User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Time-dependent effect of hypoxia on tumor progression and liver progenitor cell markers in primary liver tumors.

Primary tabs

download
  • Open access
  • PDF
  • 27.95 M
Bogaerts, Eliene Heindryckx, Femke Devisscher, Lindsey Paridaens, Annelies Vandewynckel, Yves-Paul Libbrecht, Louis [UCL] Van Vlierberghe, Hans

BACKGROUND & AIMS: Expression of liver progenitor cell (LPC) characteristics has been proposed as a negative prognostic marker in primary liver tumors. Hypoxia has been linked to activation of the Notch pathway which is responsible for activation and proliferation of LPCs and hypoxia-induced LPC activation has been shown in hepatocellular carcinoma. Our aim was to elucidate the time-dependent effects of hypoxia on the LPC niche in hepatocellular carcinoma which could aid in determining a safe time frame for use of hypoxia inducing therapies. METHODS: We used dimethyloxaloylglycine to mimic a hypoxic reaction in mice by stabilizing hypoxia-inducible factor 1 alpha at three distinct time points in diethylnitrosamine induced hepatocarcinogenesis. LPC, metastasis and Notch pathway markers were determined by quantitative PCR and (immune)histochemistry (heamatoxillin-eosin, reticulin, Sirius red and cytokeratin 19 staining). RESULTS: Activating the hypoxia inducible pathway early in hepatocarcinogenesis resulted in an increased incidence of both cholangioma and hepatocellular lesions, associated with high expression of LPC, metastatic and Notch pathway markers. Adversely, activating the hypoxic response during tumor development resulted in decreased incidence of hepatocellular lesions and increased cholangioma incidence, with an unaltered gene expression profile of LPC-, Notch pathway- and metastatic markers. A hypoxic insult at advanced stages of hepatocarcinogenesis severely increased the expression of LPC characteristics, however without increased expression of actors of the Notch pathway and metastatic markers and minor changes in incidence of hepatocellular and cholangioma lesions. CONCLUSION: Our results indicate that increased hypoxia at the onset of tumor development has detrimental effects on tumor progression; patients with HCC developed in a background of fibrosis/cirrhosis might therefore represent a more difficult treatment group. In contrast, hypoxia during tumor development appears to favor tumor outcome, highlighting the importance of early detection. Finally, hypoxia in advanced stages resulted in increased expression of LPC characteristics indicating poor outcome.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2015
Language Anglais
Journal information "PLoS One" - Vol. 10, no.3, p. e0119555 [1-17] (2015)
Peer reviewed yes
Publisher Public Library of Science ((United States) San Francisco, CA)
e-issn 1932-6203
Publication status Publié
Affiliation UCL - SSS/IREC - Institut de recherche expérimentale et clinique
MESH Subject Animals ; Gene Expression ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit ; Immunohistochemistry ; Keratin-19 ; Liver Neoplasms ; Male ; Mice ; Neoplasm Metastasis ; RNA, Messenger ; Antigens, Neoplasm ; Receptors, Notch ; Stem Cells ; Time Factors ; Biomarkers ; Carcinoma, Hepatocellular ; Cell Adhesion Molecules ; Cell Transformation, Neoplastic ; Disease Models, Animal ; Disease Progression ; Epithelial Cell Adhesion Molecule
Links
