Somatostatin in hepatocellular carcinoma: experimental and therapeutic implications

Abstract

The neuropeptide somatostatin has been shown to control the secretion of several hormones and growth factors, but also to inhibit the proliferation of several tumor cells. Hepatocellular carcinoma (HCC) is a leading cause of death all over the world due to very limited treatment modalities. Early reports showed that somatostatin may influence HCC growth, making somatostatin a potential therapeutic candidate. The introduction of somatostatin analogues with long half-lives has made this prospect feasible. In this review, experimental data regarding the presence of somatostatin receptors and their functional significance in HCC are presented. Potential mechanisms of direct anti-tumoral activity of somatostatin, including effects on tumor cell proliferation and apoptosis, inhibition of various trophic factors and angiogenesis are also reviewed, as well as indirect actions affecting liver fibrosis, inflammation and macrophage-associated innate immunity. Data on the use of somatostatin analogues for the treatment of induced HCC in experimental animals are presented and human studies of somatostatin treatment of advanced HCC are critically analyzed. Reasons and pitfalls for treatment failures are identified and indications for the proper use of somatostatin, either alone or as an adjunct to other modalities in future trials are proposed.

Keywords

Somatostatin analogues / hepatocellular carcinoma / somatostatin receptors / action mechanisms / treatment

References

[1] Kim DY.Epidemiology and surveillance of hepatocellular carcinoma.Liver Cancer2012;1:2-14 PMCID:PMC3747543

[2] Sifaki-Pistolla D,Koulentaki M,Stratakou S,Kouroumalis E.Geoepidemiology of hepatocellular carcinoma in the island of Crete, Greece. A possible role of pesticides..Liver Int2016;36:588-94

[3] Petruzziello A.Epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) related hepatocellular carcinoma.Open Virol J2018;12:26-32 PMCID:PMC5842386

[4] Krulich L,McCann SM.Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro.Endocrinology1968;83:783-90

[5] Benoit R,Bennett HP,Ravazzola M.Mufson EJ Processing of prosomatostatin.Metabolism1990;39:22-5

[6] Lamberts SWJ,de Herder WW.Octreotide.New Engl J Med1996;334:246-54

[7] Dasgupta P.Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis.Pharmacol Ther2004;102:61-85

[8] Barbieri F,Pattarozzi A,Wurth R,Corsaro A,Nizzari M.Peptide receptor targeting in cancer: the somatostatin paradigm.Int J Pept2013;2013:926295 PMCID:PMC3582104

[9] Patel YC.Somatostatin and its receptor family.Front Neuroendocrinol1999;20:157-98

[10] Abdel-Rahman O,Valle JW.Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations.Endocr Relat Cancer2014;21:R485-93

[11] Bruns C,Raulf F,Schoeffter P.Molecular pharmacology of somatostatin receptor subtype.Ann NY Acad Sci1994;733:138-46

[12] Florio T,Fattore M,Salzano S,Berlingieri MT,Schettini G.Somatostatin inhibits PC C13 thyroid cell proliferation through the modulation of phosphotyrosine phophatase activity-impairment of the somatostatinergirc effects by stable expression of EIA viral oncogene.J Biol Chem1996;271:6129-36

[13] Møller LN,Hartmann B.Somatostatin receptors.Biochim Biophys Acta2003;1616:1-84

[14] Weckbecker G,Stolz B.Somatostatin analogs for diagnosis and treatment of cancer.Pharmacol Ther1993;60:245-64

[15] Raderer M,Muller C,Kurtaran A,Fiebieger W,Scheithauer W.Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo.Int J Oncol2000;16:1197-201

[16] Reynaert H,Vandermonde A,Kumar U,Pinzani M,Geerts A.Expression of somatostatin receptors in normal and cirrhotic human liver and in hepatocellular carcinoma.Gut2004;53:1180-9 PMCID:PMC1774160

[17] Kaemmerer D,Mußbach F,Altendorf-Hofmann A,Sänger J,Lupp A.Somatostatin and CXCR4 chemokine receptor expression in hepatocellular and cholangiocellular carcinomas: tumor capillaries as promising targets.BMC Cancer2017;17:896 PMCID:PMC5745780

