The systemic inflammatory response as a source of biomarkers and therapeutic targets in hepatocellular carcinoma.
HCC
hepatocellular carcinoma
inflammation
prognosis
survival
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
07
02
2019
revised:
10
08
2019
accepted:
13
08
2019
pubmed:
23
8
2019
medline:
21
10
2020
entrez:
22
8
2019
Statut:
ppublish
Résumé
The pathogenesis of hepatocellular carcinoma (HCC) strongly relates to inflammation, with chronic up-regulation of pro-inflammatory mediators standing as a potential unifying mechanism that underscores the origin and progression of HCC independent of aetiology. Activation of the diverse pro-inflammatory mediators either within the tumour or its microenvironment is part of an active cross-talk between the progressive HCC and the host, which is known to influence clinical outcomes including recurrence after radical treatments and long-term survival. A number of clinical biomarkers to measure the severity of cancer-related inflammation are now available, most of which emerge from routine blood parameters including neutrophil, lymphocyte, platelet counts, as well as albuminaemia and C-reactive protein levels. In this review, we summarise the body of evidence supporting the biologic qualification of inflammation-based scores in HCC and review their potential in facilitating the prognostic assessment and treatment allocation in the individual patient. We also discuss the evidence to suggest modulation of tumour-promoting inflammation may act as a source of novel therapeutic strategies in liver cancer.
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
2008-2023Informations de copyright
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539-545. https://doi.org/10.1016/S0140-6736(00)04046-0
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10-29. https://doi.org/10.3322/caac.20138
Kocabayoglu P, Friedman SL. Cellular basis of hepatic fibrosis and its role in inflammation and cancer. Front Biosci (Schol Ed). 2013;5:217-230. http://www.ncbi.nlm.nih.gov/pubmed/23277047. Accessed September 17, 2018.
Maki A, Kono H, Gupta M, et al. Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma. Ann Surg Oncol. 2007;14(3):1182-1190. https://doi.org/10.1245/s10434-006-9049-1
Lade A, Noon LA, Friedman SL. Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr Opin Oncol. 2014;26(1):100-107. https://doi.org/10.1097/CCO.0000000000000042
Cornellà H, Alsinet C, Villanueva A. Molecular pathogenesis of hepatocellular carcinoma. Alcohol Clin Exp Res. 2011;35(5):821-825. https://doi.org/10.1111/j.1530-0277.2010.01406.x
Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144(3):512-527. https://doi.org/10.1053/j.gastro.2013.01.002
Budhu A, Wang XW. The role of cytokines in hepatocellular carcinoma. J Leukocyte Biol. 2006;80(6):1197-1213. https://doi.org/10.1189/jlb.0506297
Budhu A, Forgues M, Ye Q-H, et al. 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(2):99-111. https://doi.org/10.1016/j.ccr.2006.06.016
Zhou H, Huang H, Shi J, et al. Prognostic value of interleukin 2 and interleukin 15 in peritumoral hepatic tissues for patients with hepatitis B-related hepatocellular carcinoma after curative resection. Gut. 2010;59(12):1699-1708. https://doi.org/10.1136/gut.2010.218404
Beckebaum S, Zhang X, Chen X, et al. Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res. 2004;10(21):7260-7269. https://doi.org/10.1158/1078-0432.CCR-04-0872
Arihara F, Mizukoshi E, Kitahara M, et al. Increase in CD14+HLA-DR−/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother. 2013;62(8):1421-1430. https://doi.org/10.1007/s00262-013-1447-1
Zhang J-P, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol. 2009;50(5):980-989. https://doi.org/10.1016/j.jhep.2008.12.033
Hwang S-J, Luo J-C, Li C-P, et al. Thrombocytosis: a paraneoplastic syndrome in patients with hepatocellular carcinoma. World J Gastroenterol. 2004;10(17):2472-2477. http://www.ncbi.nlm.nih.gov/pubmed/15300887. Accessed September 17, 2018.
