Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

Cancer Letters

Volumn 367, Issue 1, 2015, Pages 1-11

  Chen, Jiang ^a   Jin, Renan ^a   Zhao, Jie ^a   Liu, Jinghua ^a   Ying, Hanning ^a   Yan, Han ^a   Zhou, Senjun ^a   Liang, Yuelong ^a   Huang, Diyu ^a   Liang, Xiao ^a   Yu, Hong ^a   Lin, Hui ^a   Cai, Xiujun ^a  

^a ZHEJIANG UNIVERSITY   (China)

Author keywords

Acquired resistance; Advanced hepatocellular carcinoma (HCC); Cancer stem cells (CSCs); Epithelial mesenchymal transitions (EMT) and mesenchymal epithelial transitions (MET); Microenvironment

Indexed keywords

ALPHA INTERFERON; BELINOSTAT; BEVACIZUMAB; EVEROLIMUS; INTERLEUKIN 1BETA; INTERLEUKIN 6; IRINOTECAN; LINIFANIB; MUPARFOSTAT; NOTCH RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PIDILIZUMAB; PLACEBO; PROTEIN 14 3 3; RAF PROTEIN; RAS PROTEIN; SONIC HEDGEHOG PROTEIN; SORAFENIB; TIVANTINIB; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR; ANTINEOPLASTIC AGENT; CARBANILAMIDE DERIVATIVE; NICOTINAMIDE; PROTEIN KINASE INHIBITOR;

ADVANCED CANCER; AUTOPHAGY; CANCER RESISTANCE; CANCER STEM CELL; CANCER SURVIVAL; DRUG EFFICACY; DRUG INHIBITION; DRUG TARGETING; EPITHELIAL MESENCHYMAL TRANSITION; FIBROGENESIS; FIBROSIS; HEPATITIS B VIRUS; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HYPOXIA; LIVER CELL CARCINOMA; NONHUMAN; OVERALL SURVIVAL; OXIDATIVE STRESS; PERSONALIZED MEDICINE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); SHORT SURVEY; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT; TUMOR VASCULARIZATION; VIRUS REACTIVATION; ANALOGS AND DERIVATIVES; ANIMAL; CARCINOMA, HEPATOCELLULAR; DRUG EFFECTS; DRUG RESISTANCE; ENZYMOLOGY; LIVER NEOPLASMS; MOLECULARLY TARGETED THERAPY; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CARCINOMA, HEPATOCELLULAR; DRUG RESISTANCE, NEOPLASM; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; LIVER NEOPLASMS; MOLECULAR TARGETED THERAPY; NEOPLASTIC STEM CELLS; NIACINAMIDE; PHENYLUREA COMPOUNDS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84939256488     PISSN: 03043835     EISSN: 18727980     Source Type: Journal    
DOI: 10.1016/j.canlet.2015.06.019     Document Type: Review

References (167)

1. Yu G., Jing Y., Kou X., Ye F., Gao L., Fan Q., et al. Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma. PLoS ONE 2013, 8:e73312.
2. Ferlay J., Soerjomataram I., Ervik M., Dikshit R., Eser S., Mathers C., et al. GLOBOCAN 2012 v1. 0 2013, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, Fr Int Agency Res Cancer, Available from, accessed on 12.12.13. http://globocan.iarc.fr.
3. Page A.J., Cosgrove D.C., Philosophe B., Pawlik T.M. Hepatocellular carcinoma: diagnosis, management, and prognosis. Surg. Oncol. Clin. N. Am 2014, 23:289-311.
4. Pahwa A., Beckett K., Channual S., Tan N., Lu D.S., Raman S.S. Efficacy of the American Association for the Study of Liver Disease and Barcelona criteria for the diagnosis of hepatocellular carcinoma. Abdom. Imaging 2014, 39:753-760.
5. Wang L., Yao M., Dong Z., Zhang Y., Yao D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumour Biol 2014, 35:9-20.
6. Giannelli G., Rani B., Dituri F., Cao Y., Palasciano G. Moving towards personalised therapy in patients with hepatocellular carcinoma: the role of the microenvironment. Gut 2014, 63:1668-1676.
