A novel oxygen carrier “YQ23” suppresses the liver tumor metastasis by decreasing circulating endothelial progenitor cells and regulatory T cells

BMC Cancer

Chang Xian Li²  Bing L Wong¹  Chang Chun Ling²  Yuen Yuen Ma²  Yan Shao²  Wei Geng²  Xiang Qi²  Sze Hang Lau¹  Sui Yi Kwok¹  Na Wei¹  Fei Chuen Tzang¹  Kevin TP Ng²  Xiao Bing Liu²  Chung Mau Lo²  Kwan Man² 

[1] New B Innovation Limited, Hong Kong, China

[2] Department of Surgery and Centre for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China

关键词: Tregs;    EPCs;    Hepatic I/R injury;    Tumor metastasis;    HCC;    YQ23;   

Others  :  858864
DOI  :  10.1186/1471-2407-14-293

 received in 2013-09-25, accepted in 2014-04-21,  发布年份 2014

【 摘 要 】

Background

Surgical therapies are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor metastasis after liver surgery remains a severe problem. We aim to investigate the roles and the underlying mechanism of YQ23, stabilized non-polymeric diaspirin cross-linked tetrameric hemoglobin, in liver tumor metastasis after major hepatectomy and partial hepatic ischemia reperfusion (I/R) injury.

Methods

An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Major hepatectomy for tumor-bearing lobe and partial hepatic I/R injury were performed at two weeks after orthotopic liver tumor implantation. YQ23 (0.2 g/kg) was administered at 1 hour before ischemia and immediately after reperfusion. Blood samples were collected at day 0, 1, 7, 14, 21 and 28 for detection of circulating endothelial progenitor cells (EPCs) and regulatory T cells (Tregs).

Results

Our results showed that YQ23 treatment effectively inhibited intrahepatic and lung metastases together with less tumor angiogenesis at 4 weeks after major hepatectomy and partial hepatic I/R injury. The levels of circulating EPCs and Tregs were significantly decreased in YQ23 treatment group. Furthermore, YQ23 treatment also increased liver tissue oxygenation during hepatic I/R injury. Up-regulation of HO1 and down-regulation of CXCR3, TNF-α and IL6 were detected after YQ23 treatment.

Conclusions

YQ23 treatment suppressed liver tumor metastasis after major hepatectomy and partial hepatic I/R injury in a rat liver tumor model through increasing liver oxygen and reducing the populations of circulating EPCs and Tregs.

