The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targetsReport as inadecuate

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Infectious Agents and Cancer

, 9:27

First Online: 20 August 2014Received: 14 November 2012Accepted: 23 June 2014DOI: 10.1186-1750-9378-9-27

Cite this article as: Pivonello, C., De Martino, M.C., Negri, M. et al. Infect Agents Cancer 2014 9: 27. doi:10.1186-1750-9378-9-27


Hepatocellular carcinoma HCC is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin SST pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors SSTRs are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument.

This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.

KeywordsGH-IGF1 axis Somatostatin Somatostatin receptors Normal liver Hepatocarcinogenesis Hepatocarcinoma AbbreviationsAFPalpha-fetoprotein

AKT-PKBprotein kinase B

ALSacid-labile subunit protein

CSCcancer stem cells



ECendothelial cell

EGFRepidermal growth factor receptor

ERKextracellular signal-regulated kinases


GHgrowth hormone

GHBPgrowth-hormone binding protein

GHRgrowth hormone receptor

GHRHgrowth-hormone-releasing hormone


HCChepatocellular carcinoma

HSChepatic stellate cell

HSPGheparansulfate proteoglycans

IGF1insulin-like growth factor 1

IGF1Rinsulin-like growth factor 1 receptor

IGF2insulin-like growth factor 2

IGF2Rinsulin-like growth factor 2 receptor

IGFBPinsulin-like growth factor binding protein


IRinsulin receptor

IRSinsulin receptor substrate

JAKjanus kinase protein

KCKupffer cell

LARlong-acting release

LDLlow-density lipoprotein

LPLlipoprotein lipase


MAPKmitogen-activated protein kinase


mTORmammalian target of Rapamycin

NAFLDnon-alcoholic fatty liver disease

NETneuroendocrine tumours

PARPpoly ADP-ribose polymerase

PBMCperipheral blood mononuclear cells

PETpositron emission tomography

PI3Kphosphatidylinositol 3-Kinase

QoLquality of life

Rbretinobloastoma gene

SAsomatostatin analogue

SRslow release


SSTRsomatostatin receptor

STATsignal transducers and activators of transcription

TACEtransarterial chemoembolisation

TGFtransforming growth factor

TNFtumour necrosis factor

VEGFvascular-endothelial growth factor


Electronic supplementary materialThe online version of this article doi:10.1186-1750-9378-9-27 contains supplementary material, which is available to authorized users.

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Author: Claudia Pivonello - Maria Cristina De Martino - Mariarosaria Negri - Gaia Cuomo - Federica Cariati - Francesco Izzo - Annam


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