Endocrine Abstracts

JOINT1417

Liver cancer is the sixth most incident and third most lethal cancer type worldwide. Among its subtypes, hepatocellular carcinoma (HCC) is predominant, comprising 90% of the cases. The overall 5-year survival rate of HCC patients is still extremely low (20%), partially due to a high intra- and intertumoral heterogeneity that severely complicates systemic treatment (first line: immunotherapy, second line: tyrosine kinase inhibitors). Despite its known role as a (neuro)endocrine hub, classic (neuro)endocrine tumour profiling and approaches [i.e., somatostatin (SST) system receptor expression and ligand response] have been poorly explored in HCC, with limited and inconclusive results. For this reason, this study aimed to obtain a molecular and functional description of the SST system in HCC. To achieve this, we used 2 internal retrospective cohorts [Retrospective-1 (R1): HCC vs. non-tumoral adjacent tissue (NTAT) (n= 93); Retrospective-2 (R2): HCC vs. NTAT (n= 58), cirrhotic (n= 39) and healthy liver tissue (n= 5)], 6 in silico cohorts [GSE6764 (n= 65), GSE14323 (n= 107), GSE14520 (n= 247), GSE164760 (n= 141), CPTAC-PDC000198 (n= 165), TCGA-LIHC (n= 369)] and 4 human liver cell lines [healthy hepatocytes (THLE-2), hepatoblastoma (HepG2) and HCC (Hep3B, SNU-387)]. SST receptor (SSTR1-5) and ligand (SST, CST) expression was assessed by RT-qPCR (all models) and immunohistochemistry [IHC, subset (n= 25) of R1]. Cell lines were also employed to evaluate the expression of key neuroendocrine markers and SST receptor (SSTR) downstream effectors, in addition to their functional response to SSTRs natural ligands, classic analogues (octreotide, lanreotide, pasireotide) and novel agonists (BIM-23926, BIM-23120) by different in vitro assays (proliferation, colony and hepatosphere formation). HCC patient samples were characterised by a general SST system expression downregulation, which was linked to complex patterns of tumour aggressiveness through clinical variables (e.g., survival, recurrence, microvascular invasion and portal hypertension) and complemented by IHC staining results [positiveness of infiltrating immune cells (SSTR1, SSTR2) and vascular endothelia (SSTR5)]. Cell lines mimicked this expression pattern, where the highest SSTR expression was found in low (HepG2) and intermediate (Hep3B) aggressiveness liver cancer cells. Accordingly, antitumoral effects were observed among the different in vitro assays for octreotide, pasireotide, BIM-23926 and BIM-23120 in HepG2; all ligands except SST in Hep3B and SST and CST in SNU-387. These results could be explained through biased signalling by specific neuroendocrine markers and SSTR-downstream effectors profiles (e.g., CDH1 in Hep3B, AIP in SNU-387). In conclusion, our data suggests that the SST system is an intricate, yet exploitable source of informative biomarkers and individualised therapeutic options in HCC.