Czubayko F, Liaudet-Coopman E D, Aigner A, Tuveson A T, Berchem G J, Wellstein A
Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.
Nat Med. 1997 Oct;3(10):1137-40. doi: 10.1038/nm1097-1137.
The growth and metastatic spread of cancer is directly related to tumor angiogenesis, and the driving factors need to be understood to exploit this process therapeutically. However, tumor cells and their normal stroma express a multitude of candidate angiogenic factors, and very few specific inhibitors have been generated to assess which of these gene products are only innocent bystanders and which contribute significantly to tumor angiogenesis and metastasis. Here we investigated whether the expression in tumors of a secreted fibroblast growth factor (FGF)-binding protein (FGF-BP) that mobilizes and activates locally stored FGFs (ref. 11) can serve as an angiogenic switch molecule. Developmental expression of the retinoid-regulated FGF-BP gene is prominent in the skin and intestine during the perinatal phase and is down-modulated in the adult. The gene is, however, upregulated in carcinogen-induced skin tumors, in squamous cell carcinoma (SCC) and in some colon cancer cell lines and tumor samples. To assess the significance of FGF-BP expression in tumors, we depleted human SCC (ME-180) and colon carcinoma (LS174T) cell lines of their endogenous FGF-BP by targeting with specific ribozymes. We found that the reduction of FGF-BP reduced the release of biologically active basic FGF (bFGF) from cells in culture. Furthermore, the growth and angiogenesis of xenograft tumors in mice was decreased in parallel with the reduction of FGF-BP. This suggests that human tumors can utilize FGF-BP as an angiogenic switch molecule.
癌症的生长和转移扩散与肿瘤血管生成直接相关，为了从治疗上利用这一过程，需要了解其驱动因素。然而，肿瘤细胞及其正常基质表达多种候选血管生成因子，而用于评估这些基因产物中哪些只是无辜旁观者、哪些对肿瘤血管生成和转移有显著作用的特异性抑制剂却很少。在此，我们研究了一种分泌型成纤维细胞生长因子（FGF）结合蛋白（FGF-BP）在肿瘤中的表达是否可作为一种血管生成开关分子，该蛋白能动员并激活局部储存的FGF（参考文献11）。类视黄醇调节的FGF-BP基因在围产期的皮肤和肠道中发育表达显著，在成年期下调。然而，该基因在致癌物诱导的皮肤肿瘤、鳞状细胞癌（SCC）以及一些结肠癌细胞系和肿瘤样本中上调。为了评估FGF-BP在肿瘤中表达的意义，我们用特异性核酶靶向去除人SCC（ME-180）和结肠癌细胞系（LS174T）中的内源性FGF-BP。我们发现，FGF-BP的减少降低了培养细胞中生物活性碱性FGF（bFGF）的释放。此外，小鼠异种移植瘤的生长和血管生成与FGF-BP的减少同步降低。这表明人类肿瘤可利用FGF-BP作为一种血管生成开关分子。
