Döme Balázs, Rásó Erzsébet, Dobos Judit, Mészáros Livia, Varga Norbert, Puskás László G, Fehér Liliána Z, Lörincz Tamár, Ladányi Andrea, Trikha Mohit, Honn Kenneth V, Tímár József
Department of Tumor Progression, National Institute of Oncology, Budapest, Hungary.
Int J Cancer. 2005 Aug 10;116(1):27-35. doi: 10.1002/ijc.20991.
Previous studies indicated that transfection of the platelet integrin alphaIIbbeta3 into human melanoma cells expressing integrin alphavbeta3 promoted their in vivo (but not in vitro) growth and cell survival. To reveal the underlying pathomechanism, we have analyzed the angiogenic phenotype of alphaIIbbeta3 integrin-transduced human melanoma cells expressing integrin alphavbeta3. Upon heterotopic or orthotopic (intracutaneous) injections into SCID mice, the alphaIIbbeta3 integrin-overexpressing clones, ESL, ESH, 19L and 19H, grew more rapidly than the mock transfectant (alphavbeta3 expressing) clone, 3.1P. Morphometry demonstrated an increased intratumoral microvessel density in 19L and 19H tumors compared to 3.1P. Immunocytochemistry and flow cytometry indicated that vascular endothelial growth factor (VEGF) is constitutively expressed in the majority of the cells of both the mock and the alphaIIbbeta3 integrin-transfected clones. However, the mock transfectant clone, 3.1P, did not express basic fibroblast growth factor (bFGF) at protein level (<1%), unlike the alphaIIbbeta3 integrin-transfected clones, 19L and 19H, (33.9 and 84.1%, respectively). Quantitative PCR analysis of 6 related human melanoma clones with various levels of alphaIIbbeta3 integrin expressions revealed a correlation between the alphaIIb protein and bFGF mRNA expressions. Furthermore, cDNA microarray analysis of the 19H cells revealed 12 downregulated and 36 upregulated genes [among them 3 upregulated vasculogenic mimicry-genes (CD34, endothelin receptor B, Prostaglandin I-2 synthase)] when compared to 3.1P cells. The altered bFGF expression may be influenced by integrin-linked signaling, since bbeta3-endonexin is upregulated in alphaIIbbeta3-transfected cells and tyrosine kinase inhibitors downregulate bFGF both at mRNA and protein levels. We propose here that the illegitimate expression of alphaIIbbeta3 integrin in human melanoma cells already expressing alphavbeta3 integrin may alter their in vivo growth properties due to the modulation of their angiogenic phenotype.
先前的研究表明，将血小板整合素αIIbβ3转染到表达整合素αvβ3的人黑色素瘤细胞中，可促进其体内（而非体外）生长和细胞存活。为揭示潜在的发病机制，我们分析了转导αIIbβ3整合素的表达整合素αvβ3的人黑色素瘤细胞的血管生成表型。将过表达αIIbβ3整合素的克隆ESL、ESH、19L和19H异位或原位（皮内）注射到SCID小鼠体内后，其生长速度比mock转染子（表达αvβ3）克隆3.1P更快。形态计量学显示，与3.1P相比，19L和19H肿瘤内的微血管密度增加。免疫细胞化学和流式细胞术表明，血管内皮生长因子（VEGF）在mock和αIIbβ3整合素转染克隆的大多数细胞中均持续表达。然而，mock转染子克隆3.1P在蛋白水平（<1%）不表达碱性成纤维细胞生长因子（bFGF），这与αIIbβ3整合素转染克隆19L和19H不同（分别为33.9%和84.1%）。对6个具有不同αIIbβ3整合素表达水平的相关人黑色素瘤克隆进行定量PCR分析，发现αIIb蛋白与bFGF mRNA表达之间存在相关性。此外，与3.1P细胞相比，对19H细胞进行cDNA微阵列分析发现有12个基因下调，36个基因上调[其中3个上调的血管生成拟态基因（CD34、内皮素受体B、前列腺素I-2合成酶）]。bFGF表达的改变可能受整合素相关信号传导的影响，因为β3内毒素在αIIbβ3转染细胞中上调，酪氨酸激酶抑制剂在mRNA和蛋白水平均下调bFGF。我们在此提出，在已表达αvβ3整合素的人黑色素瘤细胞中αIIbβ3整合素的异常表达可能因其血管生成表型的调节而改变其体内生长特性。
Int J Cancer. 2002-9-10
Biochem Biophys Res Commun. 2020-3-9
Oncol Res. 2025-1-16
Cancer Metastasis Rev. 2023-3
J Exp Clin Cancer Res. 2018-4-27
Pathol Oncol Res. 2012-3-24
Zotero 插件