Targets of fibroblast growth factor 1 (FGF-1) and FGF-2 signaling involved in the invasive and tumorigenic behavior of carcinoma cells
Targets of fibroblast growth factor 1 (FGF-1) and FGF-2 signaling involved in the invasive and tumorigenic behavior of carcinoma cells
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DOI：
10.1091/mbc.e04-04-0336
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发表时间：
2004-10-01
影响因子：
3.3
通讯作者：
Jouanneau, J
中科院分区：
文献类型：
--
作者：
Billottet, C;Elkhatib, N;Jouanneau, J
成纤维细胞生长因子-1和-2具有潜在的生物学活性，与恶性肿瘤的发生发展密切相关。在NBT-II细胞系统中研究了它们在肿瘤进展中的自分泌和非自分泌活性。细胞被操纵以产生和自分泌成纤维细胞生长因子-1或-2，或者只产生而不对这些因素作出反应。自分泌细胞具有高度侵袭性和致瘤性，对成纤维细胞生长因子受体(FGFR)信号转导的特异性靶点的确定进行了评估。体外研究表明，非自分泌细胞的行为类似于上皮亲本细胞，而自分泌细胞具有间质表型，与尿激酶型纤溶酶原激活剂受体(UPAR)的过度表达、E-钙粘附素的内化以及β-连环素从细胞表面向胞浆和胞核的重新分布有关。UPAR被定义为早期靶点，而E-钙粘附素和白细胞共同抗原相关蛋白酪氨酸磷酸酶(LAR-PTP)是成纤维细胞生长因子信号转导的晚期靶点，FGFR1的激活在调节这些靶点方面比FGFR2更有效。自分泌细胞的行为与E-钙粘素和LAR-PTP的肿瘤抑制活性降低是一致的。这些分子分析表明，这两种生长因子在肿瘤进展中的潜力高度依赖于特定的FGFR信号，并强调了其作为抗肿瘤治疗靶点的重要性。
Fibroblast growth factor (FGF)-1 and -2 have potent biological activities implicated in malignant tumor development. Their autocrine and nonautocrine activity in tumor progression of carcinoma was investigated in the NBT-II cell system. Cells were manipulated to either produce and be autocrine for FGF-1 or -2 or to only produce but not respond to these factors. The autocrine cells are highly invasive and tumorigenic and the determination of specific targets of FGF/fibroblast growth factor receptor (FGFR) signaling was assessed. In vitro studies showed that nonautocrine cells behave like epithelial parental cells, whereas autocrine cells have a mesenchymal phenotype correlated with the overexpression of urokinase plasminogen activator receptor (uPAR), the internalization of E-cadherin, and the redistribution of beta-catenin from the cell surface to the cytoplasm and nucleus. uPAR was defined as an early target, whereas E-cadherin and the leukocyte common antigen-related protein-tyrosine phosphatase (LAR-PTP) were later targets of FGF signaling, with FGFR1 activation more efficient than FGFR2 at modulating these targets. Behavior of autocrine cells was consistent with a decrease of tumor-suppressive activities of both E-cadherin and LAR-PTP. These molecular analyses show that the potential of these two growth factors in tumor progression is highly dependent on specific FGFR signaling and highlights its importance as a target for antitumor therapy.