Aino H, Sumie S, Niizeki T, et al. Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis. Mol Clin Oncol. 2014;2(3):393-398. https://doi.org/10.3892/mco.2014.259
Hao KE, Luk JM, Lee N, et al. Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters. BMC Cancer. 2009;9(1):389. https://doi.org/10.1186/1471-2407-9-389
Kinoshita A, Onoda H, Imai N, et al. Elevated plasma fibrinogen levels are associated with a poor prognosis in patients with hepatocellular carcinoma. Oncology. 2013;85(5):269-277. https://doi.org/10.1159/000355502
Nagai S, Abouljoud MS, Kazimi M, Brown KA, Moonka D, Yoshida A. Peritransplant lymphopenia is a novel prognostic factor in recurrence of hepatocellular carcinoma after liver transplantation. Transplantation. 2014;97(6):694-701. https://doi.org/10.1097/01.TP.0000437426.15890.1d
Facciorusso A, Del Prete V, Antonino M, et al. Serum ferritin as a new prognostic factor in hepatocellular carcinoma patients treated with radiofrequency ablation. J Gastroenterol Hepatol. 2014;29(11):1905-1910. https://doi.org/10.1111/jgh.12618
Sieghart W, Pinter M, Hucke F, et al. Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma. Hepatology. 2013;57(6):2224-2234. https://doi.org/10.1002/hep.26057
Kato A, Tsuji T, Sakao Y, et al. A comparison of systemic inflammation-based prognostic scores in patients on regular hemodialysis. Nephron Extra. 2013;3(1):91-100. https://doi.org/10.1159/000355148
Pinato DJ, Stebbing J, Ishizuka M, et al. A novel and validated prognostic index in hepatocellular carcinoma: the inflammation based index (IBI). J Hepatol. 2012;57(5):1013-1020. https://doi.org/10.1016/j.jhep.2012.06.022
Guthrie G, Charles KA, Roxburgh C, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218-230. https://doi.org/10.1016/j.critrevonc.2013.03.010
McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013;39(5):534-540. https://doi.org/10.1016/j.ctrv.2012.08.003
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-444. https://doi.org/10.1038/nature07205
Chen L, Zhang Q, Chang W, Du Y, Zhang H, Cao G. Viral and host inflammation-related factors that can predict the prognosis of hepatocellular carcinoma. Eur J Cancer. 2012;48(13):1977-1987. https://doi.org/10.1016/j.ejca.2012.01.015
Scapini P, Morini M, Tecchio C, et al. CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J Immunol. 2004;172(8):5034-5040. http://www.ncbi.nlm.nih.gov/pubmed/15067085. Accessed September 17, 2018.
Kuang D-M, Zhao Q, Wu Y, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54(5):948-955. https://doi.org/10.1016/j.jhep.2010.08.041
Motomura T, Shirabe K, Mano Y, et al. Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58(1):58-64. https://doi.org/10.1016/j.jhep.2012.08.017
Zhou S-L, Dai Z, Zhou Z-J, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology. 2012;56(6):2242-2254. https://doi.org/10.1002/hep.25907
Haider C, Hnat J, Wagner R, et al. Transforming growth factor-β and Axl induce CXCL5 and neutrophil recruitment in hepatocellular carcinoma. Hepatology. 2018;69(1):222-236. https://doi.org/10.1002/hep.30166
Li LI, Xu LI, Yan J, et al. CXCR32-CXCL1 axis is correlated with neutrophil infiltration and predicts a poor prognosis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2015;34(1):129. https://doi.org/10.1186/s13046-015-0247-1
Imai Y, Kubota Y, Yamamoto S, et al. Neutrophils enhance invasion activity of human cholangiocellular carcinoma and hepatocellular carcinoma cells: an in vitro study. J Gastroenterol Hepatol. 2005;20(2):287-293. https://doi.org/10.1111/j.1440-1746.2004.03575.x
Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell. 2009;16(3):183-194. https://doi.org/10.1016/j.ccr.2009.06.017
Mazzocca A, Antonaci S, Giannelli G. The TGF-β signaling pathway as a pharmacological target in a hepatocellular carcinoma. Curr Pharm Des. 2012;18(27):4148-4154. http://www.ncbi.nlm.nih.gov/pubmed/22630081. Accessed September 17, 2018.
Mano Y, Shirabe K, Yamashita Y-I, et al. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma. Ann Surg. 2013;258(2):301-305. https://doi.org/10.1097/SLA.0b013e318297ad6b
Hagemann T, Wilson J, Burke F, et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol. 2006;176(8):5023-5032. http://www.ncbi.nlm.nih.gov/pubmed/16585599. Accessed September 17, 2018.
Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 2009;69(20):8067-8075. https://doi.org/10.1158/0008-5472.CAN-09-0901
Chan T, Wiltrout RH, Weiss JM. Immunotherapeutic modulation of the suppressive liver and tumor microenvironments. Int Immunopharmacol. 2011;11(7):879-889. https://doi.org/10.1016/j.intimp.2010.12.024
Kapanadze T, Gamrekelashvili J, Ma C, et al. Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J Hepatol. 2013;59(5):1007-1013. https://doi.org/10.1016/j.jhep.2013.06.010
Zheng J, Cai J, Li H, et al. Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio as prognostic predictors for hepatocellular carcinoma patients with various treatments: a meta-analysis and systematic review. Cell Physiol Biochem. 2017;44(3):967-981. https://doi.org/10.1159/000485396
Li X-F, Chen D-P, Ouyang F-Z, et al. Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma. J Hepatol. 2015;62(1):131-139. https://doi.org/10.1016/J.JHEP.2014.08.023
Kusumanto YH, Dam WA, Hospers G, Meijer C, Mulder NH. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis. 2003;6(4):283-287. https://doi.org/10.1023/B:AGEN.0000029415.62384.ba
Cheng Y, Li H, Deng Y, et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018;9(4):422. https://doi.org/10.1038/s41419-018-0458-4
Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493-e503. https://doi.org/10.1016/S1470-2045(14)70263-3
Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol. 2014;229(8):1005-1015. https://doi.org/10.1002/jcp.24539
Bihari C, Rastogi A, Shasthry SM, et al. Platelets contribute to growth and metastasis in hepatocellular carcinoma. APMIS. 2016;124(9):776-786. https://doi.org/10.1111/apm.12574
Carr BI, Guerra V. HCC and its microenvironment. Hepatogastroenterology. 2013;60(126):1433-1437. https://doi.org/10.5754/hge121028
Kao W-Y, Chiou Y-Y, Hung H-H, et al. Risk factors for long-term prognosis in hepatocellular carcinoma after radiofrequency ablation therapy. Eur J Gastroenterol Hepatol. 2011;23(6):1. https://doi.org/10.1097/MEG.0b013e328346d529
Hung H-H, Su C-W, Lai C-R, et al. Fibrosis and AST to platelet ratio index predict post-operative prognosis for solitary small hepatitis B-related hepatocellular carcinoma. Hepatol Int. 2010;4(4):691-699. https://doi.org/10.1007/s12072-010-9213-3
Shen S-L, Fu S-J, Chen B, et al. Preoperative aspartate aminotransferase to platelet ratio is an independent prognostic factor for hepatitis B-induced hepatocellular carcinoma after hepatic resection. Ann Surg Oncol. 2014;21(12):3802-3809. https://doi.org/10.1245/s10434-014-3771-x
Carr BI, Lin C-Y, Lu S-N. Platelet-related phenotypic patterns in hepatocellular carcinoma patients. Semin Oncol. 2014;41(3):415-421. https://doi.org/10.1053/j.seminoncol.2014.04.001
Sarrouilhe D, Clarhaut J, Defamie N, Mesnil M. Serotonin and cancer: what is the link? Curr Mol Med. 2015;15(1):62-77. http://www.ncbi.nlm.nih.gov/pubmed/25601469. Accessed September 17, 2018.
Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 1999;59(6):1295-1300. http://www.ncbi.nlm.nih.gov/pubmed/10096562. Accessed September 17, 2018.