7. Wu Q., Yang Z., Nie Y., Shi Y., Fan D. Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett 2014, 347:159-166.
8. Saunders N.A., Simpson F., Thompson E.W., Hill M.M., Endo-Munoz L., Leggatt G., et al. Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives. EMBO Mol. Med 2012, 4:675-684.
9. Lo J., Lau E.Y., Ching R.H., Cheng B.Y., Ma M.K., Ng I.O., et al. NF-kappaB mediated CD47 upregulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma. Hepatology 2015.
10. Keating G.M., Santoro A. Sorafenib a review of its use in advanced hepatocellular carcinoma. Drugs 2009, 69:223-240.
11. Galmiche A., Chauffert B., Barbare J.C. New biological perspectives for the improvement of the efficacy of sorafenib in hepatocellular carcinoma. Cancer Lett 2014, 346:159-162.
12. Castillo J., Erroba E., Perugorria M.J., Santamaria M., Lee D.C., Prieto J., et al. Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res 2006, 66:6129-6138.
13. Ezzoukhry Z., Louandre C., Trecherel E., Godin C., Chauffert B., Dupont S., et al. EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib. Int. J. Cancer 2012, 131:2961-2969.
14. Liu L., Cao Y., Chen C., Zhang X., McNabola A., Wilkie D., et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006, 66:11851-11858.
15. Cheng A.-L., Kang Y.-K., Chen Z., Tsao C.-J., Qin S., Kim J.S., 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.
16. Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.-F., et al. Sorafenib in advanced hepatocellular carcinoma. NEJM 2008, 359:378-390.
17. Huang X.Y., Ke A.W., Shi G.M., Zhang X., Zhang C., Shi Y.H., et al. alphaB-crystallin complexes with 14-3-3zeta to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma. Hepatology 2013, 57:2235-2247.
18. Chiou J.-F., Tai C.-J., Huang M.-T., Wei P.-L., Wang Y.-H., An J., et al. Glucose-regulated protein 78 is a novel contributor to acquisition of resistance to sorafenib in hepatocellular carcinoma. Ann. Surg. Oncol 2010, 17:603-612.
19. Chen K.-F., Chen H.-L., Tai W.-T., Feng W.-C., Hsu C.-H., Chen P.-J., et al. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J. Pharmacol. Exp. Ther 2011, 337:155-161.
20. Lu Y.Y., Feng F., Zhang F., Gao X., Wang C., Chang X., et al. A novel mechanism of PXR mediated Sorafenib drug resistance in HCC through MDR and CYP3A4. Hepatology 2013, 1084A.
21. Nieto M.A., Cano A. The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin. Cancer Biol 2012, 22:361-368.
22. Shaul Y.D., Freinkman E., Comb W.C., Cantor J.R., Tam W.L., Thiru P., et al. Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell 2014, 158:1094-1109.
23. Thiery J.P., Acloque H., Huang R.Y., Nieto M.A. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139:871-890.
24. Uchibori K., Kasamatsu A., Sunaga M., Yokota S., Sakurada T., Kobayashi E., et al. Establishment and characterization of two 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Int. J. Oncol 2012, 40:1005-1010.
25. Carmona F.J., Davalos V., Vidal E., Gomez A., Heyn H., Hashimoto Y., et al. A comprehensive DNA methylation profile of epithelial-to-mesenchymal transition. Cancer Res 2014, 74:5608-5619.
26. de Reyniès A., Jaurand M.-C., Renier A., Couchy G., Hysi I., Elarouci N., et al. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition. Clin. Cancer Res 2014, 20:1323-1334.
27. Kunnimalaiyaan S., Gamblin T.C., Kunnimalaiyaan M. Role of notch3 in epithelial-to-mesenchymal transition of HCC. Cancer Res 2014, 74:5289.
28. Morris J.P., Wang S.C., Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat. Rev. Cancer 2010, 10:683-695.
29. Lamouille S., Xu J., Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol 2014, 15:178-196.
30. Ke Z., Caiping S., Qing Z., Xiaojing W. Sonic hedgehog-Gli1 signals promote epithelial-mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway. Med. Oncol 2015, 32:368.
31. Zhou Z.-J., Dai Z., Zhou S.-L., Hu Z.-Q., Chen Q., Zhao Y.-M., et al. HNRNPAB induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by transcriptionally activating SNAIL. Cancer Res 2014, 74:2750-2762.
