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Terai et al. The liver and metastatic uveal melanoma

the liver are still highly speculative. It is assumed that Chromosomal and genetic abnormalities
multiple factors contribute to development of metastasis UM has unique genetic abnormality profiles compared
and growth of UM cells in the liver. The proposed to cutaneous melanoma (CM). Mutation of BRCA1-
mechanisms are summarized as follows. associated protein 1 (BAP1), located on chromosome
3p21, was frequently identified in metastatic UM [19-21] .
Slow hepatic blood circulation Particularly, it was reported that BAP1 mutation in UM
The liver sinusoids are located at a confluence of cells may cause the liver tropism [22] . However, this
arterial (hepatic artery) and venous (portal vein) might be an over-simplified explanation for the liver
blood, mixing the oxygen-rich blood from the hepatic tropism as a certain fraction of metastatic UM retained
artery and the nutrient-rich blood from the portal vein. their BAP1 expression and monosomy 3 is not always
They are a type of capillary-like blood vessels with seen in hepatic metastasis. Polysomy 8q is rather
fenestrated, discontinuous endothelium. Slow flow a common feature of metastatic UM, and the role of
in the liver sinusoids maximizes the contact between this chromosomal abnormality on hepatic metastasis
hepatic cells and pathogenic molecules to filter them should be further explored [23,24] .
prior to circulation. The slow and tortuous sinusoidal
blood flow can trap UM cells in the liver [13,14] . The expression of adhesion molecules in the
sinusoid
Interaction between chemo-attractants and Vascular cell adhesion molecule-1 (VCAM-1) is
their receptors expressed on sinusoidal endothelial cells and might
The chemokines produced in the liver might attract UM trap tumor cells in slow blood flow [13,25] . VCAM-1 is
cells to the liver and interact with chemokine receptors expressed on endothelial cells under inflammatory
on their surface. A typical example is the interaction conditions, and mediate rolling and adhesion of various
between CXCR4 and its ligand CXCL12 that is rich subsets of leukocytes as well as tumor cells for the
in the liver [15] . Primary UM cell lines express CXCR4. recruitment and settlement of these cells from the blood
Blockage of CXCR4 on UM significantly reduced stream. In animal models, partial-hepatectomy induced
migration to human liver extract [16] . An alternative expression of inflammatory cytokines such as tumor
explanation for chemokine-related liver tropism is the necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 as
loss of chemokine receptors in the liver. It has been well as the expression of VCAM-1 and facilitated liver
reported that extracts from the liver down-regulated metastasis [26] . Endothelial cell expression of VCAM-1
the expression of CXCR4 and CCR7 on primary UM showed adhesion of human malignant melanoma cells
cell lines [16] . Retention of UM cells in the liver may not that expressed very late activation antigen-4 (VLA-4)
solely be related to a chemokine gradient toward the on their surface [27] .
liver, but could also be related to the loss of chemokine
receptors once melanoma cells reach the liver. Angiogenesis factors rich in the liver
IL-8 and vascular endothelial growth factor (VEGF) are
Another example is c-Met, a receptor for hepatocyte rich in the liver and could promote the angiogenesis of
growth factor (HGF). c-Met-expressing UM cells tumor in the liver microenvironment [28] . Hepatic stellate
interact with HGF produced in the liver [14] . Primary cells (HSCs) in the tumor stroma predominantly produce
UM cells that metastasized had higher levels of c-Met IL-8, and neutralizing IL-8 with antibody dramatically
expression than tumors that did not metastasize. The reduces angiogenic effects [28] . IL-8 also induces the
expression of c-Met in the primary UM specimens expression of VEGFR2 and VEGF on endothelial cells
significantly increased the risk of subsequent liver through NFkB activation, and mediates autocrine and
metastasis [14] . paracrine stimulation of vascular endothelium.
Growth factors rich in the liver Immuno-modulatory microenvironment
The insulin-like growth factor-1 (IGF-1) plays a major As stated in the following section, the liver is considered
[29,30]
role in tumor transformation, maintenance of malignant to be an immuno-modulatory organ and this
phenotype, promotion of cell growth, and prevention immunologically complex microenvironment could
of apoptosis. It is mainly produced in the liver. High promote tumor metastasis and growth in the liver.
expression of IGF-1 receptor (IGF-1R) has been
detected in UM hepatic metastasis specimens [17] . IMMUNOLOGICAL ASPECTS OF THE LIVER
The association between the expression of IGF-1R IMMUNE MICROENVIRONMENT
on tumors and the progression of UM also has been
reported [18] . Additionally, HGF could facilitate the The liver has acomplex immune microenvironment.
growth of c-Met-expressing UM cells in the liver. It is continually exposed to foreign pathogens such

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