Takagi S, Sato S, Oh-hara T, et al. Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2. Han Z, ed. PLoS ONE. 2013;8(8):e73609. https://doi.org/10.1371/journal.pone.0073609
Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239-252. https://doi.org/10.1038/nrc2618
Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20(5):576-590. https://doi.org/10.1016/j.ccr.2011.09.009
Zhang R, Guo H, Xu J, et al. Activated platelets inhibit hepatocellular carcinoma cell differentiation and promote tumor progression via platelet-tumor cell binding. Oncotarget. 2016;7(37):60609-60622. https://doi.org/10.18632/oncotarget.11300
D’Alessandro R, Refolo MG, Lippolis C, et al. Antagonism of Sorafenib and Regorafenib actions by platelet factors in hepatocellular carcinoma cell lines. BMC Cancer. 2014;14(1):351. https://doi.org/10.1186/1471-2407-14-351
Carr BI, Cavallini A, D’Alessandro R, et al. Platelet extracts induce growth, migration and invasion in human hepatocellular carcinoma in vitro. BMC Cancer. 2014;14(1):43. https://doi.org/10.1186/1471-2407-14-43
Sitia G. Platelets promote liver immunopathology contributing to hepatitis B virus-mediated hepatocarcinogenesis. Semin Oncol. 2014;41(3):402-405. https://doi.org/10.1053/j.seminoncol.2014.04.013
Scheiner B, Kirstein M, Popp S, et al. Association of platelet count and mean platelet volume with overall survival in patients with cirrhosis and unresectable hepatocellular carcinoma. Liver Cancer. 2019;8(3):203-217. https://doi.org/10.1159/000489833
Boneu B, Bugat R, Boneu A, Eche N, Sie P, Combes P-F. Exhausted platelets in patients with malignant solid tumors without evidence of active consumption coagulopathy. Eur J Cancer Clin Oncol. 1984;20(7):899-903. https://doi.org/10.1016/0277-5379(84)90161-5
Balduini CL, Noris P, Spedini P, Belletti S, Zambelli A, Da Prada GA. Relationship between size and thiazole orange fluorescence of platelets in patients undergoing high-dose chemotherapy. Br J Haematol. 1999;106(1):202-207. https://doi.org/10.1046/j.1365-2141.1999.01475.x
Carr BI, Guerra V. Thrombocytosis and hepatocellular carcinoma. Dig Dis Sci. 2013;58(6):1790-1796. https://doi.org/10.1007/s10620-012-2527-3
Kinoshita A, Onoda H, Imai N, et al. Comparison of the prognostic value of inflammation-based prognostic scores in patients with hepatocellular carcinoma. Br J Cancer. 2012;107(6):988-993. https://doi.org/10.1038/bjc.2012.354
Hu B, Yang X-R, Xu Y, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20(23):6212-6222. https://doi.org/10.1158/1078-0432.CCR-14-0442
Kishimoto T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther. 2006;8(Suppl 2):S2. https://doi.org/10.1186/ar1916
Pinato DJ, Bains J, Irkulla S, et al. Advanced age influences the dynamic changes in circulating C-reactive protein following injury. J Clin Pathol. 2013;66(8):695-699. https://doi.org/10.1136/jclinpath-2012-201374
Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805-1812. https://doi.org/10.1172/JCI18921
Su H-X, Zhou H-H, Wang M-Y, et al. Mutations of C-reactive protein (CRP)-286 SNP, APC and p53 in colorectal cancer: implication for a CRP-Wnt crosstalk. PLoS ONE. 2014;9(7):e102418. https://doi.org/10.1371/journal.pone.0102418
Prizment AE, Folsom AR, Dreyfus J, et al. Plasma C-reactive protein, genetic risk score, and risk of common cancers in the atherosclerosis risk in communities study. Cancer Causes Control. 2013;24(12):2077-2087. https://doi.org/10.1007/s10552-013-0285-y
Kondo S, Ueno H, Hosoi H, et al. Clinical impact of pentraxin family expression on prognosis of pancreatic carcinoma. Br J Cancer. 2013;109(3):739-746. https://doi.org/10.1038/bjc.2013.348
Laird BJ, McMillan DC, Fayers P, et al. The systemic inflammatory response and its relationship to pain and other symptoms in advanced cancer. Oncologist. 2013;18(9):1050-1055. https://doi.org/10.1634/theoncologist.2013-0120
Pinato DJ, Karamanakos G, Arizumi T, et al. Dynamic changes of the inflammation-based index predict mortality following chemoembolisation for hepatocellular carcinoma: a prospective study. Aliment Pharmacol Ther. 2014;40(11-12):1270-1281. https://doi.org/10.1111/apt.12992
Llovet J, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(03):329-338. https://doi.org/10.1055/s-2007-1007122
Chen X-P, Qiu F-Z, Wu Z-D, Zhang Z-W, Huang Z-Y, Chen Y-F. Long-term outcome of resection of large hepatocellular carcinoma. Br J Surg. 2006;93(5):600-606. https://doi.org/10.1002/bjs.5335