32. Semenza G. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene 2013, 32:4057-4063.
33. Yuki K., Hirohashi S., Sakamoto M., Kanai T., Shimosato Y. Growth and spread of hepatocellular carcinoma: a review of 240 consecutive autopsy cases. Cancer 1990, 66:2174-2179.
34. Thiery J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2:442-454.
35. Cousins F.L., Murray A., Esnal A., Gibson D.A., Critchley H.O., Saunders P.T. Evidence from a mouse model that epithelial cell migration and mesenchymal-epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation. PLoS ONE 2014, 9:e86378.
36. Polyak K., Weinberg R.A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 2009, 9:265-273.
37. Chao Y., Wu Q., Shepard C., Wells A. Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. Clin. Exp. Metastasis 2012, 29:39-50.
38. Gujral T.S., Chan M., Peshkin L., Sorger P.K., Kirschner M.W., MacBeath G. A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell 2014, 159:844-856.
39. Cojoc M., Peitzsch C., Kurth I., Trautmann F., Kunz-Schughart L.A., Telegeev G.D., et al. Aldehyde dehydrogenase is regulated by Beta-catenin/TCF and promotes radioresistance in prostate cancer progenitor cells. Cancer Res 2015.
40. Liu H., Yin J., Wang H., Jiang G., Deng M., Zhang G., et al. FOXO3a modulates WNT/beta-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells. Cell. Signal 2015, 27:510-518.
41. Bao B., Azmi A.S., Ali S., Ahmad A., Li Y., Banerjee S., et al. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochim. Biophys. Acta 1826, 2012:272-296.
42. Lamouille S., Derynck R. Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-β-induced epithelial-mesenchymal transition. Cells Tissues Organs 2010, 193:8.
43. Korpal M., Ell B.J., Buffa F.M., Ibrahim T., Blanco M.A., Celià-Terrassa T., et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat. Med 2011, 17:1101-1108.
44. Gros J., Tabin C.J. Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition. Science 2014, 343:1253-1256.
45. Grünert S., Jechlinger M., Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat. Rev. Mol. Cell Biol 2003, 4:657-665.
46. Timmerman L.A., Grego-Bessa J., Raya A., Bertran E., Perez-Pomares J.M., Diez J., et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 2004, 18:99-115.
47. Leong K.G., Niessen K., Kulic I., Raouf A., Eaves C., Pollet I., et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J. Exp. Med 2007, 204:2935-2948.
48. Sahlgren C., Gustafsson M.V., Jin S., Poellinger L., Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl. Acad. Sci. U.S.A. 2008, 105:6392-6397.
49. Mani S.A., Guo W., Liao M.-J., Eaton E.N., Ayyanan A., Zhou A.Y., et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133:704-715.
50. Mallini P., Lennard T., Kirby J., Meeson A. Epithelial-to-mesenchymal transition: what is the impact on breast cancer stem cells and drug resistance. Cancer Treat. Rev 2014, 40:341-348.
51. Bhat-Nakshatri P., Appaiah H., Ballas C., Pick-Franke P., Goulet R., Badve S., et al. SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24-phenotype. BMC Cancer 2010, 10:411.
52. Hollier B.G., Tinnirello A.A., Werden S.J., Evans K.W., Taube J.H., Sarkar T.R., et al. FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res 2013, 73:1981-1992.
53. Bruix J., Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011, 53:1020-1022.
54. Mulholland D.J., Kobayashi N., Ruscetti M., Zhi A., Tran L.M., Huang J.T., et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res 2012, 72:1878-1889.
55. Buonato J.M., Lazzara M.J. ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition. Cancer Res 2014, 74:309-319.
56. Hou C.H., Lin F.L., Hou S.M., Liu J.F. Cyr61 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by Raf-1/MEK/ERK/Elk-1/TWIST-1 signaling pathway. Mol. Cancer 2014, 13:236.
57. McKay M.M., Ritt D.A., Morrison D.K. RAF inhibitor-induced KSR1/B-RAF binding and its effects on ERK cascade signaling. Curr. Biol 2011, 21:563-568.
58. Poulikakos P.I., Zhang C., Bollag G., Shokat K.M., Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010, 464:427-430.