[18] Notas G,Mastrodimou N,Vasilaki A,Castanas E,Kouroumalis E.Cortistatin production by HepG2 human hepatocellular carcinoma cell line and distribution of somatostatin receptors.J Hepatol2004;40:792-8

[19] Samonakis DN,Christodoulakis N.Mechanisms of action and resistance of somatostatin analogues for the treatment of hepatocellular carcinoma: a message not well taken.Dig Dis Sci2008;53:2359-65

[20] Siehler S,Hoyer D.[125I]Tyr10-cortistatin14 labels all five somatostatin receptors.Naunyn Schmiedebergs Arch Pharmacol1998;357:483-9

[21] Reubi JC,Cescato R,Stettler C.Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotidetreated patients.J Clin Endocrinol Metab2010;95:2343-50 PMCID:PMC2869539

[22] Reynaert H,Qin H,Chatterjee N,Quartier E,Urbain D,Patel YC.Somatostatin suppresses endothelin-1 induced rat hepatic stellate cell contraction via somatostatin receptor subtype 1.Gastroenterology2001;121:915-30

[23] Song SH,Li T,Peng JR,Wei YH.Expression of subtypes of somatostatin receptors in hepatic stellate cells.World J Gastroenterol2004;10:1663-5 PMCID:PMC4572775

[24] Klironomos S,Sfakianaki O,Xidakis C.Octreotide modulates the effects on fibrosis of TNF-α, TGF-β and PDGF in activated rat hepatic stellate cells.Regul Pept2014;188:5-12

[25] Notas G,Valatas V,Mastrodimou N,Kolios G,Kouroumalis E.LPS modifies the expression and accumulation of somatostatin receptors in rat Kupffer cells.J Hepatol2005;42:232

[26] Xidakis C,Notas N,Kolios G,Thermos K.RT-PCR and immunocytochemistry studies support the presence of somatostatin, cortistatin and somatostatin receptor subtypes in rat Kupffer..Cells Reg Pept2007;143:76-82

[27] Reubi JC,Jonas S,Neuhaus P,Wiedenmann B.Regulatory peptide receptors in human hepatocellular carcinomas.Gut1999;45:766-74 PMCID:PMC1727725

[28] Blaker M,Gocht A,Schulz M,Pace A,de Weerth A.Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas.J Hepatol2004;41:112-8

[29] Xie YM,Wei B,Tang CW.Correlation of somatostatin receptor expression in human hepatocellular carcinoma tissue to serum alpha-fetoprotein concentration.Ai Zheng2007;26:688-92(in Chinese)

[30] Verhoef C,Hofland LJ,de Wilt JH,de Man RA,van Eijck CH.Somatostatin receptor in human hepatocellular carcinomas: biological, patient and tumor characteristics.Dig Surg2008;25:21-6

[31] Koc EU,Yerci O.Somatostatin receptor 1 (SSTR1) and somatostatin receptor 5 (SSTR5) expression in hepatocellular carcinoma.Hepatogastroenterology2013;60:1693-7

[32] Chou CK,Ting LP,Su TS,Suen CS,Chang CM.Selective suppression of insulin-induced proliferation of cultured human hepatoma cells by somatostatin.J Clin Invest1987;79:175-8 PMCID:PMC424015

[33] Chen X,Ai Z.Antineoplastic mechanism of octreotide action in human hepatoma.Chin Med J2001;114:1167-70

[34] Liu HL,Wang L.Octreotide inhibits proliferation and induces apoptosis of hepatocellular carcinoma cells.Acta Pharmacol Sin2004;25:1380-6

[35] Hua YP,Peng BG,Lai JM,Liang LJ.Mechanisms and influence of octreotide-induced regulation of somatostatin receptor 2 on hepatocellular carcinoma.Chemotherapy2009;55:312-20

[36] Lü XH,Xie Y.Differences of therapeutic efficacy between different kinds of somatostatin analogue for primary hepatocellular carcinoma.Sichuan Da Xue Xue Bao Yi Xue Ban2017;48:549-55(in Chinese)