Sherman M. Recurrence of hepatocellular carcinoma. N Engl J Med. 2008;359(19):2045-2047. https://doi.org/10.1056/NEJMe0807581
Dan J, Zhang Y, Peng Z, et al. Postoperative neutrophil-to-lymphocyte ratio change predicts survival of patients with small hepatocellular carcinoma undergoing radiofrequency ablation. Villa E, ed. PLoS ONE. 2013;8(3):e58184. https://doi.org/10.1371/journal.pone.0058184
Chen T-M, Lin C-C, Huang P-T, Wen C-F. Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation. J Gastroenterol Hepatol. 2012;27(3):553-561. https://doi.org/10.1111/j.1440-1746.2011.06910.x
Rebonato A, Graziosi L, Maiettini D, et al. Inflammatory markers as prognostic factors of survival in patients affected by hepatocellular carcinoma undergoing transarterial chemoembolization. Gastroenterol Res Pract. 2017;2017:1-9. https://doi.org/10.1155/2017/4164130
Taussig MD, Irene Koran ME, Mouli SK, et al. Neutrophil to lymphocyte ratio predicts disease progression following intra-arterial therapy of hepatocellular carcinoma. HPB. 2017;19(5):458-464. https://doi.org/10.1016/j.hpb.2017.01.013
Fujiwara Y, Shiba H, Furukawa K, et al. Glasgow prognostic score is related to blood transfusion requirements and post-operative complications in hepatic resection for hepatocellular carcinoma. Anticancer Res. 2010;30(12):5129-5136. http://www.ncbi.nlm.nih.gov/pubmed/21187501. Accessed September 17, 2018.
Horino K, Beppu T, Kuroki H, et al. Glasgow prognostic score as a useful prognostic factor after hepatectomy for hepatocellular carcinoma. Int J Clin Oncol. 2013;18(5):829-838. https://doi.org/10.1007/s10147-012-0451-3
Ishizuka M, Kubota K, Kita J, et al. Impact of a novel inflammation-based prognostic system on patients undergoing surgery for hepatocellular carcinoma: a retrospective study of 398 Japanese patients. J Clin Oncol. 28(15_suppl):4111-4111. https://doi.org/10.1200/jco.2010.28.15_suppl.4111
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-700. https://doi.org/10.1056/NEJM199603143341104
Klintmalm GB. Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg. 1998;228(4):479-490. http://www.ncbi.nlm.nih.gov/pubmed/9790338. Accessed September 17, 2018.
Yao F, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33(6):1394-1403. https://doi.org/10.1053/jhep.2001.24563
Shindoh J, Sugawara Y, Nagata R, et al. Evaluation methods for pretransplant oncologic markers and their prognostic impacts in patient undergoing living donor liver transplantation for hepatocellular carcinoma. Transpl Int. 2014;27(4):391-398. https://doi.org/10.1111/tri.12274
Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734-1739. https://doi.org/10.1016/S0140-6736(02)08649-X
Bruix J, Sherman M; Practice Guidelines Committee, American Association for the study of liver diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208-1236. https://doi.org/10.1002/hep.20933
Bolondi L, Burroughs A, Dufour J-F, et al. Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis. 2013;32(4):348-359. https://doi.org/10.1055/s-0032-1329906
Kadalayil L, Benini R, Pallan L, et al. A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer. Ann Oncol. 2013;24(10):2565-2570. https://doi.org/10.1093/annonc/mdt247
Hucke F, Sieghart W, Pinter M, et al. The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE. J Hepatol. 2014;60(1):118-126. https://doi.org/10.1016/j.jhep.2013.08.022
Adhoute X, Penaranda G, Naude S, et al. Retreatment with TACE: the ABCR SCORE, an aid to the decision-making process. J Hepatol. 2015;62(4):855-862. https://doi.org/10.1016/j.jhep.2014.11.014
Hucke F, Pinter M, Graziadei I, et al. How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma. J Hepatol. 2014;61(6):1287-1296. https://doi.org/10.1016/j.jhep.2014.07.002
Pinato DJ, Sharma R. An inflammation-based prognostic index predicts survival advantage after transarterial chemoembolization in hepatocellular carcinoma. Transl Res. 2012;160(2):146-152. https://doi.org/10.1016/j.trsl.2012.01.011
Pinato DJ, Arizumi T, Allara E, et al. Validation of the hepatoma arterial embolization prognostic score in European and Asian populations and proposed modification. Clin Gastroenterol Hepatol. 2015;13(6):1204-1208.e2. https://doi.org/10.1016/j.cgh.2014.11.037
Morimoto M, Numata K, Moriya S, et al. Inflammation-based prognostic score for hepatocellular carcinoma patients on sorafenib treatment. Anticancer Res. 2012;32(2):619-623. http://www.ncbi.nlm.nih.gov/pubmed/22287754. Accessed September 17, 2018.