59. Miyahara K., Nouso K., Yamamoto K. Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age. World J. Gastroenterol 2014, 20:4151.
60. Schlegel N.C., von Planta A., Widmer D.S., Dummer R., Christofori G. PI3K signalling is required for a TGF beta-induced epithelial-mesenchymal-like transition (EMT-like) in human melanoma cells. Exp. Dermatol 2015, 24:22-28.
61. Lin G.Y., Gai R.H., Chen Z.B., Wang Y.J., Liao S.D., Dong R., et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 prevents epithelial-mesenchymal transition induced by hypoxia and TGF-beta 1. Eur. J. Pharmacol 2014, 729:45-53.
62. Gruvberger-Saal S.K., Parsons R. Is the small heat shock protein αB-crystallin an oncogene?. J. Clin. Invest 2006, 116:30.
63. Seitz S., Korsching E., Weimer J., Jacobsen A., Arnold N., Meindl A., et al. Genetic background of different cancer cell lines influences the gene set involved in chromosome 8 mediated breast tumor suppression. Genes Chromosomes Cancer 2006, 45:612-627.
64. Moyano J.V., Evans J.R., Chen F., Lu M., Werner M.E., Yehiely F., et al. αB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer. J. Clin. Invest 2006, 116:261.
65. Holcakova J., Hernychová L., Bouchal P., Brozkova K., Zaloudik J., Valík D., et al. Identification of alphaB-crystallin, a biomarker of renal cell carcinoma by SELDI-TOF MS. Int. J. Biol. Markers 2007, 23:48-53.
66. Tang Q., Liu Y.-F., Zhu X.-J., Li Y.-H., Zhu J., Zhang J.-P., et al. Expression and prognostic significance of the αB-crystallin gene in human hepatocellular carcinoma. Hum. Pathol 2009, 40:300-305.
67. Rajakulendran T., Sahmi M., Lefrancois M., Sicheri F., Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 2009, 461:542-545.
68. Bae J.S., Noh S.J., Kim K.M., Jang K.Y., Chung M.J., Kim D.G., et al. Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma. Int. J. Oncol 2014, 44:129-136.
69. Fernando J., Malfettone A., Cepeda E.B., Vilarrasa-Blasi R., Bertran E., Raimondi G., et al. A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells. Int. J. Cancer 2015, 136:E161-E172.
70. van Zijl F., Zulehner G., Petz M., Schneller D., Kornauth C., Hau M., et al. Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol 2009, 5:1169-1179.
71. Gulhati P., Bowen K.A., Liu J.Y., Stevens P.D., Rychahou P.G., Chen M., et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011, 71:3246-3256.
72. Li C.W., Xia W., Huo L., Lim S.O., Wu Y., Hsu J.L., et al. Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res 2012, 72:1290-1300.
73. Hao K., Tian X.D., Qin C.F., Xie X.H., Yang Y.M. Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis. Oncol. Rep 2013, 29:1124-1132.
74. Bai Y., Lu H., Wu C., Liang Y., Wang S., Lin C., et al. Resveratrol inhibits epithelial-mesenchymal transition and renal fibrosis by antagonizing the hedgehog signaling pathway. Biochem. Pharmacol 2014, 92:484-493.
75. Yu L., Mu Y., Sa N., Wang H., Xu W. Tumor necrosis factor alpha induces epithelial-mesenchymal transition and promotes metastasis via NF-kappaB signaling pathway-mediated TWIST expression in hypopharyngeal cancer. Oncol. Rep 2014, 31:321-327.
76. Pantschenko A.G., Pushkar I., Anderson K.H., Wang Y., Miller L.J., Kurtzman S.H., et al. The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumor progression. Int. J. Oncol 2003, 23:269-284.
77. Leibovich-Rivkin T., Liubomirski Y., Bernstein B., Meshel T., Ben-Baruch A. Inflammatory factors of the tumor microenvironment induce plasticity in nontransformed breast epithelial cells: EMT, invasion, and collapse of normally organized breast textures. Neoplasia 2013, 15:1330-1346.
78. Lindsey S., Langhans S.A. Crosstalk of oncogenic signaling pathways during epithelial-mesenchymal transition. Front. Oncol 2014, 4:358.
79. Shiota M., Bishop J.L., Nip K.M., Zardan A., Takeuchi A., Cordonnier T., et al. Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res 2013, 73:3109-3119.