[37] Xie Y,Wang CH.Effect of HBV X gene transfection on octreotide-inhibited growth of hepatocellular carcinoma cell line HepG2.Ai Zheng2005;24:965-9(in Chinese)

[38] Neaud V,Guirouilh J,Balabaud C,Rosenbaum J.Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor.Hepatology1997;26:1458-66

[39] Theret K,Turlin B,Bioulac-Sage P,Boudjéma K.Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas.Hepatology2001;34:82-8

[40] Pan Q,Lu HM,Wang YQ.Antiproliferative and proapoptotic effects of somatostatin on activated hepatic stellate cells.World J Gastroenterol2004;10:1015-8 PMCID:PMC4717091

[41] Reynaert H,Jia Y,Chatterjee N,Geerts A.Somatostatin at nanomolar concentration reduces collagen I and III synthesis by, but not proliferation of activated rat hepatic stellate cells.Br J Pharmacol2005;146:77-88 PMCID:PMC1576247

[42] Wang C,Tang L.Inhibition effects of octreotide on the growth of hepatocellular carcinoma in vitro and in vivo.Zhonghua Yi Xue Za Zhi2001;81:1194-7(in Chinese)

[43] Ferjoux G,Cordelier P,Lopez F,Buscail L.Signal transduction of somatostatin receptors negatively controlling cell proliferation.J Physiol Paris2000;94:205-10

[44] Florio T,Carey KD,Stork PJ.Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1).Mol Endocrinol1999;13:24-37

[45] Cordelier P,Bousquet C,Am OC,Vaysse N,Buscail L.Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5.Proc Natl Acad Sci U S A1997;94:9343-8 PMCID:PMC23188

[46] Lahlou H,Esteve JP,Pradayrol L,Susini C.sst2 Somatostatin receptor inhibits cell proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 activation.J Biol Chem2003;278:39356-71

[47] Neel BG.Protein tyrosine phosphatases in signal transduction.Curr Opin Cell Biol1997;9:193-204

[48] War SA.Coexpression of human somatostatin receptor-2 (SSTR2) and SSTR3 modulates antiproliferative signaling and apoptosis.J Mol Signal2012;7:5 PMCID:PMC3403965

[49] Grant M,Jaquet P,Kumar U.Cell growth inhibition and functioning of human somatostatin receptor type 2 are modulated by receptor heterodimerization.Mol Endocrinol2008;22:2278-92 PMCID:PMC5419397

[50] Teijeiro R,Costoja J,Bello J,Arce V.Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53.Cell Physiol Biochem2002;12:31-8

[51] Lasfer M,Schally AV,Halmos G,Feldmann G.Potent induction of apoptosis in human hepatoma cell lines by targeted cytotoxic somatostatin analogue AN-238.J Hepatol2005;42:230-7

[52] Theodoropoulou M,Laupheimer S,Florio Pagotto U T.Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression.Cancer Res2006;66:1576-82

[53] Tsagarakis NJ,Batistakis AG,Kouroumalis EA.Octreotide induces caspase activation and apoptosis in human hepatoma HepG2 cells.World J Gastroenterol2011;17:313-21 PMCID:PMC3022290

[54] Ma Q,Liu JC,Ge J,Jiang S.Octreotide induces apoptosis of human hepatoma cells by the mechanism of facilitating the Fas/FasL gene expression therein.Zhonghua Yi Xue Za Zhi2008;88:716-8(in Chinese)

[55] Notas G,Nifli AP,Papasava D,Kouroumalis E.The inhibitory effect of opioids on HepG2 cells is mediated via interaction with somatostatin receptors.Eur J Pharmacol2007;555:1-7

[56] Avella DM,Donahue RN,McLaughlin PJ,Staveley-O'Carrol KF.The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer.Am J Physiol Regul Integr Comp Physiol2010;298:R459-66 PMCID:PMC2828179

[57] Ren SG,Melmed S.Somatostatin analog induces insulin-like growth factor binding protein-1 (IGFBP-1) expression in human hepatoma cells.Endocrinology1992;131:2479-81

[58] Scharf JG,Ramadori G.The IGF axis and hepatocarcinogenesis.Mol Pathol2001;54:138-44 PMCID:PMC1187051

