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Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33 Page 7 of 18

Kupffer cells was reversed by octreotide as a down-regulation of pro-apoptotic and an early increase of anti-
apoptotic molecules were demonstrated .
[85]

Another important function of liver associated macrophages is mediated through the production of
chemokines and their actions on their receptors. The co-operation of CCR2 bearing macrophages and T cells
results in the clearance of senescent hepatocytes, thus preventing HCC development. In case of established
HCC, however, recruitment of CCR2 positive macrophages leads to accumulation of suppressive TAMs
resulting in tumor progression due to the inhibition of CD8 T lymphocytes and natural killer cells . CCL2
[86]
is highly expressed and is a prognostic factor in HCC. Inhibition of CCL2/CCR2 signaling suppressed liver
tumor in experimental animals through activation of T cell anti-tumor response as expected .
[87]
CC chemokines and particularly CCL2 (MCP-1) are also involved in the progression of liver fibrosis .
[88]
Kupffer cells were shown to secrete large amounts of CC chemokines (MCP-1, Rantes) and CXC chemokines
(IL-8, MIP-2) after LPS stimulation. Octreotide inhibited only CC chemokines but not CXC chemokine
secretion, an effect mediated by PI3-kinase. Therefore inhibition by octreotide of CC chemokines and
specifically MCP-1 will lead to reduced HCC growth both directly inhibiting the accumulation of tumor
suppressive macrophages and indirectly reducing fibrosis. Whether modifications of macrophage micro-
environment influence HCC progression remains to be elucidated .
[89]

Strictly speaking, although hepatic stellate cells are not members of the innate immune system, they
may participate in inflammation producing pro-inflammatory molecules [90,91] . Somatostatin inhibited the
secretion of the pro-inflammatory cytokines IL-1beta and IL-8 from rat liver stellate cells .
[92]
Indirect anti-neoplastic effect through modulation of fibrosis
Most HCCs are developed in a cirrhotic background. As mentioned before, SST has a profound effect
on hepatic stellate cells reducing collagen I and III production and also procollagen production through
activation of phosphotyrosine (PTP) and phosphoserine-phosphothreonine (STP) phosphatases without
affecting stellate cell proliferation. A direct action of SST on stellate cells has been proposed [16,21] .

Moreover SST may influence fibrosis through its action on Kupffer cells augmenting matrix degradation.
Kupffer cells produce large amounts of MMP1 (the enzyme responsible for native collagen degradation),
and lipopolysaccharide activation induces a significant early increased production of MMP1. Octreotide
had a synergistic effect with lipopolysaccharide on MMP1 secretion. In addition lipopolysaccharide and
octreotide, alone or in combination, induced a significant inhibition of the large amounts of TGF-b1
produced by unstimulated Kupffer cells. Inhibition of TGFb1 implied that SST may also indirectly influence
stellate cells and liver fibrosis . Some of the anti-tumoral actions of SST have been reviewed [94,95] . Figure 1
[93]
summarizes the cellular pathways of SST actions in HCC.

In vivo animal data
In an earlier report, HCCs were developed after implantation of Morris hepatoma cells in rats. Partial
hepatectomy enhanced tumor progress, but treatment with octreotide inhibited the growth of the tumor .
[96]
Similarly octreotide was shown to inhibit liver regeneration after partial hepatectomy .
[97]
Subsequent studies from China have corroborated these results using the nude mice HCC xenograft model
and octreotide administration. Tumor weights were significantly reduced, the growth was inhibited and
secondary primaries and lung metastases were also decreased. More importantly, survival of the treated
animals was significantly prolonged [98,99] . Recent studies reported on the effect of a combination of a COX 2
inhibitor with an SSA. They have demonstrated that the combination had an anti proliferative effect but
most importantly it suppressed the metastasis of HCC in nude mice . Moreover the same combination
[100]