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Page 4 of 18 Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33

Functional data
Early preclinical studies have demonstrated that both natural SST and its synthetic analogues exert an
anti-proliferative effect in hepatoma cell lines [32,33] . In addition to proliferation, SSAs were shown not only
to decrease cells in the S-phase but most importantly to induce apoptosis in a dose-dependent manner in
HepG2 cells . These effects on proliferation and apoptosis were verified and correlated with the presence of
[15]
SST receptors in HCC cell lines. Apoptosis was significantly lower in normal hepatocytes .
[34]
In contrast with these studies, no influence of SSAs on either proliferation or apoptosis could be identified
in another study. However the migration of hepatoma cells (HepG2 and HuH7) was significantly reduced
after incubation with a selective SSTR1 agonist in Boyden invasion chambers. These findings may indicate a
reduced invasive capability of hepatoma cells attributable to the presence of SSTR1 .
[16]
Negative results on proliferation and apoptosis were also verified using a different cell line. Short-term
octreotide treatment of Bel-7402 cells did not affect cell proliferation and apoptosis. The SSTR2 protein level
was significantly decreased after exposure to octreotide . Different results were very recently obtained
[35]
using the same Bel-7402 cells. All SSAs tested increased cellular apoptosis but had no effect on cellular
proliferation while the effect on SSTRs expression was variable .
[36]
However in vivo experimental data have demonstrated that SST significantly inhibits tumor proliferation.
The same investigators, have convincingly shown that long-term SSA treatment effectively inhibited the
development and growth of HCC and improved survival rates, possibly through resensitization and
upregulation of SSTR2 and SSTR5 [35,36] .

A very interesting observation was reported by Xie et al. . While octreotide significantly enhanced apoptosis
[37]
on HepG2, no such response was observed in HepG2 cells transfected with the HBV X gene. Moreover the
expression of SSTR2 and SSTR5 was reduced in these cells. This may have therapeutic implications.

The role of HSCs/myofibroblasts in HCC has not been extensively investigated but early studies indicate that
they favor tumor progression producing hepatocyte growth factor [38,39] . SST or its SSAs have been reported
to influence hepatic stellate cells and indirectly the progress of HCC. Thus SST at nanomolar concentrations
was found to decrease rat HSC proliferation and increase apoptosis .
[40]
SST caused a significant decrease of collagens I and III production by activated rat HSCs without reduction
of cell proliferation thus implicating a direct action of somatostatin on HSC .
[41]
The effect of octreotide on cellular proliferation of isolated rat hepatic stellate cells was recently investigated in
our lab. The drug had no effect on proliferation but strongly inhibited procollagen production from activated
stellate cells. It also inhibited PDFG and TGFb1 dependent procollagen production probably through activation
of phosphotyrosine phosphatase (PTP) and phosphoserine-phosphothreonine phosphatase (STP) .
[24]
Mode of action
Octreotide is effective in inhibiting growth of HCC in vivo and in vitro . There are several potential
[42]
mechanisms through which SST and SSAs might inhibit HCC progress.

Cell proliferation and apoptosis
Despite the negative results mentioned before it is accepted today that SST and SSAs have a direct
antiproliferative effect on cancer cells via specific SSTRs. SSTRs 1, 4 and 5 modulate the MAP kinase
pathway and induce G1 cell cycle arrest . However, the cell cycle arrest mechanisms depend on the SSTR
[43]