  1. Van Steenkiste Christophe, Ribera Jordi, Geerts Anja, Pauta Montse, Tugues Sònia, Casteleyn Christophe, Libbrecht Louis, Olievier Kim, Schroyen Ben, Reynaert Hendrik, van Grunsven Leo A., Blomme Bram, Coulon Stephanie, Heindryckx Femke, De Vos Martine, Stassen Jean Marie, Vinckier Stefan, Altamirano Jose, Bataller Ramón, Carmeliet Peter, Van Vlierberghe Hans, Colle Isabelle, Morales-Ruiz Manuel, Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice, 10.1002/hep.24238
  2. Heindryckx Femke, Mertens Koen, Charette Nicolas, Vandeghinste Bert, Casteleyn Christophe, Van Steenkiste Christophe, Slaets Dominique, Libbrecht Louis, Staelens Steven, Starkel Peter, Geerts Anja, Colle Isabelle, Van Vlierberghe Hans, Kinetics of angiogenic changes in a new mouse model for hepatocellular carcinoma, 10.1186/1476-4598-9-219
  3. Llovet Josep M., Ricci Sergio, Mazzaferro Vincenzo, Hilgard Philip, Gane Edward, Blanc Jean-Frédéric, de Oliveira Andre Cosme, Santoro Armando, Raoul Jean-Luc, Forner Alejandro, Schwartz Myron, Porta Camillo, Zeuzem Stefan, Bolondi Luigi, Greten Tim F., Galle Peter R., Seitz Jean-François, Borbath Ivan, Häussinger Dieter, Giannaris Tom, Shan Minghua, Moscovici Marius, Voliotis Dimitris, Bruix Jordi, Sorafenib in Advanced Hepatocellular Carcinoma, 10.1056/nejmoa0708857
  4. Heindryckx Femke, Coulon Stephanie, Terrie Ellen, Casteleyn Christophe, Stassen Jean-Marie, Geerts Anja, Libbrecht Louis, Allemeersch Joke, Carmeliet Peter, Colle Isabelle, Van Vlierberghe Hans, The placental growth factor as a target against hepatocellular carcinoma in a diethylnitrosamine-induced mouse model, 10.1016/j.jhep.2012.09.032
  5. Pàez-Ribes Marta, Allen Elizabeth, Hudock James, Takeda Takaaki, Okuyama Hiroaki, Viñals Francesc, Inoue Masahiro, Bergers Gabriele, Hanahan Douglas, Casanovas Oriol, Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis, 10.1016/j.ccr.2009.01.027
  6. Ebos John M.L., Lee Christina R., Cruz-Munoz William, Bjarnason Georg A., Christensen James G., Kerbel Robert S., Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis, 10.1016/j.ccr.2009.01.021
  7. Heindryckx Femke, Bogaerts Eliene, Coulon Stephanie H., Devlies Hilde, Geerts Anja M., Libbrecht Louis, Stassen Jean Marie, Carmeliet Peter, Colle Isabelle O., Van Vlierberghe Hans R., Inhibition of the placental growth factor decreases burden of cholangiocarcinoma and hepatocellular carcinoma in a transgenic mouse model : , 10.1097/meg.0b013e3283554219
  8. Liang Yingjian, Zheng Tongsen, Song Ruipeng, Wang Jiabei, Yin Dalong, Wang Luoluo, Liu Haitao, Tian Lantian, Fang Xiang, Meng Xianzhi, Jiang Hongchi, Liu Jiaren, Liu Lianxin, Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma, 10.1002/hep.26224
  9. Fausto Nelson, Liver regeneration and repair: Hepatocytes, progenitor cells, and stem cells, 10.1002/hep.20214
  10. Spee B., Carpino G., Schotanus B. A., Katoonizadeh A., Borght S. V., Gaudio E., Roskams T., Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling, 10.1136/gut.2009.188367
  11. Van Hul Noémi K. M., Abarca-Quinones Jorge, Sempoux Christine, Horsmans Yves, Leclercq Isabelle A., Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury, 10.1002/hep.22820
  12. Boulter Luke, Govaere Olivier, Bird Tom G, Radulescu Sorina, Ramachandran Prakash, Pellicoro Antonella, Ridgway Rachel A, Seo Sang Soo, Spee Bart, Van Rooijen Nico, Sansom Owen J, Iredale John P, Lowell Sally, Roskams Tania, Forbes Stuart J, Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease, 10.1038/nm.2667
  13. Progenitor Cells in Diseased Human Liver, 10.1055/s-2004-815564
  14. E Bogaerts, Int J Oncol, 44, 1015 (2014)
  15. Strazzabosco Mario, Fabris Luca, The balance between Notch/Wnt signaling regulates progenitor cells’ commitment during liver repair: Mystery solved?, 10.1016/j.jhep.2012.08.006