[59] Huynh H,Ooi L.A possible role for insulin-like growth factor binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation.Cell Growth Differ2002;13:115-22

[60] Scharf JG.The role of the IGF axis in hepatocarcinogenesis.Horm Metab Res2003;35:685-93

[61] Alexia C,Lasfer M,Groyer A.An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis.Biochem Pharmacol2004;68:1003-15

[62] Pivonello C,Negri M,Cariati F,Colao A.The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets.Infect Agent Cancer2014;9:27 PMCID:PMC4164328

[63] Hasskarl J,Schmid HA.Somatostatin receptors in non-neuroendocrine malignancies: the potential role of somatostatin analogs in solid tumors.Future Oncol2011;7:895-913

[64] Downward J.Targeting RAS signalling pathways in cancer therapy.Nat Rev Cancer2003;3:11-22

[65] Hwang YH,Kim S,Kim T,Lee B,Kim J.Over-expression of c-raf-1 protooncogene in liver cirrhosis and hepatocellular carcinoma.Hepatol Res2004;29:113-21

[66] Roberts PJ.Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.Oncogene2007;26:3291-310

[67] Caraglia M,Marra M,Venuta S.Targeting Raf-kinase: molecular rationales and translational issues.Ann Oncol2006;17:124-7

[68] Bousquet C,Vernejoul F,Buscail L.Somatostatin receptors and regulation of cell proliferation.Dig Liver Dis2004;36:S2-7

[69] Adams RL,Lindow SW,Atkin SL.Somatostatin receptors 2 and 5 are preferentially expressed in proliferating endothelium.Br J Cancer2005;92:1493-8 PMCID:PMC2362009

[70] Jia WD,Sun HC,Xu RN.Effect of octreotide on angiogenesis induced by hepatocellular carcinoma in vivo.Hepatobiliary Pancreat Dis Int2003;2:404-9

[71] Jia WD,Xu RN,Wang L,Wang J,Zhai ZM.Octreotide acts as an antitumor angiogenesis compound and suppresses tumor growth in nude mice bearing human hepatocellular carcinoma xenografts.J Cancer Res Clin Oncol2003;129:327-34

[72] Garcia de la Torre N,Turner HE.Antiangiogenic effects of somatostatin analogues.Clin Endocrinol2002;57:425-41

[73] Ristori C,Pavan B,Casini G,Dal Monte M.Adenylyl cyclase/cAMP system involvement in the antiangiogenic effect of somatostatin in the retina. Results from transgenic mice..Neurochem Res2008;33:1247-55

[74] Gao JH,Feng S,Lu YY,Liu R,Huang ZY,Yang JH,Tang CW.Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.Angiogenesis2016;19:501-11 PMCID:PMC5026725

[75] Lamberts SW,Hofland LJ.Somatostatin analogs in the diagnosis and treatment of cancer.Trends Endocrinol Metab2002;13:451-7

[76] Lattuada D,Crotta K,Franco P,Marelli O.Inhibitory effect of pasireotide and octreotide on lymphocyte activation.J Neuroimmunol2007;182:153-9

[77] Dalm VASH,Lamberts SW.Future clinical prospects in somatostatin/cortistatin/somatostatin receptor field.Mol Cell Endocrinol2008;286:262-77

[78] Pintér E,Szolcsányi J.Inhibitory effect of somatostatin on inflammation and nociception.Pharmacol Ther2006;112:440-56

[79] Chao TC,Chen MF.Somatostatin modulates the function of Kupffer cells.Reg Pept1997;69:143-9

[80] Valatas V,Manoussou P,Notas G,Kouroumalis EA.Secretion of inflammatory mediators by isolated rat Kupffer cells: the effect of octreotide.Reg Pept2004;120:215-22

[81] Zhu XD,Zhuang PY,Zhang W,Wu WZ,Tang ZY.High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma.J Clin Oncol2008;26:2707-16

[82] Wan S,Kryczek I,Welling TH.Myeloid cells in hepatocellular carcinoma.Hepatology2015;62:1304-12 PMCID:PMC4589430

