1. Department of Urology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, P.R. China
2. Department of Urology, Shandong Provincial Hospital, 324 Jingwuweiqi Road, Jinan, 250014, P.R.China
3. Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, P.R. China
Background and aim: 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.
Methods: The VX2 bladder tumor models were established by injecting mixed cell suspensions (106 of VX2 tumor cells and 0/106/107 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 106 VX2 tumor cells and 106 autologous MSCs.
Results: 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 p<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 p<0.05), as well as the mRNA levels of bFGF, HGF were higher in group C than group B (p<0.05), and the protein levels of bFGF, TGFβ-1 were higher in group C than group B (p<0.05). The mRNA and protein levels of MMP2 were significantly higher in group B, C than group A (p<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 p<0.05).
Conclusion: MSCs participate in tumor stroma remodeling via inducing overexpression of some important growth factors and MMPs.
Keywords: mesenchymal stem cell, VX2 tumor, tumor stroma remodeling, growth factors, matrix metalloproteinases