Tsunoda Satoshi, Nakamura Toshiyuki, Sakurai Hiroaki, Saiki Ikuo
Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., 301, Gensuke, Fujieda, Shizuoka, 426-0088, Japan.
Cancer Sci. 2007 Apr;98(4):541-8. doi: 10.1111/j.1349-7006.2007.00432.x. Epub 2007 Mar 14.
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.
成纤维细胞生长因子（FGF）-2被认为在多种肿瘤的新血管形成中起关键作用；然而，其在肿瘤进展中的精确作用尚未完全明确。在本研究中，我们已明确了FGF-2在B16-BL6小鼠黑色素瘤细胞中的作用，重点关注肿瘤生长初始阶段的影响。在初始阶段，将FGF-2注射到背部皮肤的肿瘤接种部位。FGF-2可诱导显著的肿瘤生长和淋巴结转移。这与宿主基质中新生血管形成的增加密切相关。FGF-2还可募集宿主基质中的炎性细胞和间充质细胞。在足垫接种部位单次注射FGF-2后，还观察到肿瘤显著生长、肺转移以及肿瘤实质内密集的新生血管形成。相比之下，在远离足垫肿瘤的部位重复注射FGF-2对促进肿瘤生长和转移无效。FGF-2的这些促进作用可被局部注射糖皮质激素所阻断，这表明FGF-2诱导的宿主炎症反应与FGF-2诱导的肿瘤进展相关。此外，尽管FGF-2在体外并未促进B16-BL6细胞的细胞增殖和血管内皮生长因子A（VEGFA）mRNA表达，但FGF-2可诱导宿主基质而非肿瘤组织中的VEGFA表达，并且局部注射抗VEGFA中和抗体可在体内抑制FGF-2的这些活性。这些结果表明，肿瘤生长初始阶段丰富的FGF-2可诱导宿主基质中依赖VEGFA的密集新生血管形成，并支持显著的肿瘤生长和转移。