[83] Wan S,Kryczek I,Sadovskaya A,Simeone DM,Welling TH.Tumor associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells.Gastroenterology2014;147:1393-404 PMCID:PMC4253315

[84] Sica A,Mantovani A.Macrophage plasticity and polarizationin liver homeostasis and pathology.Hepatology2014;59:2034-42

[85] Xidakis C,Valatas V,Mouzas I.Effect of octreotide on apoptosis-related proteins in rat Kupffer cells: a possible anti-tumour mechanism.Anticancer Res2004;24:833-41

[86] Eggert T,Ji J,Yevsa T,Medina-Echeverz J,Forgues M,Heikenwalder M,Zender L.Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression.Cancer Cell2016;30:533-47

[87] Li X,Yuan Y,Li B,Chu R,Xie D,Wang H.Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma.Gut2017;66:157-67

[88] Baeck C,Bartneck M,Heymann F,Hittatiya K,Luedde T,Tacke F.Pharmacological inhibition of the chemokine CCL2 (MCP-1) accelerates liver fibrosis regression by suppressing Ly-6C+ macrophage infiltration.Hepatology2014;59:1060-72

[89] Valatas V,Manousou P,Xidakis C,Kouroumalis E.Octreotide regulates CC but not CXC LPS-induced chemokine secretion in rat Kupffer cells.Br J Pharmacol2004;141:477-87 PMCID:PMC1574216

[90] Fujita T,Ito Y,Moniaga CS,Majima M.Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis.Hepatology2016;63:1325-39

[91] Fujita T.Roles of hepatic stellate cells in liver inflammation: a new perspective.Inflamm Regen2016;36:1 PMCID:PMC5721720

[92] Lang A,Fidder HH,Bar-Meir S.Somatostatin inhibits pro-inflammatory cytokine secretion from rat hepatic stellate cells.Liver Int2005;25:808-16

[93] Xidakis C,Manoussou P,Valatas V,Kouroumalis E.Production of pro- and anti-fibrotic agents by rat Kupffer cells: the effect of octreotide.Dig Dis Sci2005;50:935-41

[94] Pyronnet S,Najib S,Laklai H.Antitumor effects of somatostatin.Mol Cell Endocrinol2008;286:230-7

[95] Shaaban S,Ibrahim EE.Chemotherapeutic agents for the treatment of hepatocellular carcinoma: efficacy and mode of action.Oncol Rev2014;8:246 PMCID:PMC4419609

[96] Schindel DT.Hepatic resection enhances growth of residual intrahepatic and subcutaneous hepatoma, which is inhibited by octreotide.J Pediatr Surg1997;32:995-7

[97] Papalampros E,Filis K,Kourelis T,Bastounis E.Liver pathology and cell proliferation after octreotide administration following partial hepatectomy in rats: an experimental study.Dig Dis Sci2002;47:1953-8

[98] Hua YP,Liang LJ,Lai JM.The study of inhibition effect of octreotide on the growth of hepatocellular carcinoma xenografts in situ in nude mice.Zhonghua Wai Ke Za Zhi2005;43:721-5(in Chinese)

[99] Jia WD,Wang W,Li JS,Ren WH,Yu JH.A somatostatin analogue, octreotide, inhibits the occurrence of second primary tumors and lung metastasis after resection of hepatocellular carcinoma in mice.Tohoku J Exp Med2009;218:155-60

[100] Xie Y,Wang C.SOM230 combined with celecoxib prolongs survival in nude mice with HepG-2 xenografts.Cancer Biol Ther2011;12:86-92

[101] Tong H,Zhang CL,Wen SL,Wen FQ,Tang CW.Transcatheter arterial embolization followed by octreotide and celecoxib synergistically prolongs survival of rabbits with hepatic VX2 allografts.J Dig Dis2013;14:29-37

[102] Tong H,Zhang CL,Wen SL,Tang CW.Octreotide and celecoxib synergistically encapsulate VX2 hepatic allografts following transcatheter arterial embolisation.Exp Ther Med2013;5:777-82 PMCID:PMC3570131

[103] Borbath I,Abarca-Quinones J,Lebrun V,Sempoux C.Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide.Cancer Sci2007;98:1831-9

