Fibroblast growth factor-2-induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization
Fibroblast growth factor-2-induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization
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DOI：
10.1111/j.1349-7006.2007.00432.x
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发表时间：
2007-04-01
期刊：
影响因子：
5.7
通讯作者：
Saiki, Ikuo
中科院分区：
文献类型：
--
作者：
Tsunoda, Satoshi;Nakamura, Toshiyuki;Saiki, Ikuo
成纤维细胞生长因子-2被认为在一些肿瘤的新生血管形成中起关键作用，然而，它在肿瘤进展中的确切作用还不完全清楚。在本研究中，我们表征了成纤维细胞生长因子-2在B16-BL6小鼠黑色素瘤细胞中的作用，重点是在肿瘤生长的初始阶段的作用。初始阶段在背部皮肤肿瘤接种部位注射成纤维细胞生长因子-2。成纤维细胞生长因子-2诱导明显的肿瘤生长和淋巴结转移。这与宿主基质中新生血管的增加密切相关。成纤维细胞生长因子-2还在宿主基质中招募炎性细胞和间充质细胞。在足垫接种部位一次性注射成纤维细胞生长因子-2后，肿瘤生长明显，肺转移，肿瘤实质内有大量新生血管形成。相反，在远离足底肿瘤的部位反复注射成纤维细胞生长因子-2在促进肿瘤生长和转移方面没有效果。局部注射糖皮质激素可阻断成纤维细胞生长因子-2的这些促进作用，提示成纤维细胞生长因子-2诱导的宿主炎症反应与成纤维细胞生长因子-2诱导的肿瘤进展有关。另外，尽管成纤维细胞生长因子-2在体外不能促进B16-BL6细胞的增殖和血管内皮生长因子A(VEGFA)的表达，但成纤维细胞生长因子-2在宿主间质而不是在肿瘤组织中诱导了VEGFA的表达，局部注射抗VEGFA的中和抗体在体内抑制了成纤维细胞生长因子-2的这些活性。这些结果表明，在肿瘤生长的初始阶段，丰富的成纤维细胞生长因子-2诱导依赖VEGFA的宿主基质中密集的新生血管，并支持显著的肿瘤生长和转移。
Fibroblast growth factor (FGF)-2 has been considered to play a critical role in neovascularization in several tumors; however, its precise role in tumor progression is not fully understood. In the present study, we have characterized the role of FGF-2 in B16-BL6 mouse melanoma cells, focusing on effects during the initial phase of tumor growth. FGF-2 was injected at the tumor inoculation site of dorsal skin during the initial phase. FGF-2 induced marked tumor growth and lymph node metastasis. This was well correlated with an increase in neovascularization in the host stroma. FGF-2 also recruited inflammatory and mesenchymal cells in host stroma. Marked tumor growth, pulmonary metastasis and intensive neovascularization in tumor parenchyma were also observed after a single injection of FGF-2 into the footpad inoculation site. In contrast, repeated injections of FGF-2 at a site remote from the footpad tumor were ineffective in promoting tumor growth and metastasis. These promoting activities of FGF-2 were blocked by local injections of a glucocorticoid hormone, suggesting that host inflammatory responses induced by FGF-2 are associated with FGF-2-induced tumor progression. In addition, although FGF-2 did not promote cellular proliferation and vascular endothelial growth factor A (VEGFA) mRNA expression in B16-BL6 cells in vitro, FGF-2 induced VEGFA expression in host stroma rather than tumor tissue, and local injections of a neutralizing antibody against VEGFA inhibited these activities of FGF-2 in vivo. These results indicate that abundant FGF-2 during the initial phase of tumor growth induces VEGFA-dependent intensive neovascularization in host stroma, and supports marked tumor growth and metastasis.