The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion
The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion
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DOI：
10.3892/ijo_00000124
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发表时间：
2009-01-01
影响因子：
5.2
通讯作者：
Schaaf, Antonela
中科院分区：
文献类型：
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作者：
Hildenbrand, Ralf;Schaaf, Antonela
尿激酶系统与肿瘤扩散有关。丝氨酸蛋白酶尿激酶型纤溶酶原激活剂（uPA）及其受体（uPAR）及其抑制剂（PAI-1）在生理和病理条件下参与控制细胞外转换、细胞迁移、侵袭、细胞信号传导、增殖、凋亡和血管生成，导致各种不同的反应。uPA和PAI-1是第一个以最高水平的证据证实其在乳腺癌临床应用的新型肿瘤生物学因子。然而，目前尚不清楚它们在肿瘤基质中的（相对）水平还是在肿瘤细胞本身中与患者预后最相关。本研究首次采用激光捕获显微解剖分离浸润性乳腺癌的肿瘤细胞和间质组织，并采用elisa法检测LIPA、uPAR和PAI-1水平。此外，我们通过免疫组织化学和原位杂交定位了uPA、uPAR和PAI-1在浸润性乳腺癌（n=30）和导管原位癌（DCIS, n=30）中的分布。我们已经证明，仅在肿瘤间质、仅在肿瘤细胞和未分离的乳腺癌组织中，LIPA、uPAR和PAI-1水平无显著差异（p < 0.05）。我们的研究结果表明，这些因子在两个腔室和未分离的乳腺癌组织中的相似表达水平可能对乳腺癌的临床行为产生相同的影响。这些结果对组织取样的实际应用具有重要意义。对于使用uPA和PAI-1水平作为乳腺癌的预后和预测因素，肿瘤组织标本中肿瘤间质的数量与评估患者预后无关。我们的研究结果被免疫组织化学和原位杂交分析证实，在几乎所有的浸润性癌和DCIS病例中，成纤维细胞以及巨噬细胞强烈表达uPA、uPAR和PAI-1。根据我们的免疫组织学结果，几乎所有DCIS的肌上皮细胞都表现出uPA， uPAR和PAI-1，我们详细研究了这些重要的宿主细胞。我们通过多模态方法证实了uPAR和PAI-1蛋白和mRNA在大多数DCIS肌上皮细胞中表达。此外，我们提供的证据表明，rnyo上皮细胞的uPAR表达对于uPAR vitronectin相关的细胞-基质相互作用是重要的，这种相互作用调节细胞的粘附和脱离。我们推测，在DCTS中，抗侵袭性肌上皮细胞层的缺失可能是由PAI-1引发的，并且可能是随后肿瘤细胞侵袭的早期迹象。
The urokinase-system has been implicated in tumor spread. The serine protease urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1) are involved in the control of extracellular turnover, cell migration, invasion, cell signalling, proliferation, apoptosis and angiogenesis leading to a variety of different responses, under both physiological and pathological conditions. uPA and PAI-1 were the first novel tumor biological factors to be validated at the highest level of evidence regarding their clinical utility in breast cancer. However, it is unclear whether it is their (relative) levels in the tumor stroma or in the tumor cells themselves that is the most relevant to patients outcome. This is the first study in which tumor cells and stromal tissue of invasive breast carcinomas were separated by laser capture microdissection followed by ELISA-based determination of the LIPA, uPAR and PAI-1 levels. In addition, we localized uPA, uPAR and PAI-1 distribution in invasive breast cancer (n=30) and in ductal carcinoma in situ (DCIS, n=30) by immunohistochemistry and in situ hybridization. We have demonstrated that no significant differences between LIPA, uPAR and PAI-1 levels in tumor stroma only, tumor cells only and not separated breast cancer tissue exist (p > 0.05). Our results suggest that similar expression levels of these factors in both compartments and in not separated breast cancer tissue may have the same impact on the clinical behavior of breast cancer. These results are an important issue for practical use Of tissue sampling. For using uPA and PAI-1 levels as prognostic and predictive factors in breast cancer the quantity of tumor stroma in the tumor tissue specimen is not relevant for assessment patients outcome. Our results were confirmed by immunohistochemistry and in situ hybridization analysis showing that in nearly all cases of invasive carcinomas and DCIS fibroblasts as well as macrophages strongly express uPA, uPAR and PAI-1. Prompted by Our immunohistological results that nearly all myoepithelial cells of DCIS exhibit uPA, uPAR and PAI-1, we investigated these important host cells in detail. We have demonstrated by multimodal methods that uPAR and PAI-1 protein and mRNA is expressed in most myoepithelial cells of DCIS. Additionally, we furnish evidence that uPAR expression of rnyoepithelial cells are important for uPAR Vitronectin-associated cell-matrix interaction, which regulates cell adhesion and detachment. We speculate that the loss of the anti-invasive myoepithelial cell layer in DCTS may be triggered by PAI-1 and could be an early sign of subsequent tumor cell invasion.