【 授权许可】

   
2014 Li et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Bosch FX, Ribes J, Diaz M, Cleries R: Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004, 127(5 Suppl 1):S5-S16.
• [2]Shah SA, Cleary SP, Wei AC, Yang I, Taylor BR, Hemming AW, Langer B, Grant DR, Greig PD, Gallinger S: Recurrence after liver resection for hepatocellular carcinoma: risk factors, treatment, and outcomes. Surgery 2007, 141(3):330-339.
• [3]Sakon M, Umeshita K, Nagano H, Eguchi H, Kishimoto S, Miyamoto A, Ohshima S, Dono K, Nakamori S, Gotoh M, Monden M: Clinical significance of hepatic resection in hepatocellular carcinoma: analysis by disease-free survival curves. Arch Surg 2000, 135(12):1456-1459.
• [4]Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T: Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999, 5(4):434-438.
• [5]Lemoli RM, Catani L, Talarico S, Loggi E, Gramenzi A, Baccarani U, Fogli M, Grazi GL, Aluigi M, Marzocchi G, Bernardi M, Pinna A, Bresadola F, Baccarani M, Andreone P: Mobilization of bone marrow-derived hematopoietic and endothelial stem cells after orthotopic liver transplantation and liver resection. Stem Cells 2006, 24(12):2817-2825.
• [6]Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, De Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK: Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 2012, 109(41):E2784-E2793.
• [7]Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, Pieczek A, Iwaguro H, Hayashi SI, Isner JM, Asahara T: Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 2000, 86(12):1198-1202.
• [8]Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J: Hypoxia controls CD4 + CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 2008, 38(9):2412-2418.
• [9]Chang EI, Thangarajah H, Hamou C, Gurtner GC: Hypoxia, hormones, and endothelial progenitor cells in hemangioma. Lymphat Res Biol 2007, 5(4):237-243.
• [10]Ling CC, Ng KT, Shao Y, Geng W, Xiao JW, Liu H, Li CX, Liu XB, Ma YY, Yeung WH, Qi X, Yu J, Wong N, Zhai Y, Chan SC, Poon RT, Lo CM, Man K: Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth. J Hepatol 2014, 60(1):103-109.
• [11]Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC, Antin JH, Myerson D, Hamilton SR, Vogelstein B, Kinzler KW, Lengauer C: Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 2005, 11(3):261-262.
• [12]Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S: Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001, 7(11):1194-1201.
• [13]Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V: Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008, 319(5860):195-198.
• [14]Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell 2008, 133(5):775-787.
• [15]Shimizu J, Yamazaki S, Sakaguchi S: Induction of tumor immunity by removing CD25 + CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999, 163(10):5211-5218.
• [16]Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH: Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 2001, 61(12):4766-4772.
• [17]Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B: Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 2003, 9(2):606-612.
• [18]Feng X, Li B, Ye H, Long D: Increased frequency of CD4 + CD25(high)FoxP3+ regulatory T cells in patients with hepatocellular carcinoma. Arch Immunol Ther Exp 2011, 59(4):309-314.
• [19]Liu XB, Cheng Q, Geng W, Ling CC, Liu Y, Ng KT, Yam JW, Guan XY, Lo CM, Man K: Enhancement of cisplatin-based TACE by a hemoglobin-based oxygen carrier in an orthotopic rat HCC model. Artif Cells Nanomed Biotechnol 2013. Epub ahead of print
• [20]Li CX, Shao Y, Ng KT, Liu XB, Ling CC, Ma YY, Geng W, Fan ST, Lo CM, Man K: FTY720 suppresses liver tumor metastasis by reducing the population of circulating endothelial progenitor cells. PLoS One 2012, 7(2):e32380.
• [21]Man K, Ng KT, Xu A, Cheng Q, Lo CM, Xiao JW, Sun BS, Lim ZX, Cheung JS, Wu EX, Sun CK, Poon RT, Fan ST: Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling. Clin Cancer Res 2010, 16(3):967-977.
• [22]Man K, Ng KT, Lo CM, Ho JW, Sun BS, Sun CK, Lee TK, Poon RT, Fan ST: Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases–activation of cell invasion and migration pathways. Liver Transpl 2007, 13(12):1669-1677.
• [23]Shen XD, Ke B, Zhai Y, Gao F, Busuttil RW, Cheng G, Kupiec-Weglinski JW: Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury. Am J Transplant 2005, 5(8):1793-1800.
• [24]Rookmaaker MB, Tolboom H, Goldschmeding R, Zwaginga JJ, Rabelink TJ, Verhaar MC: Bone-marrow-derived cells contribute to endothelial repair after thrombotic microangiopathy. Blood 2002, 99(3):1095.
• [25]Walter DH, Rittig K, Bahlmann FH, Kirchmair R, Silver M, Murayama T, Nishimura H, Losordo DW, Asahara T, Isner JM: Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002, 105(25):3017-3024.
• [26]Nozawa H, Chiu C, Hanahan D: Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 2006, 103(33):12493-12498.
• [27]Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N: Tumor refractoriness to anti-VEGF treatment is mediated by CD11b + Gr1+ myeloid cells. Nat Biotechnol 2007, 25(8):911-920.
• [28]Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J: Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 2005, 115(12):3623-3633.
• [29]Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C: IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 2007, 110(9):3192-3201.