80. Li P., Yang R., Gao W.Q. Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer. Mol. Cancer 2014, 13:55.
81. Sheshadri N., Catanzaro J.M., Bott A.J., Sun Y., Ullman E., Chen E.I., et al. SCCA1/SERPINB3 promotes oncogenesis and epithelial-mesenchymal transition via the unfolded protein response and IL6 signaling. Cancer Res 2014, 74:6318-6329.
82. De Luca A., Carotenuto A., Rachiglio A., Gallo M., Maiello M.R., Aldinucci D., et al. The role of the EGFR signaling in tumor microenvironment. J. Cell. Physiol 2008, 214:559-567.
83. Oishi N., Yamashita T., Kaneko S. Molecular biology of liver cancer stem cells. Liver Cancer 2014, 3:71.
84. Levental K.R., Yu H., Kass L., Lakins J.N., Egeblad M., Erler J.T., et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009, 139:891-906.
85. Dick J.E. Tumor archaeology: tracking leukemic evolution to its origins. Sci. Trans. Med 2014, 6:238fs223.
86. McMillin D.W., Delmore J., Weisberg E., Negri J.M., Geer D.C., Klippel S., et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat. Med 2010, 16:483-489.
87. Mitsiades C.S., Mitsiades N., Munshi N.C., Anderson K.C. Focus on multiple myeloma. Cancer Cell 2004, 6:439-444.
88. Ni H.-M., Bhakta A., Wang S., Li Z., Manley S., Huang H., et al. Role of hypoxia inducing factor-1β in alcohol-induced autophagy, steatosis and liver injury in mice. PLoS ONE 2014, 9:e115849.
89. Nguyen T.V., Sleiman M., Moriarty T., Herrick W.G., Peyton S.R. Extracellular matrix stiffness protects carcinoma cells from sorafenib via JNK signaling 2014, 1-2. in: Northeast Bioengineering Conference (NEBEC), 2014 40th Annual, IEEE.
90. Iyer A.K., Singh A., Ganta S., Amiji M.M. Role of integrated cancer nanomedicine in overcoming drug resistance. Adv. Drug Deliv. Rev 2013, 65:1784-1802.
91. Jain R.K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med 2001, 7:987-989.
92. Bonnet D., Dick J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med 1997, 3:730-737.
93. Zhu Z., Hao X., Yan M., Yao M., Ge C., Gu J., et al. Cancer stem/progenitor cells are highly enriched in CD133+ CD44+ population in hepatocellular carcinoma. Int. J. Cancer 2010, 126:2067-2078.
94. Clarke M.F., Dick J.E., Dirks P.B., Eaves C.J., Jamieson C.H., Jones D.L., et al. Cancer stem cells - perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006, 66:9339-9344.
95. Ailles L.E., Weissman I.L. Cancer stem cells in solid tumors. Curr. Opin. Biotechnol 2007, 18:460-466.
96. Kennedy J.A., Barabé F., Poeppl A.G., Wang J.C., Dick J.E. Comment on "Tumor growth need not be driven by rare cancer stem cells". Science 2007, 318:1722.
97. Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006, 444:756-760.
98. Wu K.-J., Yang M.-H. Epithelial-mesenchymal transition and cancer stemness: the Twist1-Bmi1 connection. Biosci. Rep 2011, 31:449-455.
99. Bielecka Z.F., Czarnecka A.M., Solarek W., Kornakiewicz A., Szczylik C. Mechanisms of acquired resistance to tyrosine kinase inhibitors in clear-cell renal cell carcinoma (ccRCC). Curr. Signal Transduct. Ther 2014, 8:218.
100. Biddle A., Mackenzie I.C. Cancer stem cells and EMT in carcinoma. Cancer Metastasis Rev 2012, 31:285-293.
101. Chang C., Hung M. The role of EZH2 in tumour progression. Br. J. Cancer 2012, 106:243-247.
102. Kiesslich T., Neureiter D. Advances in targeting the Hedgehog signaling pathway in cancer therapy. Expert Opin. Ther. Targets 2012, 16:151-156.
103. Zhou J.-J., Deng X.-G., He X.-Y., Zhou Y., Yu M., Gao W.-C., et al. Knockdown of NANOG enhances chemosensitivity of liver cancer cells to doxorubicin by reducing MDR1 expression. Int. J. Oncol 2014, 44:2034-2040.