  16. Mathieu J., Zhang Z., Zhou W., Wang A. J., Heddleston J. M., Pinna C. M. A., Hubaud A., Stadler B., Choi M., Bar M., Tewari M., Liu A., Vessella R., Rostomily R., Born D., Horwitz M., Ware C., Blau C. A., Cleary M. A., Rich J. N., Ruohola-Baker H., HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells, 10.1158/0008-5472.can-10-3320
  17. Heindryckx Femke, Kuchnio Anna, Casteleyn Christophe, Coulon Stephanie, Olievier Kim, Colle Isabelle, Geerts Anja, Libbrecht Louis, Carmeliet Peter, Van Vlierberghe Hans, Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice, 10.1016/j.jhep.2012.02.021
  18. Sapisochin Gonzalo, Fidelman Nicholas, Roberts John P., Yao Francis Y., Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma, 10.1002/lt.22307
  19. Zen Chikako, Zen Yoh, Mitry Ragai R., Corbeil Denis, Karbanová Jana, O'Grady John, Karani John, Kane Pauline, Heaton Nigel, Portmann Bernard C., Quaglia Alberto, Mixed phenotype hepatocellular carcinoma after transarterial chemoembolization and liver transplantation, 10.1002/lt.22314
  20. Ding Shi-Jian, Li Yan, Tan Ye-Xiong, Jiang Man-Rong, Tian Bo, Liu Ying-Kun, Shao Xiao-Xia, Ye Sheng-Long, Wu Jia-Rui, Zeng Rong, Wang Hong-Yang, Tang Zhao-You, Xia Qi-Chang, From Proteomic Analysis to Clinical Significance : Overexpression of Cytokeratin 19 Correlates with Hepatocellular Carcinoma Metastasis, 10.1074/mcp.m300094-mcp200
  21. Ma S, Lee T K, Zheng B-J, Chan K W, Guan X-Y, CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway, 10.1038/sj.onc.1210811
  22. Uenishi Takahiro, Kubo Shoji, Yamamoto Takatsugu, Shuto Taichi, Ogawa Masao, Tanaka Hiromu, Tanaka Shogo, Kaneda Kenji, Hirohashi Kazuhiro, Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence, 10.1111/j.1349-7006.2003.tb01366.x
  23. Yang Wen, Wang Chao, Lin Yan, Liu Qiong, Yu Le-xing, Tang Liang, Yan He-Xin, Fu Jing, Chen Yao, Zhang Hui-Lu, Tang Liang, Zheng Long-Yi, He Ya-Qin, Li Yu-Qiong, Wu Fu-Quan, Zou Shan-Shan, Li Zhong, Wu Meng-Chao, Feng Gen-Sheng, Wang Hong-Yang, OV6+ tumor-initiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma, 10.1016/j.jhep.2012.04.024
  24. Zulehner Gudrun, Mikula Mario, Schneller Doris, van Zijl Franziska, Huber Heidemarie, Sieghart Wolfgang, Grasl-Kraupp Bettina, Waldhör Thomas, Peck-Radosavljevic Markus, Beug Hartmut, Mikulits Wolfgang, Nuclear β-Catenin Induces an Early Liver Progenitor Phenotype in Hepatocellular Carcinoma and Promotes Tumor Recurrence, 10.2353/ajpath.2010.090300
  25. Devisscher Lindsey, Hindryckx Pieter, Olievier Kim, Peeters Harald, De Vos Martine, Laukens Debby, Inverse correlation between metallothioneins and hypoxia-inducible factor 1 alpha in colonocytes and experimental colitis, 10.1016/j.bbrc.2011.11.031
  26. Geerts Anja M., Vanheule Eline, Praet Marleen, Van Vlierberghe Hans, De Vos Martine, Colle Isabelle, Comparison of three research models of portal hypertension in mice: macroscopic, histological and portal pressure evaluation : Research models of portal hypertension, 10.1111/j.1365-2613.2008.00597.x
  27. Okabe M., Tsukahara Y., Tanaka M., Suzuki K., Saito S., Kamiya Y., Tsujimura T., Nakamura K., Miyajima A., Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver, 10.1242/dev.031369
  28. Schnell Ulrike, Cirulli Vincenzo, Giepmans Ben N.G., EpCAM: Structure and function in health and disease, 10.1016/j.bbamem.2013.04.018
  29. Heindryckx F CS, Terrie E, Casteleyn C, Stassen J-M, Geerts A, Louis Libbrecht, Joke Allemeersch, Peter Carmeliet, Isabelle Colle & Hans Van Vlierberghe. The placental growth factor as a target against hepatocellular carcinoma in an orthotopic mouse model. J Hepatol. 2012;Submitted.