[104] Borbath I,Sempoux C,Desaege C.Efficacy of lanreotide in preventing the occurrence of chemically induced hepatocellular carcinoma in rats.Chem Biol Interact2010;183:238-48

[105] Borbath I.Chemoprevention of hepatocellular carcinoma. Proof of concept in animal models..Acta Gastroenterol Belg2011;74:34-44

[106] Abdel-Hamid NM,Nazmy MH,Thabet K.The effect of co-administration of Lawsonia inermis extract and octreotide on experimental hepatocellular carcinoma.Environ Health Prev Med2015;20:195-203 PMCID:PMC4434234

[107] Wang XX,Li M,Qiang O,Liu R.Effects of octreotide on hepatic glycogenesis in rats with high fat dietinduced obesity.Mol Med Rep2017;16:109-18 PMCID:PMC5482138

[108] Kouroumalis E,Thermos K,Moschandrea J.Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study.Gut1998;42:442-7 PMCID:PMC1727020

[109] Samonakis DN,Arnaoutis T,Leontidis C,Kouroumalis E.Treatment of hepatocellular carcinoma with long acting somatostatin analogues.Oncol Rep2002;9:903-7

[110] Patsanas T,Ilias A,Tzarou V,Kitis G.Octreotide in the treatment of inoperable hepatocellular carcinoma.Ann Gastroenterol2004;17:69-74

[111] Dimitroulopoulos D,Tsamakidis K,Andriotis E,Fotopoulou A,Bazinis A,Paraskevas E.Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial.World J Gastroenterol2007;13:3164-70 PMCID:PMC4436600

[112] Pan DY,Chen JW,Zhou YK.Tamoxifen combined with octreotide or regular chemotherapeutic agents in treatment of primary liver cancer: a randomized controlled trial.Hepatobiliary Pancreat Dis Int2003;2:211-5

[113] Gill ML,Sattar S.Treatment outcomes with long acting octreotide in inoperable hepatocellular carcinoma: a local experience and review of literature.J Pak Med Assoc2005;55:135-8

[114] Shah U,Allen J,Bernard S,Venook AP.A phase II study of long-acting octreotide in patients with advanced hepatocellular carcinoma and CLIP score of 3 or higher.Gastrointest Cancer Res2009;3:45-8 PMCID:PMC2684718

[115] Schöniger-Hekele M,Peck-Radosavljevic M.Octreotide treatment of patients with hepatocellular carcinoma--a retrospective single centre controlled study.J Exp Clin Cancer Res2009;28:142 PMCID:PMC2779805

[116] Raderer M,Kurtaran A,Valencak JB,Vorbeck F,Scheithauer W.Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide.Am J Gastroenterol1999;94:278-9

[117] Siveke J,Herberhold C.Complete regression of advanced HCC with long acting octreotide.Gut2003;52:1531 PMCID:PMC1773832

[118] Borbath I,Guiot Y,Sempoux C.Lanreotide treatment of metastatic hepatocellular carcinoma resulting in partial regression and more than 3 years of progression-free survival.Acta Gastroenterologica Belgica2012;75:270-3

[119] Treiber G,Rocken C,Malfertheiner P.Impact of biomarkers on disease survival and progression in patients treated with octreotide for advanced hepatocellular carcinoma.J Cancer Res Clin Oncol2006;132:699-708

[120] Li S,Shen Z.Characterization of somatostatin receptor 2 and 5 expression in operable hepatocellular carcinomas.Hepatogastroenterology2012;59:2054-8

[121] Liu Y,Mu Y.Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B-related hepatocellular carcinoma following octreotide long-acting release treatment.Oncology Lett2013;6:821-8 PMCID:PMC3789087

[122] Plentz RR,Kubicka S,Gebel M,Rudolph KL.Hepatocellular carcinoma and octreotide: treatment results in prospectively assigned patients with advanced tumor and cirrhosis stage.J Gastroenterol Hepatol2005;20:1422-8

[123] Montella L,Caraglia M,Guarrasi R,Palmeri A,Nocera V,Ariete M,Del Prete S.Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: a single center experience.Oncol Rep2008;20:385-90