104. Gedaly R., Galuppo R., Musgrave Y., Angulo P., Hundley J., Shah M., et al. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J. Surg. Res 2013, 185:225-230.
105. Xin H.-W., Ambe C.M., Hari D.M., Wiegand G.W., Miller T.C., Chen J.-Q., et al. Label-retaining liver cancer cells are relatively resistant to sorafenib. Gut 2013, 62:1777-1786.
106. Hernandez-Gea V., Toffanin S., Friedman S.L., Llovet J.M. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 2013, 144:512-527.
107. Von Marschall Z., Cramer T., Höcker M., Finkenzeller G., Wiedenmann B., Rosewicz S. Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut 2001, 48:87-96.
108. Shi Y.-H., Ding Z.-B., Zhou J., Hui B., Shi G.-M., Ke A.-W., et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy 2011, 7:1159-1172.
109. Zhu A.X., Duda D.G., Sahani D.V., Jain R.K. HCC and angiogenesis: possible targets and future directions. Nat. Rev. Clin. Oncol 2011, 8:292-301.
110. LeCouter J., Moritz D.R., Li B., Phillips G.L., Liang X.H., Gerber H.-P., et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003, 299:890-893.
111. Lichtenberger B.M., Tan P.K., Niederleithner H., Ferrara N., Petzelbauer P., Sibilia M. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 2010, 140:268-279.
112. Coulon S., Heindryckx F., Geerts A., Van Steenkiste C., Colle I., Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int 2011, 31:146-162.
113. Faivre S.J., Santoro A., Kelley R.K., Merle P., Gane E., Douillard J.-Y., et al. A phase 2 study of a novel transforming growth factor-beta (TGF-{beta} 1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC) 2014, LBA173. in: ASCO Annual Meeting Proceedings.
114. Roussos E.T., Condeelis J.S., Patsialou A. Chemotaxis in cancer. Nat. Rev. Cancer 2011, 11:573-587.
115. Trimboli A.J., Cantemir-Stone C.Z., Li F., Wallace J.A., Merchant A., Creasap N., et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 2009, 461:1084-1091.
116. Wu X.Z., Xie G.R., Chen D. Hypoxia and hepatocellular carcinoma: the therapeutic target for hepatocellular carcinoma. J. Gastroenterol. Hepatol 2007, 22:1178-1182.
117. Jiao M., Nan K.-J. Activation of PI3 kinase/Akt/HIF-1α pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma. Int. J. Oncol 2012, 40:461-468.
118. Liang Y., Zheng T., Song R., Wang J., Yin D., Wang L., et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology 2013, 57:1847-1857.
119. Shirabe K., Mano Y., Muto J., Matono R., Motomura T., Toshima T., et al. Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg. Today 2012, 42:1-7.
120. Bareford M.D., Park M.A., Yacoub A., Hamed H.A., Tang Y., Cruickshanks N., et al. Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Cancer Res 2011, 71:4955-4967.
121. Shimizu S., Takehara T., Hikita H., Kodama T., Tsunematsu H., Miyagi T., et al. Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int. J. Cancer 2012, 131:548-557.
122. Berasain C., Castillo J., Perugorria M.J., Latasa M.U., Prieto J., Avila M.A. Inflammation and liver cancer: new molecular links. Ann. N. Y. Acad. Sci 2009, 1155:206-221.
123. Pattullo V. Hepatitis B reactivation in the setting of chemotherapy and immunosuppression - prevention is better than cure. World J. Hepatol 2015, 7:954-967.
124. D'Angelo S., Secondulfo M., De Cristofano R., Sorrentino P. Sorafenib and entecavir: the dioscuri of treatment for advanced hepatocellular carcinoma?. World J. Gastroenterol 2013, 19:2141-2143.
125. Zuo C., Xia M., Wu Q., Zhu H., Liu J., Liu C. Role of antiviral therapy in reducing recurrence and improving survival in hepatitis B virus-associated hepatocellular carcinoma following curative resection (Review). Oncol. Lett 2015, 9:527-534.