  30. Govaere O, Komuta M Fau—Berkers J, Berkers J Fau—Spee B, Spee B Fau—Janssen C, Janssen C Fau—de Luca F, de Luca F Fau—Katoonizadeh A, et al. Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. (1468–3288 (Electronic)).
  31. Vander Borght Sara, Komuta Mina, Libbrecht Louis, Katoonizadeh Aezam, Aerts Raymond, Dymarkowski Steven, Verslype Chris, Nevens Frederik, Roskams Tania, Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin : MRP1 expression in hepatocellular carcinoma, 10.1111/j.1478-3231.2008.01889.x
  32. Webb James D., Coleman Mathew L., Pugh Christopher W., Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing, 10.1007/s00018-009-0147-7
  33. Ke Q., Costa M., Hypoxia-Inducible Factor-1 (HIF-1), 10.1124/mol.106.027029
  34. Choi Bo Yoon, Nguyen Mindie H, The Diagnosis and Management of Benign Hepatic Tumors : , 10.1097/01.mcg.0000159226.63037.a2
  35. Copple Bryan L., Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-β-dependent mechanisms, 10.1111/j.1478-3231.2010.02205.x
  36. Lau C. K., Yang Z. F., Ho D. W., Ng M. N., Yeoh G. C.T., Poon R. T.P., Fan S. T., An Akt/Hypoxia-Inducible Factor-1 /Platelet-Derived Growth Factor-BB Autocrine Loop Mediates Hypoxia-Induced Chemoresistance in Liver Cancer Cells and Tumorigenic Hepatic Progenitor Cells, 10.1158/1078-0432.ccr-08-2127
  37. Durnez A, Verslype C, Nevens F, Fevery J, Aerts R, Pirenne J, Lesaffre E, Libbrecht L, Desmet V, Roskams T, The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin, 10.1111/j.1365-2559.2006.02468.x
  38. Timme Cindy R., Gruidl Mike, Yeatman Timothy J., Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells, 10.1007/s10495-013-0883-x
  39. Zhang Cathy C., Yan Zhengming, Zong Qing, Fang Douglas D., Painter Cory, Zhang Qin, Chen Enhong, Lira Maruja E., John-Baptiste Annette, Christensen James G., Synergistic Effect of the γ-Secretase Inhibitor PF-03084014 and Docetaxel in Breast Cancer Models, 10.5966/sctm.2012-0096
  40. Michalopoulos George K., Barua Lindsay, Bowen William C., Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury, 10.1002/hep.20600
  41. Michalopoulos G, Hepatocytes undergo phenotypic transformation to biliary epithelium in organoid cultures, 10.1053/jhep.2002.34858
Bibliographic reference Bogaerts, Eliene ; Heindryckx, Femke ; Devisscher, Lindsey ; Paridaens, Annelies ; Vandewynckel, Yves-Paul ; et. al. Time-dependent effect of hypoxia on tumor progression and liver progenitor cell markers in primary liver tumors.. In: PLoS One, Vol. 10, no.3, p. e0119555 [1-17] (2015)
Permanent URL http://hdl.handle.net/2078.1/186991