Angiogenesis-associated protein annexin II in breast cancer: Selective expression in invasive breast cancer and contribution to tumor invasion and progression
Angiogenesis-associated protein annexin II in breast cancer: Selective expression in invasive breast cancer and contribution to tumor invasion and progression
复制标题
DOI：
10.1016/j.yexmp.2006.03.003
复制
发表时间：
2006-10-01
影响因子：
3.6
通讯作者：
Sharma, Mahesh C.
中科院分区：
文献类型：
--
作者：
Sharma, Meena R.;Koltowski, Lauren;Sharma, Mahesh C.
许多晚期人类肿瘤，包括乳腺癌，都过度产生纤溶酶，而纤溶酶是已知的促进血管生成和转移的物质。人们对这种效应的机制知之甚少。在此，我们报道了在正常和增生性导管上皮细胞和导管复合体中检测不到的膜联蛋白II，它是tPA(组织型纤溶酶原激活剂)和纤溶酶原的内皮共同受体。相反，它在浸润性乳腺癌和导管原位癌(DCIS)中持续表达，表明它参与了乳腺癌的发生。利用已建立的侵袭性/转移性的MDA-MB231细胞系和非侵袭性/非转移性的人乳腺癌细胞系MCF-7，研究了Annexin II调控乳腺癌进展和转移的机制。Western和Northern印迹分析表明，Annexin II在MDA-NM231细胞中选择性表达，但在低侵袭性MCF-7细胞中不表达，提示其参与了浸润性乳腺癌。由于膜联蛋白II是纤溶酶原的受体，我们在体外测试了MDA-MB231细胞是否能够产生纤溶酶。MDA-MB231细胞膜以时间依赖的方式诱导纤溶酶生成，而MCF-7细胞膜不能将纤溶酶原转化为纤溶酶。产生的纤溶酶能够降解细胞外基质，从而促进细胞的侵袭和迁移，这是血管生成和转移所需的生物学功能。抗Annexin II或Angiostatin的单抗可以阻断纤溶酶的产生及其依赖的侵袭和迁移，Angiostatin是血管生成、乳腺癌和转移的有效抑制剂。我们的发现表明，依赖膜联蛋白II的人乳腺癌细胞局部产生纤溶酶可能有助于血管生成和转移。这些结果表明，膜联蛋白II可能是抗血管生成和抗乳腺癌新疗法的一个有吸引力的靶点。(C)2006 Elsevier Inc.保留所有权利。
Many advanced human tumors including breast cancer overproduce plasmin that is known to promote angiogenesis and metastasis. The mechanism of this effect is poorly understood. Here we report that annexin II, an endothelial co-receptor for tPA (tissue-type plasminogen activator) and plasminogen, was undetectable in normal and hyperplastic ductal epithelial cells and ductal complexes. By contrast, it was consistently expressed in invasive breast cancer and ductal carcinoma in situ (DCIS) indicating its involvement in breast cancer. Using the well established invasive/metastatic MDA-MB231 cell line and the noninvasive/nonmetastatic MCF-7 human breast cancer cell line, we investigated the mechanism by which annexin II regulates breast cancer progression and metastasis. Western and Northern blot analyses demonstrate selective expression of annexin II in MDA-NM231 cells but not in poorly invasive MCF-7 cells suggesting its participation in invasive breast cancer. Since annexin II is a receptor for plasminogen, we tested whether MDA-MB231 cells are capable of producing plasmin in vitro. MDA-MB231 cell membranes induced plasmin generation in a time-dependent manner while those from MCF-7 cells failed to convert plasminogen to plasmin. The generated plasmin is capable of degrading ECM consequently facilitating cell invasion and migration, biological functions required for angiogenesis and metastasis. Plasmin generation and its dependent invasion and migration can be blocked by a monoclonal antibody to annexin II or angiostatin, potent inhibitors of angiogenesis, breast cancer, and metastasis. Our findings indicate that annexin II-dependent localized plasmin generation by human breast cancer cells could contribute to angiogenesis and metastasis. These results suggest that annexin II may be an attractive target for new anti-angiogenic and anti-breast cancer therapies. (c) 2006 Elsevier Inc. All rights reserved.