Zheng Y-B, Zhao W, Liu B, et al. The blood neutrophil-to-lymphocyte ratio predicts survival in patients with advanced hepatocellular carcinoma receiving sorafenib. Asian Pac J Cancer Prev. 2013;14(9):5527-5531. http://www.ncbi.nlm.nih.gov/pubmed/24175853. Accessed September 17, 2018.
Sprinzl MF, Reisinger F, Puschnik A, et al. Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology. 2013;57(6):2358-2368. https://doi.org/10.1002/hep.26328
Kacevska M, Downes MR, Sharma R, et al. Extrahepatic cancer suppresses nuclear receptor-regulated drug metabolism. Clin Cancer Res. 2011;17(10):3170-3180. https://doi.org/10.1158/1078-0432.CCR-10-3289
Ma R, Zhang W, Tang KE, et al. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. Nat Commun. 2013;4(1):2508. https://doi.org/10.1038/ncomms3508
Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 2012;13(5):518-527. https://doi.org/10.1016/S1470-2045(12)70112-2
Gala MK, Chan AT. Molecular pathways: aspirin and Wnt signaling-a molecularly targeted approach to cancer prevention and treatment. Clin Cancer Res. 2015;21(7):1543-1548. https://doi.org/10.1158/1078-0432.CCR-14-0877
Li JH, Wang Y, Xie XY, et al. Aspirin in combination with TACE in treatment of unresectable HCC: a matched-pairs analysis. Am J Cancer Res. 2016;6(9):2109-2116.
Xia H, Lee KW, Chen J, et al. Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib. Cell Death Discovery. 2017;3:17058. https://doi.org/10.1038/cddiscovery.2017.58
Sitia G, Aiolfi R, Di Lucia P, et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci. 2012;109(32):E2165-E2172. https://doi.org/10.1073/pnas.1209182109
Kondo M, Yamamoto H, Nagano H, et al. Increased expression of COX-2 in nontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res. 1999;5(12):4005-4012. http://www.ncbi.nlm.nih.gov/pubmed/10632332. Accessed September 17, 2018.
Song R, Song H, Liang Y, et al. Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis. Hepatology. 2014;60(5):1659-1673. https://doi.org/10.1002/hep.27312
Seufert BL, Poole EM, Whitton J, et al. IκBKβ and NFκB1, NSAID use and risk of colorectal cancer in the Colon Cancer Family Registry. Carcinogenesis. 2013;34(1):79-85. https://doi.org/10.1093/carcin/bgs296
Iannacone M, Sitia G, Isogawa M, et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med. 2005;11(11):1167-1169. https://doi.org/10.1038/nm1317
Pinter M, Jain RK. Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci Transl Med. 2017;9(410):1-3. https://doi.org/10.1126/scitranslmed.aan5616
George AJ, Thomas WG, Hannan RD. The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer. 2010;10(11):745-759. https://doi.org/10.1038/nrc2945
Okwan-Duodu D, Landry J, Shen XZ, Diaz R. Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis. Am J Physiol Integr Comp Physiol. 2013;305(3):R205-R215. https://doi.org/10.1152/ajpregu.00544.2012
Ji Y, Wang Z, Li Z, et al. Angiotensin II enhances proliferation and inflammation through AT1/PKC/NF-κB signaling pathway in hepatocellular carcinoma cells. Cell Physiol Biochem. 2016;39(1):13-32. https://doi.org/10.1159/000445602
Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol. 2012;22(1):33-40. https://doi.org/10.1016/j.semcancer.2011.12.005
Martin F, Apetoh L, Ghiringhelli F. Controversies on the role of Th17 in cancer: a TGF-β-dependent immunosuppressive activity? Trends Mol Med. 2012;18(12):742-749. https://doi.org/10.1016/j.molmed.2012.09.007
Ugel S, De Sanctis F, Mandruzzato S, Bronte V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest. 2015;125(9):3365-3376. https://doi.org/10.1172/JCI80006
David J, Dominguez C, Hamilton D, Palena C. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines. 2016;4(3):22. https://doi.org/10.3390/vaccines4030022
Frenzel H, Pries R, Brocks CP, Jabs WJ, Wittkopf N, Wollenberg B. Decreased migration of myeloid dendritic cells through increased levels of C-reactive protein. Anticancer Res. 27(6B), 4111-4115. http://www.ncbi.nlm.nih.gov/pubmed/18225580. Accessed August 7, 2019.
