JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B 2014 Vol.15 No.8 P.701-712

Sunitinib mesylate inhibits proliferation of human colonic stromal fibroblasts in vitro and in vivo *

Author(s): Zhan-huai Wang^1,2, Qiong Li¹, Shu-qin Ruan³, Qian Xiao¹, Yue Liu¹, Ye-ting Hu¹, Li-feng Hu¹, Hai-yan Chen¹, Shu Zheng¹, Su-zhan Zhang¹, Ke-feng Ding^1,2
Affiliation(s): 1. MOE Key Laboratory of Cancer Prevention & Intervention, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences, Cancer Institute, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; more
Corresponding email(s): dingkefeng@126.com
Key Words: Colon cancer, Cancer-associated fibroblasts, Sunitinib mesylate, Platelet-derived growth factor (PDGF), PDGF receptor (PDGFR)

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Abstract: Objective: Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts. Methods: Cell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated platelet-derived growth factor receptor β (PDGFR-β), Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibroblasts in nude mice was employed to test anti-growth efficacy in vivo. Results: Sunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell+colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil. Conclusions: sunitinib mesylate inhibited the proliferation of primary human colonic fibroblasts through target-inhibited PDGFR signaling in vitro and in vivo.

舒尼替尼对结肠成纤维细胞体内外抑制机制研究

研究目的：探索小分子酪氨酸激酶抑制剂舒尼替尼（sunitinib）对结肠肿瘤微环境中的肿瘤相关成纤维细胞的作用及其机制。
创新要点：舒尼替尼通过抑制肿瘤间质成纤维细胞的生长，间接发挥抗肿瘤效应，为结肠癌综合治疗的提供新途径。
研究方法：通过细胞周期分析和细胞增殖测定进行舒尼替尼体外抑制肿瘤细胞的研究。采用Western-blot检测磷酸化血小板衍生生长因子β受体（PDGFR-β）、蛋白激酶B（Akt）及细胞外信号调节蛋白激酶（ERK）的蛋白水平。通过注射肠腺癌细胞株SW620和结肠成纤维细胞构建的裸鼠移植瘤模型来研究舒尼替尼的体内抑瘤效果。
重要结论：舒尼替尼可有效抑制结肠癌来源的原代结肠成纤维细胞生长，该抑制作用主要通过抑制血小板衍生生长因子（PDGF）信号通路得以实现。
结肠癌；肿瘤相关成纤维细胞；舒尼替尼；血小板衍生生长因子（PDGF）；血小板衍生生长因子受体（PDGFR）

References

[1] Allinen, M., Beroukhim, R., Cai, L., 2004. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell, 6(1):17-32.

[2] Bauer, M., Su, G., Casper, C., 2010. Heterogeneity of gene expression in stromal fibroblasts of human breast carcinomas and normal breast. Oncogene, 29(12):1732-1740.

[3] Bergsten, E., Uutela, M., Li, X., 2001. PDGF-D is a specific, protease-activated ligand for the PDGF β-receptor. Nat Cell Biol, 3(5):512-516.

[4] Chow, L.Q., Eckhardt, S.G., 2007. Sunitinib: from rational design to clinical efficacy. J Clin Oncol, 25(7):884-896.

[5] Cui, L., Ohuchida, K., Mizumoto, K., 2010. Prospectively isolated cancer-associated CD10⁺ fibroblasts have stronger interactions with CD133⁺ colon cancer cells than with CD133⁻ cancer cells. PLoS ONE, 5(8):e12121

[6] Demetri, G.D., van Oosterom, A.T., Garrett, C.R., 2006. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet, 368(9544):1329-1338.

[7] Ding, W., Cai, T., Zhu, H., 2010. Synergistic antitumor effect of trail in combination with sunitinib in vitro and in vivo . Cancer Lett, 293(2):158-166.

[8] Gioni, V., Karampinas, T., Voutsinas, G., 2008. Imatinib mesylate inhibits proliferation and exerts an antifibrotic effect in human breast stroma fibroblasts. Mol Cancer Res, 6(5):706-714.

[9] Haubeiss, S., Schmid, J.O., Murdter, T.E., 2010. Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer, 9(1):168

[10] Heldin, C.H., Westermark, B., 1999. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev, 79(4):1283-1316.

[11] Heldin, C.H., Ostman, A., Ronnstrand, L., 1998. Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta-Rev Cancer, 1378(1):F79-F113.

[12] Henriksson, M.L., Edin, S., Dahlin, A.M., 2011. Colorectal cancer cells activate adjacent fibroblasts resulting in FGF1/FGFR3 signaling and increased invasion. Am J Pathol, 178(3):1387-1394.

[13] Kalluri, R., 2003. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer, 3(6):422-433.

[14] Kitadai, Y., Sasaki, T., Kuwai, T., 2006. Expression of activated platelet-derived growth factor receptor in stromal cells of human colon carcinomas is associated with metastatic potential. Int J Cancer, 119(11):2567-2574.

[15] LaRochelle, W.J., Jeffers, M., McDonald, W.F., 2001. PDGF-D, a new protease-activated growth factor. Nat Cell Biol, 3(5):517-521.

[16] Li, X., Ponten, A., Aase, K., 2000. PDGF-c is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol, 2(5):302-309.

[17] Liao, D., Luo, Y., Markowitz, D., 2009. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS ONE, 4(11):e7965

[18] Mendel, D.B., Laird, A.D., Xin, X., 2003. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res, 9(1):327-337.

[19] Micke, P., Ostman, A., 2005. Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy. Expert Opin Ther Targets, 9(6):1217-1233.

[20] Motzer, R.J., Hutson, T.E., Tomczak, P., 2007. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med, 356(2):115-124.

[21] Mueller, L., Goumas, F.A., Himpel, S., 2007. Imatinib mesylate inhibits proliferation and modulates cytokine expression of human cancer-associated stromal fibroblasts from colorectal metastases. Cancer Lett, 250(2):329-338.

[22] Mueller, L., Goumas, F.A., Affeldt, M., 2007. Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. Am J Pathol, 171(5):1608-1618.

[23] Orimo, A., Gupta, P.B., Sgroi, D.C., 2005. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121(3):335-348.

[24] Raymond, E., Dahan, L., Raoul, J.L., 2011. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med, 364(6):501-513.

[25] Siegel, R., Ma, J., Zou, Z., 2014. Cancer statistics, 2014. CA Cancer J Clin, 64(1):9-29.

[26] Tomasek, J.J., Gabbiani, G., Hinz, B., 2002. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol, 3(5):349-363.

[27] Tyan, S.W., Kuo, W.H., Huang, C.K., 2011. Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis. PLoS ONE, 6(1):e15313

[28] Zhang, Y., Tang, H., Cai, J., 2011. Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett, 303(1):47-55.

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舒尼替尼对结肠成纤维细胞体内外抑制机制研究

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