heparanase is an endoglucuronidase that uniquely cleaves the heparan sulfate side chains of heparan sulfate proteoglycans. This activity ultimately alters the structural integrity of the ECM and basement membrane that becomes more prone to cellular invasion by metastatic cancer cells and cells of the immune system. In addition, enzymatically inactive heparanase was found to facilitate the proliferation and survival of cancer cells by activation of signaling molecules such as Akt, Src, signal transducer and activation of transcription (Stat), and epidermal growth factor receptor. This function is thought to be executed by the C-terminal domain of heparanase (8c), because over expression of this domain in cancer cells accelerated signaling cascades and tumor growth. We have used the regulatory elements of the mouse mammary tumor virus (MMTV) to direct the expression heparanase and the C-domain (8c) to the mammary gland epithelium of transgenic mice. Here, we report that mammary gland branching morphogenesis is increased in MMTV-heparanase and MMTV-8c mice, associating with increased Akt, Stat5 and Src phosphorylation. Furthermore, we found that the growth of tumors generated by mouse breast cancer cells and the resulting lung metastases are enhanced in MMTV-heparanase mice, thus supporting the notion that heparanase contributed by the tumor microenvironment (i.e., normal mammary epithelium) plays a decisive role in tumorigenesis. Remarkably, MMTV-8c mice develop spontaneous tumors in their mammary and salivary glands. Although this occurs at low rates and requires long latency, it demonstrates decisively the pro-tumorigenic capacity of heparanase signaling.

中文翻译：

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将乙酰肝素酶靶向乳腺上皮可增强乳腺发育并促进肿瘤生长和转移。

乙酰肝素酶是一种内切葡糖醛酸糖苷酸酶，其独特地裂解硫酸乙酰肝素蛋白聚糖的硫酸乙酰肝素侧链。该活性最终改变了ECM和基底膜的结构完整性，从而更易于被转移性癌细胞和免疫系统细胞侵袭。此外，发现无酶乙酰肝素酶可通过激活信号分子（例如Akt，Src，信号转导子和转录激活（Stat）和表皮生长因子受体）促进癌细胞的增殖和存活。该功能被认为由乙酰肝素酶（8c）的C-末端结构域执行，因为该结构域在癌细胞中的过表达加速了信号级联和肿瘤生长。我们已经使用小鼠乳腺肿瘤病毒（MMTV）的调控元件来指导表达乙酰肝素酶和C结构域（8c）到转基因小鼠的乳腺上皮。在这里，我们报告在MMTV-乙酰肝素酶和MMTV-8c小鼠中乳腺分支形态发生增加，与增加的Akt，Stat5和Src磷酸化相关。此外，我们发现在MMTV-乙酰肝素酶小鼠中，由小鼠乳腺癌细胞产生的肿瘤的生长以及由此产生的肺转移得到了增强，从而支持了由肿瘤微环境（即正常的乳腺上皮）贡献的乙酰肝素起决定性作用的观点。在肿瘤发生中。值得注意的是，MMTV-8c小鼠的乳腺和唾液腺中会出现自发性肿瘤。尽管这种情况的发生率较低且需要较长的等待时间，