126. Descamps V., Helle F., Louandre C., Martin E., Brochot E., Izquierdo L., et al. The kinase-inhibitor sorafenib inhibits multiple steps of the Hepatitis C Virus infectious cycle in vitro. Antiviral Res 2015, 118:93-102.
127. Cabrera R., Limaye A.R., Horne P., Mills R., Soldevila-Pico C., Clark V., et al. The anti-viral effect of sorafenib in hepatitis C-related hepatocellular carcinoma. Aliment. Pharmacol. Ther 2013, 37:91-97.
128. Himmelsbach K., Hildt E. The kinase inhibitor Sorafenib impairs the antiviral effect of interferon alpha on hepatitis C virus replication. Eur. J. Cell Biol 2013, 92:12-20.
129. Zhang Q.B., Sun H.C., Zhang K.Z., Jia Q.A., Bu Y., Wang M., et al. Suppression of natural killer cells by sorafenib contributes to prometastatic effects in hepatocellular carcinoma. PLoS ONE 2013, 8:e55945.
130. Mao K., Zhang J., He C., Xu K., Liu J., Sun J., et al. Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib. Cancer Lett 2014, 352:245-252.
131. Cheng A.L., Guan Z., Chen Z., Tsao C.J., Qin S., Kim J.S., et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur. J. Cancer 2012, 48:1452-1465.
132. Bolondi L., Caspary W., Bennouna J., Thomson W., Van Steenbergen F., Degos M., et al. Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): subgroup analysis of the SHARP trial.[Abstract] 2008, 25-27. Presented at the 2008 Gastrointestinal Cancers Symposium; Orlando, FL.
133. Rota Caremoli E., Labianca R. Tivantinib: critical review with a focus on hepatocellular carcinoma. Expert Opin. Investig. Drugs 2014, 23:1563-1574.
134. Yamanaka K., Petrulionis M., Lin S., Gao C., Galli U., Richter S., et al. Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma - systematic review and meta-analysis. Cancer Med 2013, 2:862-871.
135. Yeo W., Chung H.C., Chan S.L., Wang L.Z., Lim R., Picus J., et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J. Clin. Oncol 2012, 30:3361-3367.
136. V. Tovar, Cornella, A. Villanueva, FGF signaling is involved in acquired resistance to sorafenib in an in vivo model of hepatocellular carcinoma, Presented at the International Liver Cancer Association Conference, Hong Kong, China, September 2-4, 2011 (abstr 0-006).
137. Llovet J.M., Decaens T., Raoul J.L., Boucher E., Kudo M., Chang C., et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J. Clin. Oncol 2013, 31:3509-3516.
138. Cainap C., Qin S.K., Huang W.T., Chung I.J., Pan H.M., Cheng Y., et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J. Clin. Oncol 2013, 31.
139. Fang P., Hu J.H., Cheng Z.G., Liu Z.F., Wang J.L., Jiao S.C. Efficacy and safety of bevacizumab for the treatment of advanced hepatocellular carcinoma: a systematic review of phase II trials. PLoS ONE 2012, 7.
140. Liu C.J., Chang J., Lee P.H., Lin D.Y., Wu C.C., Jeng L.B., et al. Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World J. Gastroenterol 2014, 20:11384-11393.
141. Wang C.M., Cigliano A., Delogu S., Armbruster J., Dombrowski F., Evert M., et al. Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in hepatocarcinogenesis Implications for the treatment of human liver cancer. Cell Cycle 2013, 12:1999-2010.
142. Gedaly R., Angulo P., Hundley J., Daily M.F., Chen C., Evers B.M. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. J. Surg. Res 2012, 176:542-548.
143. Zhu A.X., Rosmorduc O., Evans T.R., Ross P.J., Santoro A., Carrilho F.J., et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol 2015, 33:559-566.
144. Huynh H., Ngo V.C., Koong H.N., Poon D., Choo S.P., Toh H.C., et al. AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J. Hepatol 2010, 52:79-87.
145. Lim H.Y., Heo J., Choi H.J., Lin C.Y., Yoon J.H., Hsu C., et al. A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin. Cancer Res 2014, 20:5976-5985.
146. Brandi G., de Rosa F., Agostini V., di Girolamo S., Andreone P., Bolondi L., et al. Metronomic capecitabine in advanced hepatocellular carcinoma patients: a phase II study. Oncologist 2013, 18:1256-1257.
