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Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33 Page 3 of 18

distribution patterns. Membrane binding sites for SST were mainly of the SSTR3 and SSTR5 types, with
a weak SSTR2 binding . Later, we demonstrated the presence of SSTR2 and SSTR5 in another hepatoma
[18]
cell line, the Hep3B cells . Importantly we have also demonstrated that HepG2 cells express cortistatin
[19]
and we attributed the SSTRs internalization to the endogenous production of cortistatin . Cortistatin is
[18]
a 17-aminoacid peptide with high affinity to all somatostatin receptor subtypes . Internalization of SST2
[20]
receptors after octreotide administration has also been reported in neuroendocrine tumors .
[21]
Liver stellate cells (HSCs)
[22]
Activated rat hepatic stellate cells were reported to express SSTR subtypes 1, 2, and 3 , while another
report found all five SSTRs in HSCs, at both the protein and mRNA level . Using a different approach,
[16]
the expression of SSTR2, SSTR3 and SSTR5, but not SSTR1 and SSTR4, was demonstrated by confocal
microscopy in rat HSCs. The mRNA expression level of SSTR2 was much higher than the other subtypes .
[23]
We have recently shown that quiescent HSCs (day 0 or day 3) do not express SSTRs by immunocytochemistry
or western blot. However at day 7, SSTRs 1, 2A, 2B, 3 and 4 started to appear in some cells activated by
adherence to plastic but only after day 10, all cells were positive for SSTRs 1, 2A, 2B, 3 and 4. Therefore, whatever
the effect of somatostatin might be on these cells, it is not evident from the beginning of any experiment .
[24]

Kupffer cells
In contrast to HSCs, quiescent rat Kupffer cells were shown to express mRNA of SSTR 1-4. However
immunocytochemistry identified only the presence of internalized SSTR 3 and SSTR4 receptors. Western
blotting on the other hand detected SSTR2 and SSTR2a. Thus it seems that in quiescent cells the detection
of SSTRs depends on the method used. Moreover Kupffer cells were found to express both somatostatin
and cortistatin, a finding that may explain the internalized receptors. Stimulation of the cells with
lipopolysacharide activated the expression of SSTR2, SSTR3 and SST4 [25,26] .

SST receptors in HCC tissue
Somatostatin receptors were identified in 41% of HCC in an earlier report on the presence of regulatory
peptides receptors in HCC. These receptors showed high affinity for both natural somatostatin and
octreotide . This observation was verified and further extended. Cirrhotic livers and HCC expressed all
[27]
five SSTRs both at the protein and mRNA levels, but normal livers were negative for all SSTRs . Moreover,
[16]
it seems that all HCCs do not display similar expression patterns for SSTRs. Expression rates as high as
75% for SSTR5 and as low as 41% for SSTR2 were demonstrated while SSTR4 was absent. There was no
correlation between SSTR expression and tumor stage or underlying liver disease . Higher overall rates
[28]
of all SST receptors were reported in both HCC and cirrhosis in a report from China. In contrast with the
previous study, high expression of SSTR4 was also identified. The protein levels of receptors were markedly
higher in HCC than in cirrhosis. Moreover there was a strong correlation of all receptors with serum AFP
levels . A high 67% expression of SSTR2 was also shown but there was no correlation with tumor molecular
[29]
characteristics including tumor suppressor genes . Very high expressions of SSTR1 and SSTR5 were also
[30]
reported in a recent study of 41 liver biopsies .
[31]
On the contrary, a recent report from Germany found very low overall rates (8%-15%) of weak SSTRs expression
in the tissue of patients with either cirrhosis or HCC. It should be stressed however that all but two of their
patients had alcohol-related disease. This is important when therapeutic implications are concerned .
[17]

Thus, the available literature indicates variable expression of SSTR subtypes in both hepatoma cell lines and
liver tissue from cirrhotic and HCC patients. This may be due to different methodologies, different etiologies
of cirrhosis and HCC or different molecular events leading to HCC. Nonetheless SSTRs are expressed in a
significant proportion of HCC and may therefore be a potential therapeutic target. This is further supported
by functional data.