Fibroblast Growth Factor/FGF Receptor 1 (FGF2/FGFR1) system regulates the growth and metastasis of different cancers. Inhibition of this signaling pathway is an attractive target for cancer therapy. Here, we aimed to reproduce the 118–126 fragment of FGF2 to interfere with the FGF2–FGFR1 interaction. To determine whether the loop structure affects the function of this fragment, we compared cyclic (disulfide-bonded) and linear peptide variants. The cyclic peptide (referred to as BGF1) effectively inhibited the FGF2-induced proliferation of HUVECs, 4T1 mammary carcinoma, U87 glioblastoma, and SKOV3 ovarian carcinoma cells. It led to apoptosis induction in HUVECs, whereas the linear peptide (referred to as BGF2) was ineffective. In a murine 4T1 tumor model, BGF1 inhibited tumor growth more effectively than Avastin and increased animals’ survival without causing weight loss, but the linear peptide BGF2 had no significant anti-tumor effects. According to immunohistochemical studies, the anti-tumor properties of BGF1 were associated with suppression of tumor cell proliferation (Ki-67 expression), angiogenesis (CD31 expression), and apoptosis induction (as was shown by increased p53 expression and TUNEL staining and decreased Bcl-2 expression). The potential of BGF1 to suppress tumor invasion was indicated by quantitative analysis of the metastasis-related proteins, including FGFR1, pFGFR1, NF-κB, p-NF-κB, MMP-9, E-cadherin, N-cadherin, and Vimentin, and supported by small animal positron emission tomography (PET) used 18Fluorodeoxyglucose (18F-FDG). These results demonstrate that the functional properties of the 118–126 region of FGF2 depend on the loop structure and the peptide derived from this fragment encourages further preclinical investigations.

中文翻译：

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FGF2 118-126 片段的抗肿瘤和抗转移活性取决于环结构

成纤维细胞生长因子/FGF 受体 1 (FGF2/FGFR1) 系统调节不同癌症的生长和转移。抑制这种信号通路是癌症治疗的一个有吸引力的目标。在这里，我们旨在复制 FGF2 的 118-126 片段以干扰 FGF2-FGFR1 相互作用。为了确定环结构是否影响该片段的功能，我们比较了环状（二硫键）和线性肽变体。环肽（简称 BGF1）有效抑制 FGF2 诱导的 HUVEC、4T1 乳腺癌、U87 胶质母细胞瘤和 SKOV3 卵巢癌细胞的增殖。它导致 HUVEC 中的细胞凋亡诱导，而线性肽（称为 BGF2）无效。在鼠 4T1 肿瘤模型中，BGF1比阿瓦斯汀更有效地抑制肿瘤生长并增加动物的存活率而不导致体重减轻，但线性肽BGF2没有显着的抗肿瘤作用。根据免疫组织化学研究，BGF1 的抗肿瘤特性与抑制肿瘤细胞增殖（Ki-67 表达）、血管生成（CD31 表达）和细胞凋亡诱导相关（如 p53 表达和 TUNEL 染色增加和 Bcl 减少所示） -2 表达式）。通过对转移相关蛋白的定量分析表明 BGF1 抑制肿瘤侵袭的潜力，包括 FGFR1、pFGFR1、NF-κB、p-NF-κB、MMP-9、E-cadherin、N-cadherin 和 Vimentin，在小动物正电子发射断层扫描 (PET) 的支持下，使用了 18 氟脱氧葡萄糖 (18F-FDG)。