Hyperproduction of hyaluronan in Neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment - Possible involvement of versican/PG-M
Hyperproduction of hyaluronan in Neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment - Possible involvement of versican/PG-M
复制标题
DOI：
10.2353/ajpath.2007.060793
复制
发表时间：
2007-03-01
影响因子：
6
通讯作者：
Itano, Naoki
中科院分区：
文献类型：
--
作者：
Koyama, Hiroshi;Hibi, Terumasa;Itano, Naoki
透明质酸浓度升高常与人类乳腺癌恶性肿瘤有关。在这里，我们利用小鼠乳腺肿瘤病毒(MMTV)-新型自发性乳腺癌转基因模型研究透明质酸在癌变和癌症进展中的作用。通过cre介导重组产生表达小鼠透明质酸合成酶2 （Has2）的条件转基因小鼠，并与MMTV-Neu小鼠杂交。在MMTV启动子控制下表达Cre重组酶时，携带Has2和new转基因的双基因小鼠表现出透明质酸基质沉积和new引发的乳腺肿瘤侵袭性生长。值得注意的是，在肿瘤细胞中，强制表达Has2会破坏细胞间粘附机制并引发细胞存活信号。与这些肿瘤细胞的改变同时发生。瘤内基质和微血管明显诱导。为了揭示透明质酸介导的新生血管形成的分子基础，我们检测了不同的透明质酸样品在体内促进血管生成的能力。在基质塞实验中，在透明质酸低聚糖或含有多聚糖的透明质酸聚集物存在的情况下，碱性成纤维细胞生长因子诱导的新生血管增加。透明质酸-胞质聚集体的管理，而不是天然透明质酸本身，促进基质细胞募集的同时内皮细胞的浸润。综上所述，这些结果表明，透明质酸的过量产生通过基质反应加速了肿瘤血管生成，特别是在花青素存在的情况下。
Elevated concentrations of hyaluronan are often associated with human breast cancer malignancy. Here, we investigated the roles of hyaluronan in carcinogenesis and cancer progression using the mouse mammary tumor virus (MMTV)-Neu transgenic model of spontaneous breast cancer. Conditional transgenic mice that express murine hyaluronan synthase 2 (Has2) by Cre-mediated recombination were generated and crossed with the MMTV-Neu mice. In expressing Cre recombinase under the control of the MMTV promoter, the bigenic mice bearing Has2 and neu transgenes exhibited a deposition of hyaluronan matrix and aggressive growth of Neu-initiated mammary tumors. Notably, forced expression of Has2 impaired intercellular adhesion machinery and elicited cell survival signals in tumor cells. Concurrent with these alterations of tumor cells. intratumoral stroma and microvessels were markedly induced. To reveal the molecular basis of hyaluronan-mediated neovascularization, various hyaluronan samples were examined for their ability to potentiate in vivo angiogenesis. In Matrigel plug assays, basic fibroblast growth factor-induced neovascularization was elevated in the presence of either hyaluronan oligosaccharides or a hyaluronan aggregate containing versican. Administration of hyaluronan-versican aggregates, but not native hyaluronan alone, promoted stromal cell recruitment concurrently with the infiltration of endothelial cells. Taken together, these results suggest that hyaluronan overproduction accelerates tumor angiogenesis through stromal reaction, notably in the presence of versican.