147. Hammond J.S., Franko J., Holloway S.E., Heckman J.T., Orons P.D., Gamblin T.C. Gemcitabine transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma. Hepatogastroenterology 2014, 61:1339-1343.
148. Wang Y., Liu Y., Liu Y., Zhou W., Wang H., Wan G., et al. A polymeric prodrug of cisplatin based on pullulan for the targeted therapy against hepatocellular carcinoma. Int. J. Pharm 2015, 483:89-100.
149. Qi W.W., Yu H.Y., Guo H., Lou J., Wang Z.M., Liu P., et al. Doxorubicin-loaded glycyrrhetinic acid modified recombinant human serum albumin nanoparticles for targeting liver tumor chemotherapy. Mol. Pharm 2015, 12:675-683.
150. Liu Y., Yue H., Xu S., Wang F., Ma N., Li K., et al. First-line gemcitabine and oxaliplatin (GEMOX) plus sorafenib, followed by sorafenib as maintenance therapy, for patients with advanced hepatocellular carcinoma: a preliminary study. Int. J. Clin. Oncol 2015.
151. Wang Z., Zhao Z., Wu T., Song L., Zhang Y. Sorafenib-irinotecan sequential therapy augmented the anti-tumor efficacy of monotherapy in hepatocellular carcinoma cells HepG2. Neoplasma 2015, 62:172-179.
152. Srimuninnimit V., Sriuranpong V., Suwanvecho S. Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: a multicenter, open-label, single-arm phase II study. Asia Pac. J. Clin. Oncol 2014, 10:255-260.
153. Abou-Alfa G.K., Johnson P., Knox J.J., Capanu M., Davidenko I., Lacava J., et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010, 304:2154-2160.
154. Hato T., Goyal L., Greten T.F., Duda D.G., Zhu A.X. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology 2014, 60:1776-1782.
155. Wang Y., Li H., Liang Q., Liu B., Mei X., Ma Y. Combinatorial immunotherapy of sorafenib and blockade of programmed death-ligand 1 induces effective natural killer cell responses against hepatocellular carcinoma. Tumour Biol 2014.
156. Chen Y., Ramjiawan R.R., Reiberger T., Ng M.R., Hato T., Huang Y., et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 2015, 61:1591-1602.
157. Vaira V., Roncalli M., Carnaghi C., Faversani A., Maggioni M., Augello C., et al. MicroRNA-425-3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma. Liver Int 2015, 35:1077-1086.
158. Scartozzi M., Faloppi L., Svegliati Baroni G., Loretelli C., Piscaglia F., Iavarone M., et al. VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study. Int. J. Cancer 2014, 135:1247-1256.
159. Luo X., Feng G.S. VEGFA genomic amplification tailors treatment of HCCs with sorafenib. Cancer Discov 2014, 4:640-641.
160. Rudalska R., Dauch D., Longerich T., McJunkin K., Wuestefeld T., Kang T.W., et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med 2014, 20:1138-1146.
161. Chen D., Zhao P., Li S.Q., Xiao W.K., Yin X.Y., Peng B.G., et al. Prognostic impact of pERK in advanced hepatocellular carcinoma patients treated with sorafenib. Eur. J. Surg. Oncol 2013, 39:974-980.
162. Tai W.T., Cheng A.L., Shiau C.W., Huang H.P., Huang J.W., Chen P.J., et al. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J. Hepatol 2011, 55:1041-1048.
163. Blivet-Van Eggelpoel M.J., Chettouh H., Fartoux L., Aoudjehane L., Barbu V., Rey C., et al. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J. Hepatol 2012, 57:108-115.
164. Shan J.J., Shen J.J., Liu L.M., Xia F., Xu C., Duan G.J., et al. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology 2012, 56:1004-1014.
165. Hagiwara S., Kudo M., Nagai T., Inoue T., Ueshima K., Nishida N., et al. Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br. J. Cancer 2012, 106:1997-2003.
166. Llovet J.M., Pena C.E.A., Lathia C.D., Shan M., Meinhardt G., Bruix J., et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin. Cancer Res 2012, 18:2290-2300.
167. Arao T., Ueshima K., Matsumoto K., Nagai T., Kimura H., Hagiwara S., et al. FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology 2013, 57:1407-1415.