Department of Urology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, P.R. China.
Department of Urology, Shandong Provincial Hospital, 324 Jingwuweiqi Road, Jinan, 250014, P.R.China.
Int J Biol Sci. 2018 Jun 3;14(9):1012-1021. doi: 10.7150/ijbs.25200. eCollection 2018.
Mesenchymal stem cells (MSCs) are capable of impacting tumor progression but its role in tumor stroma remodeling still remains unclear. This present study was aimed to evaluate the potential function of MSCs on tumor stroma remodeling using rabbits VX2 bladder tumor model. The VX2 bladder tumor models were established by injecting mixed cell suspensions (10 of VX2 tumor cells and 0/10/10 of autologous MSCs in group A, B, C, respectively) into the bladder mucosa using thirty male New Zealand white rabbits. The tumor volume was measured by ultrasound at the time points of 1st, 2nd, 3rd and 4th week after inoculation. At the end of the fourth week, the tumor tissue expressions of basic fibroblast growth factor (bFGF), transforming growth factor beta 1 (TGFβ-1), hepatocyte growth factor (HGF), matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) were determined using Real-time quantitative PCR and immunohistochemistry. Masson trichrome staining and Cy3-FITC double-labelled immunofluorescence staining were used to determine the MSCs distribution in tumor tissue in another two rabbits implanted with a cell suspension of 10 VX2 tumor cells and 10 autologous MSCs. MSCs were homogeneously distributed in tumor tissues after 7 days of inoculation, which were not consistent with the distribution of tumor stroma. After 21 days of inoculation, MSCs have been integrated into tumor interstitial tissue and mainly distributed in the mesenchyma around the tumor nest. At the 1st, 2nd, 3rd and 4th week time point, tumor volume in group A < group B < group C, and the difference has statistical significance (all <0.001).The relative mRNA and protein levels of bFGF, TGFβ-1 and HGF were significantly higher in group B and C compared with group A (all <0.05), as well as the mRNA levels of bFGF, HGF were higher in group C than group B (<0.05), and the protein levels of bFGF, TGFβ-1 were higher in group C than group B (<0.05). The mRNA and protein levels of MMP2 were significantly higher in group B, C than group A (<0.05). MMP9 was increasingly over expressed along with the growing amount of MSCs inoculated within tumor, both at the level of mRNA and protein (all <0.05). MSCs participate in tumor stroma remodeling via inducing overexpression of some important growth factors and MMPs.
间充质干细胞（MSCs）能够影响肿瘤的进展，但它在肿瘤基质重塑中的作用仍不清楚。本研究旨在通过兔 VX2 膀胱癌模型评估 MSCs 对肿瘤基质重塑的潜在功能。通过将混合细胞悬浮液（A、B、C 组分别为 10 个 VX2 肿瘤细胞和 0/10/10 个自体 MSCs）注入膀胱黏膜，建立 VX2 膀胱癌模型。在接种后第 1、2、3 和 4 周，通过超声测量肿瘤体积。第 4 周末，采用实时定量 PCR 和免疫组织化学法检测肿瘤组织中碱性成纤维细胞生长因子（bFGF）、转化生长因子β1（TGFβ-1）、肝细胞生长因子（HGF）、基质金属蛋白酶 2（MMP2）和基质金属蛋白酶 9（MMP9）的表达。另用 Masson 三色染色和 Cy3-FITC 双标记免疫荧光染色法检测在接种了 10 个 VX2 肿瘤细胞和 10 个自体 MSCs 的悬浮液的 2 只兔子的肿瘤组织中 MSCs 的分布。接种后 7 天，MSCs 均匀分布于肿瘤组织中，与肿瘤基质的分布不一致。接种后 21 天，MSCs 已整合入肿瘤间质组织，主要分布于肿瘤巢周围的间质中。在第 1、2、3 和 4 周时，A 组肿瘤体积<组 B<组 C，差异有统计学意义（均<0.001）。与 A 组相比，B 组和 C 组的 bFGF、TGFβ-1 和 HGF 的相对 mRNA 和蛋白水平明显升高（均<0.05），C 组的 bFGF、HGF mRNA 水平也高于 B 组（<0.05），C 组的 bFGF、TGFβ-1 蛋白水平也高于 B 组（<0.05）。B 组和 C 组的 MMP2 的 mRNA 和蛋白水平明显高于 A 组（均<0.05）。MMP9 的表达随着接种于肿瘤内的 MSCs 数量的增加而增加，在 mRNA 和蛋白水平均有表达（均<0.05）。MSCs 通过诱导一些重要生长因子和 MMPs 的过度表达参与肿瘤基质重塑。
