Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis

Journal of Translational Medicine

Rong-Ping Guo⁴  Chao-Nan Qian¹  Chong Zhong³  Shu-Hong Li⁴  Zhi-Xing Guo⁴  Xin-Jian Li²  Wei Wei⁴  Li-Xia Peng¹  Ming Shi⁴  Zhi-Yuan Chen¹ 

[1] Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA;Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Ave., Unit 1002, BSRB S5.8116, Houston, TX, 77030, USA;Department of Hepatobilliary Surgery, 1st Affiliated Hospital to Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, 510405, China;State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People’s Republic of China

关键词: Tumor metastasis;    Tumor growth;    Hepatocellular carcinoma;    Endothelial cells;    Dovitinib;   

Others  :  828529
DOI  :  10.1186/1479-5876-10-245

 received in 2012-08-19, accepted in 2012-11-19,  发布年份 2012

【 摘 要 】

Background

Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor β. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC).

Method

In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib.

Results

Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-β was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-β, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 μmol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells.

Conclusion

Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

【 授权许可】

   
2012 Chen et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Bruix J, Llovet JM: Major achievements in hepatocellular carcinoma. Lancet 2009, 373:614-616.
• [2]Yang JD, Roberts LR: Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol 2010, 7:448-458.
• [3]Hao MZ, Lin HL, Chen Q, Ye YB, Chen QZ, Chen MS: Efficacy of transcatheter arterial chemoembolization combined with cytokine-induced killer cell therapy on hepatocellular carcinoma: a comparative study. Chin J Cancer 2010, 29:172-177.
• [4]Qin L, Bromberg-White JL, Qian CN: Opportunities and challenges in tumor angiogenesis research: back and forth between bench and bed. Adv Cancer Res 2012, 113:191-239.
• [5]Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Kammula US, Chen Y, Qin LX, Tang ZY, Wang XW: Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006, 10:99-111.
• [6]Ding T, Xu J, Zhang Y, Guo RP, Wu WC, Zhang SD, Qian CN, Zheng L: Endothelium-coated tumor clusters are associated with poor prognosis and micrometastasis of hepatocellular carcinoma after resection. Cancer 2011, 117:4878-4889.
• [7]Chen JA, Shi M, Li JQ, Qian CN: Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration. Hepatol Int 2010, 4:537-547.
• [8]Park YN, Kim YB, Yang KM, Park C: Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med 2000, 124:1061-1065.
• [9]Hu Z, Evarts RP, Fujio K, Omori N, Omori M, Marsden ER, Thorgeirsson SS: Expression of transforming growth factor alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast growth factor receptors during hepatocarcinogenesis. Carcinogenesis 1996, 17:931-938.
• [10]Maass T, Thieringer FR, Mann A, Longerich T, Schirmacher P, Strand D, Hansen T, Galle PR, Teufel A, Kanzler S: Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis. Int J Cancer 2010, 128:1259-1268.
• [11]Guo RP, Zhong C, Shi M, Zhang CQ, Wei W, Zhang YQ, Li JQ: Clinical value of apoptosis and angiogenesis factors in estimating the prognosis of hepatocellular carcinoma. J Cancer Res Clin Oncol 2006, 132:547-555.
• [12]Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al.: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009, 10:25-34.
• [13]Di Maio M, Daniele B, Perrone F: Targeted therapies: role of sorafenib in HCC patients with compromised liver function. Nat Rev Clin Oncol 2009, 6:505-506.
• [14]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378-390.
• [15]Taeger J, Moser C, Hellerbrand C, Mycielska ME, Glockzin G, Schlitt HJ, Geissler EK, Stoeltzing O, Lang SA: Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer. Mol Cancer Ther 2011, 10:2157-2167.
• [16]Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, Kirkwood JM: Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin Cancer Res 2011, 17:7451-7461.
• [17]Lee SH, Lopes de Menezes D, Vora J, Harris A, Ye H, Nordahl L, Garrett E, Samara E, Aukerman SL, Gelb AB, Heise C: In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res 2005, 11:3633-3641.
• [18]de Menezes DE L, Peng J, Garrett EN, Louie SG, Lee SH, Wiesmann M, Tang Y, Shephard L, Goldbeck C, Oei Y, et al.: CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin Cancer Res 2005, 11:5281-5291.
• [19]Xin X, Abrams TJ, Hollenbach PW, Rendahl KG, Tang Y, Oei YA, Embry MG, Swinarski DE, Garrett EN, Pryer NK, et al.: CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Clin Cancer Res 2006, 12:4908-4915.
• [20]Chen KF, Chen HL, Liu CY, Tai WT, Ichikawa K, Chen PJ, Cheng AL: Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem Pharmacol 2012, 83:769-777.
• [21]Tai WT, Cheng AL, Shiau CW, Liu CY, Ko CH, Lin MW, Chen PJ, Chen KF: Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol Cancer Ther 2011, 11:452-463.
• [22]Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, et al.: Patterns of somatic mutation in human cancer genomes. Nature 2007, 446:153-158.
• [23]Yan W, Bentley B, Shao R: Distinct angiogenic mediators are required for basic fibroblast growth factor- and vascular endothelial growth factor-induced angiogenesis: the role of cytoplasmic tyrosine kinase c-Abl in tumor angiogenesis. Mol Biol Cell 2008, 19:2278-2288.
• [24]Mendelson K, Swendeman S, Saftig P, Blobel CP: Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways. J Biol Chem 2010, 285:25024-25032.
• [25]Huang D, Ding Y, Luo WM, Bender S, Qian CN, Kort E, Zhang ZF, VandenBeldt K, Duesbery NS, Resau JH, Teh BT: Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo. Cancer Res 2008, 68:81-88.
• [26]Chen ZY, Wei W, Guo ZX, Lin JR, Shi M, Guo RP: Morphologic classification of microvessels in hepatocellular carcinoma is associated with the prognosis after resection. J Gastroenterol Hepatol 2011, 26:866-874.
• [27]Gu Y, Zhu CF, Dai YL, Zhong Q, Sun B: Inhibitory effects of genistein on metastasis of human hepatocellular carcinoma. World J Gastroenterol 2009, 15:4952-4957.
• [28]Chase A, Grand FH, Cross NC: Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood 2007, 110:3729-3734.
• [29]Huynh H, Chow PK, Tai WM, Choo SP, Chung AY, Ong HS, Soo KC, Ong R, Linnartz R, Shi MM: Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma. J Hepatol 2011, 56:595-601.
• [30]Chen L, Shi Y, Jiang CY, Wei LX, Lv YL, Wang YL, Dai GH: Coexpression of PDGFR-alpha, PDGFR-beta and VEGF as a prognostic factor in patients with hepatocellular carcinoma. Int J Biol Markers 2011, 26:108-116.
• [31]Franses JW, Edelman ER: The evolution of endothelial regulatory paradigms in cancer biology and vascular repair. Cancer Res 2011, 71:7339-7344.
• [32]Saiki I, Koike C, Obata A, Fujii H, Murata J, Kiso M, Hasegawa A, Komazawa H, Tsukada H, Azuma I, et al.: Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor-cell arrest in lungs followed by extravasation. Int J Cancer 1996, 65:833-839.
• [33]Mannori G, Santoro D, Carter L, Corless C, Nelson RM, Bevilacqua MP: Inhibition of colon carcinoma cell lung colony formation by a soluble form of E-selectin. Am J Pathol 1997, 151:233-243.