[124] Jia W,Fan P,Yang S,Wei Q.Post-TACE combination therapy of heparin and octreotide results in decreased tumor metastasis in extrahepatic tumorigenesis.Cell Biochem Biophys2012;62:35-40

[125] Tong H,Chen S,Zhang MG,Huang ZH.Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study.Oncotarget2017;8:48303-12 PMCID:PMC5564648

[126] Prete SD,Caraglia M,Cennamo G,Piai G,Tarantino L,Palmieri G,Bianco M,Savastano C,Vincenzi B,D'Agostino A,Addeo R.Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR study..Cancer Chemother Pharmacol2010;66:837-44

[127] Caraglia M,Marra M,Montella L,Sperlongano P,Naviglio B,Abbruzzese A.Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR.Cell Death Dis2011;2:e150 PMCID:PMC3122065

[128] Rabe C,Allgaier HP,Strasser C,Sauerbruch T.Clinical outcome of a cohort of 63 patients with hepatocellular carcinoma treated with octreotide.Z Gastroenterol2002;40:395-400

[129] Yuen MF,Lai CL,Lo CM,Wong WM.A randomized placebo-controlled study of long-acting octreotide for treatment of advanced hepatocellular carcinoma.Hepatology2002;36:687-91

[130] Kouroumalis E,Sordilis P.Octreotide treatment of hepatocellular carcinoma.Hepatology2003;37:477

[131] Slijkhuis WA,Hassoun ZM,Kremers WK,Gores GJ.Octreotide therapy for advanced hepatocellular carcinoma.J Clin Gastroenterol2005;39:333-8

[132] Samonakis DN,Kouroumalis EA.Octreotide for unresectable hepatocellular carcinoma: beyond the first sight.J Clin Gastroenterol2006;40:86-7

[133] Cebon J,Hargreaves C,Thompson P,Roberts S,Scott AM,Garas G,Crawford D,Basser R,Macdonald G,Nowak A,Dhillon H,Australasian Gastro-intestinal Trials group (AGITG) and Ag0001H Investigators..Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide.Br J Cancer2006;95:853-61 PMCID:PMC2360532

[134] Verset G,Reynaert H,Langlet P,Peeters M,Francque S.Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study.Br J Cancer2007;97:582-8 PMCID:PMC2360361

[135] Becker G,Olschewski M,Blum HE.Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study.Hepatology2007;45:9-15

[136] Barbare JC,Bonnetain F,Lombard-Bohas C,Raoul JL,Lemoine A,Bronowicki JP,Cazorla S,Thevenot T,Bastie A,Bedenne L.Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a phase III multicentre, randomised, double blind placebo-controlled study.Eur J Cancer2009;45:1788-97

[137] Sanoff HK,Ivanova A,McRee AJ.Everolimus and pasireotide for advanced and metastatic hepatocellular carcinoma.Invest New Drugs2015;33:505-9 PMCID:PMC4487887

[138] Feun LG,Li YY,Richman SP,Savaraj N.Phase II trial of SOM230 (pasireotide LAR) in patients with unresectable hepatocellular carcinoma.J Hepatocell Carcinoma2018;5:9-15 PMCID:PMC5769585

[139] Ji XQ,Chen H,Li SH.Somatostatin analogues in advanced hepatocellular carcinoma: an updated systematic review and meta-analysis of randomized controlled trials.Med Sci Monit2011;17:RA169-76 PMCID:PMC3539608

[140] Bruix J,American Association for the Study of Liver Diseases..Management of hepatocellular carcinoma: an update.Hepatology2011;53:1020-2 PMCID:PMC3084991

[141] Xiong ZP,Lu MH.Association between insulin-like growth factor-2 expression and prognosis after transcatheter arterial chemoembolization and octreotide in patients with hepatocellar carcinoma.Asian Pacific J Cancer Prev2012;13:3191-4

[142] Qian J,Dong Z,Qiu L,Li S,Wang Z.Characteristics of hepatic IGF-II expression and monitored levels of circulating IGF-II mRNA in metastasis of hepatocellular carcinoma.Am J Clin Pathol2010;134:799-806