Human breast tumors override the antiangiogenic effect of stromal thrombospondin-1 in vivo
Human breast tumors override the antiangiogenic effect of stromal thrombospondin-1 in vivo
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DOI：
10.1002/ijc.20584
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发表时间：
2005-09-20
影响因子：
6.4
通讯作者：
Clézardin, P
中科院分区：
文献类型：
--
作者：
Fontana, A;Filleur, S;Clézardin, P
抗血管生成细胞外基质蛋白血小板反应蛋白-1（TSP-1）抑制动物肿瘤生长和转移。然而，这些发现的临床相关性是不明确的，因为间质TSP-1表达增加与预后良好或不良相关。为了更全面地了解TSP-1在乳腺癌中的作用，我们首先使用了乳腺肿瘤发生模型，其中肿瘤相关的基质成纤维细胞被工程化以产生高水平的TSP-1。我们在这里证明了间质TSP-1延迟人MDA-MB-231/1302乳腺肿瘤生长。然而，暴露于TSP-1后MDA-MB-231/1302肿瘤生长的这种延迟与肿瘤细胞本身中血管内皮生长因子（VEGF）表达的增加有关，导致肿瘤生长速率与成纤维细胞不过度产生TSP-1的肿瘤相当。临床证据还表明，原发性乳腺癌已适应逃避间质TSP-1的影响。TSP-1被发现在人乳腺癌的间质中表达，尽管其水平与血管形成减少相关，但出乎意料地与无复发生存率降低相关。在转移性腋窝淋巴结中，肿瘤细胞表达高水平的VEGF和TSP-1表达不再与血管形成减少相关。总的来说，这些结果表明，耐药性可能在人类乳腺癌早期发展，作为高原位暴露于基质TSP-1的结果，导致疾病进展。(c)2005 Wiley-Liss，Inc.
The antiangiogenic extracellular matrix protein thrombospondin-1 (TSP-1) inhibits tumor growth and metastasis in animals. However, the clinical relevance of such findings are equivocal as increased stromal TSP-1 expression has been associated with either good or poor prognosis. In an effort to obtain a more integrated understanding of the role of TSP-1 in breast cancer, we first used a breast tumorigenesis model in which tumor-associated stromal fibroblasts were engineered to produce high levels of TSP-1. We demonstrate here that stromal TSP-1 delayed human MDA-MB-231/1302 breast tumor growth. However, this delay in MDA-MB-231/1302 tumor growth upon exposure to TSP-1 was associated with an increased vascular endothelial growth factor (VEGF) expression in tumor cells themselves, leading to a tumor growth rate comparable to that of tumors whose fibroblasts did not overproduce TSP-1. Clinical evidence also suggested that primary breast carcinomas have adapted to escape the effects of stromal TSP-1. TSP-1 was found to be expressed in the stroma of human breast carcinomas where, although its level correlated with decreased vascularization, it was unexpectedly associated with a reduction of relapse-free survival. In metastatic axillary lymph nodes, tumor cells expressed high levels of VEGF and TSP-1 expression were no longer associated with a decreased vascularization. Overall, these results suggest that a resistance may develop early in human breast cancers as a result of high in situ exposure to stromal TSP-1, leading to disease progression. (c) 2005 Wiley-Liss, Inc.