Zelenay S, van der Veen A, Böttcher J, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell. 2015;162(6):1257-1270. https://doi.org/10.1016/j.cell.2015.08.015
Flescher E, Ledbetter JA, Schieven GL, et al. Longitudinal exposure of human T lymphocytes to weak oxidative stress suppresses transmembrane and nuclear signal transduction. J Immunol. 1994;153(11):4880-4889. http//:www.ncbi.nlm.nih.gov/pubmed/7963551. Accessed August 7, 2019.
Kim H-R, Lee A, Choi E-J, et al. Reactive oxygen species prevent imiquimod-induced psoriatic dermatitis through enhancing regulatory T Cell function. Unutmaz D, ed. PLoS ONE. 2014;9(3):e91146. https://doi.org/10.1371/journal.pone.0091146
Lin X, Zheng W, Liu J, et al. Oxidative stress in malignant melanoma enhances tumor necrosis factor-α secretion of tumor-associated macrophages that promote cancer cell invasion. Antioxid Redox Signal. 2013;19(12):1337-1355. https://doi.org/10.1089/ars.2012.4617
Cortez-Retamozo V, Etzrodt M, Newton A, et al. Angiotensin II drives the production of tumor-promoting macrophages. Immunity. 2013;38(2):296-308. https://doi.org/10.1016/j.immuni.2012.10.015
Pinter M, Weinmann A, Wörns M-A, et al. Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United Eur Gastroenterol J. 2017;5(7):987-996. https://doi.org/10.1177/2050640617695698
Yoshiji H, Noguchi R, Toyohara M, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol. 2009;51(2):315-321. https://doi.org/10.1016/j.jhep.2009.04.011
Yoshiji H, Noguchi R, Ikenaka Y, et al. Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial. Oncol Rep. 2011;26(6):1547-1553. https://doi.org/10.3892/or.2011.1433
Facciorusso A, Del Prete V, Crucinio N, et al. Angiotensin receptor blockers improve survival outcomes after radiofrequency ablation in hepatocarcinoma patients. J Gastroenterol Hepatol. 2015;30(11):1643-1650. https://doi.org/10.1111/jgh.12988
Aaronson DS, Horvath CM. A road map for those who don't know JAK-STAT. Science. 2002;296(5573):1653-1655. https://doi.org/10.1126/science.1071545
Hurwitz H, Uppal N, Wagner SA, et al. A randomized double-blind phase 2 study of ruxolitinib (RUX) or placebo (PBO) with capecitabine (CAPE) as second-line therapy in patients (pts) with metastatic pancreatic cancer (mPC). J Clin Oncol. 2014;32(15_suppl):4000-4000. https://doi.org/10.1200/jco.2014.32.15_suppl.4000
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. https://doi.org/10.1056/NEJMoa0708857
Chen M-L, Yan B-S, Lu W-C, et al. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int J Cancer. 2014;134(2):319-331. https://doi.org/10.1002/ijc.28362
Cabrera R, Ararat M, Xu Y, et al. Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2013;62(4):737-746. https://doi.org/10.1007/s00262-012-1380-8
Kalathil SG, Lugade AA, Miller A, Iyer R, Thanavala Y. PD-1+ and Foxp3+ T cell reduction correlates with survival of HCC patients after sorafenib therapy. JCI Insight. 2016;1(11):1-6. https://doi.org/10.1172/jci.insight.86182
Alfaro C, Suarez N, Gonzalez A, et al. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. Br J Cancer. 2009;100(7):1111-1119. https://doi.org/10.1038/sj.bjc.6604965
Chen Y, Huang Y, Reiberger T, et al. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology. 2014;59(4):1435-1447. https://doi.org/10.1002/hep.26790
Chen Y, Ramjiawan RR, Reiberger T, et al. CXCR139 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2015;61(5):1591-1602. https://doi.org/10.1002/hep.27665
Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26(5):605-622. https://doi.org/10.1016/j.ccell.2014.10.006
