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Page 6 of 18 Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33

Pasireotide, a somatostatin analogue with high affinity for all SSTRs except SSTR4, is a more potent inhibitor
of IGF1 than octreotide . It is noteworthy that the GH-IGF system is connected with the important role of
[63]
Raf/MEK/ERK, one of the signaling cascades stimulated by IGF1R in experimentally induced apoptosis of
hepatoma cell lines and possibly explains why the Ras gene is activated in 30% of HCCs while its substrate
[64]
RAF kinase is over-expressed in many HCCs . The same pathway is activated by other growth factors
[65]
known to be over-expressed in HCC like PDGF, EGF and TGFa [66,67] .
SST also inhibits the secretion of other hormones (gastrin, glucagon, insulin) which have been shown to
be trophic factors for cancer cells but their significance in hepatocellular carcinoma evolution has not been
elucidated [7,68] .

Direct inhibition in vivo and in vitro of angiogenesis
Neo-angiogenesis is a vital process allowing tumors to grow and metastasize . The SSA octreotide was
[69]
able to inhibit angiogenesis induced by HCC in vivo . In nude mice with an implanted hepatocellular
[70]
carcinoma, octreotide showed a strong anti-angiogenic activity . Available evidence suggests that SSAs
[71]
inhibit angiogenesis either directly through somatostatin receptors on endothelial cells or indirectly through
the inhibition of vascular endothelial growth factor (VEGF) or via inhibition of adenylyl cyclase [7,72,73] .
Recently, a combination of celecoxib and octreotide was found to have a potent anti-angiogenetic activity
by decreasing the phosphorylation of the integrated signaling pathways of p-ERK kinase-HIF-1a (hypoxia-
inducible factor-1a)-VEGF . This combination has been tried in hepatocellular carcinoma as analyzed in
[74]
the relevant section.

Antineoplastic effect via immune modification - innate immunity
SST and SSAs may exert an anti-tumor activity through modulation of immune pathways. More data are
required in this field [75-77] . Many studies have been focused on the effects of somatostatin on the innate
component of immunity and in particular on inflammation and oxidative stress. Reduced secretion of
reactive oxygen species by macrophages after incubation with SST has been reported . More specifically for
[78]
the liver, the amount of hydrogen peroxide released by Kupffer cells treated with SST was reduced compared
to controls. Moreover SST also reduced production of nitric oxide and TNFa by Kupffer cells .
[79]
We have verified that octreotide reduces TNFa and NO production by Kupffer cells decreasing iNOS
activity probably through an interference with phosphatidylinositol 3-kinase pathways. Like most, if
not all cancers, HCC has an inflammatory component. SST may therefore inhibit the growth of HCC
by reducing inflammation. In this respect we showed that rat Kupffer cells treated with octreotide
produced reduced amounts of the pro-inflammatory cytokine IL-12 and increased amounts of the anti-
inflammatory IL-13 .
[80]
Macrophages are deeply involved in HCC pathogenesis through other mechanisms as well. Myeloid
cells, including tumor-associated macrophages (TAMs) have been identified in large numbers in HCC
microenvironment and are often associated with poor prognosis [81,82] .

During induction of HCC, there is an increased production of IL-6 and TGFb1 by macrophages leading to
activation of STAT3 and progression of the tumor . At the same time, predominant activation of STAT3
[83]
leads to an M2 macrophage polarization . M2 cells are involved in polarized Th2 responses and to tumor
[84]
progression and immunoregulation . TGFb1 production by Kupffer cells is reduced by octreotide in vitro,
[82]
therefore the polarization of liver resident macrophages towards the M2 phenotype may be reduced as
well . We have also proposed that the antitumor effect of octreotide in HCC may in part be explained by its
[85]
antiapoptotic effect on Kupffer cells. Using caspase3 mRNA as an index of apoptosis, we measured pro-and
antiapoptotic molecules in Kupffer cells after incubation with octreotide. The increased apoptosis of cultured