Giannelli G, Mazzocca A, Fransvea E, Lahn M, Antonaci S. Inhibiting TGF-β signaling in hepatocellular carcinoma. Biochim Biophys Acta, Rev Cancer. 2011;1815(2):214-223. https://doi.org/10.1016/j.bbcan.2010.11.004
Rodón J, Carducci M, Sepulveda-Sánchez JM, et al. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs. 2015;33(2):357-370. https://doi.org/10.1007/s10637-014-0192-4
de Gramont A, Faivre S, Raymond E. Novel TGF-β inhibitors ready for prime time in onco-immunology. Oncoimmunology. 2017;6(1):e1257453. https://doi.org/10.1080/2162402X.2016.1257453
Sacdalan DB, Lucero JA, Sacdalan DL. Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis. Onco Targets Ther. 2018;11:955-965. https://doi.org/10.2147/OTT.S153290
Tan Q, Liu S, Liang C, Han X, Shi Y. Pretreatment hematological markers predict clinical outcome in cancer patients receiving immune checkpoint inhibitors: a meta-analysis. Thorac cancer. 2018;9(10):1220-1230. https://doi.org/10.1111/1759-7714.12815
Suh KJ, Kim SH, Kim YJ, et al. Post-treatment neutrophil-to-lymphocyte ratio at week 6 is prognostic in patients with advanced non-small cell lung cancers treated with anti-PD-1 antibody. Cancer Immunol Immunother. 2018;67(3):459-470. https://doi.org/10.1007/s00262-017-2092-x
Di Giacomo AM, Ascierto PA, Queirolo P, et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann Oncol. 2015;26(4):798-803. https://doi.org/10.1093/annonc/mdu577
Diem S, Schmid S, Krapf M, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer. 2017;111:176-181. https://doi.org/10.1016/j.lungcan.2017.07.024
Bilen MA, Martini DJ, Liu Y, et al. The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy. Cancer. 2018;125(1):127-134. https://doi.org/10.1002/cncr.31778
Gervais C, Boudou-Rouquette P, Jouinot A, et al. Predictive and prognostic value of systemic inflammatory response biomarkers in patients receiving nivolumab for metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35(15_suppl):3055-3055. https://doi.org/10.1200/JCO.2017.35.15_suppl.3055
Naqash AR, Stroud C, Butt MU, et al. Co-relation of overall survival with peripheral blood-based inflammatory biomarkers in advanced stage non-small cell lung cancer treated with anti-programmed cell death-1 therapy: results from a single institutional database. Acta Oncol (Madr). 2018;57(6):867-872. https://doi.org/10.1080/0284186X.2017.1415460
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502. https://doi.org/10.1016/S0140-6736(17)31046-2
Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952. https://doi.org/10.1016/S1470-2045(18)30351-6
Flynn MJ, Sayed AA, Sharma R, Siddique A, Pinato DJ. Challenges and opportunities in the clinical development of immune checkpoint inhibitors for hepatocellular carcinoma. Hepatology. 2018;69(5):2258-2270. https://doi.org/10.1002/hep.30337
Raoul J-L, Sangro B, Forner A, et al. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev. 2011;37(3):212-220. https://doi.org/10.1016/j.ctrv.2010.07.006
Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol. 2015;62(5):1187-1195. https://doi.org/10.1016/j.jhep.2015.02.010
Gillani TB, Rawling T, Murray M. Cytochrome P450-mediated biotransformation of sorafenib and Its N-oxide metabolite: implications for cell viability and human toxicity. Chem Res Toxicol. 2015;28(1):92-102. https://doi.org/10.1021/tx500373g
Howell J, Pinato DJ, Ramaswami R, et al. Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib. Oncotarget. 2017;8(22):36161-36170. https://doi.org/10.18632/oncotarget.15322