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Sawayama et al. J Cancer Metastasis Treat 2018;4:10 I http://dx.doi.org/10.20517/2394-4722.2017.79 Page 9 of 15

A meta-analysis of nine studies (incorporating 1208 patients) was conducted to evaluate the relationship
between MMP-7 and GC prognosis. Higher MMP-7 expression is associated with deeper invasion [pooled
odds ratio (OR) = 3.20; 95% CI = 1.14-8.96; P = 0.026], higher TNM stage (pooled OR = 3.67; 95% CI =
2.281-5.99; P < 0.001), lymph node metastasis (pooled OR = 2.84; 95% CI = 1.89-4.25; P < 0.001), and distant
metastasis (pooled OR = 3.68; 95% CI = 1.85-7.29; P < 0.001), but not with histological grade. Higher MMP-
7 expression is associated with significantly shorter overall survival (HR = 2.01, 95% CI = 1.62-2.50, P <
0.001) [102] . Ten studies with 1478 patients were included to perform a meta-analysis of the survival results
to evaluate the relationship between MMP-9 and GC prognosis. Overexpression of MMP-9 tends to be
associated with lymph node metastasis (OR = 1.91, 95% CI = 1.40-2.59; P < 0.05) and presence of vascular
invasion (OR = 2.64, 95% CI = 1.52-4.59; P < 0.05). MMP-9 overexpression is associated with shorter overall
survival of GC patients (HR = 1.69, 95% Cl = 1.29-2.23; P < 0.001) [103] .

Many factors that stimulate MMP expression have been reported in diverse cancer cells, such as
[107]
[110]
interleukins [104-106] , epidermal growth factor , fibroblast growth factor [108,109] and NF-kB . IL-1alpha induces
MMP-1 in the stimulation of dermal fibroblasts of human melanoma cells [104] . MMP-9 and MMP-14 mRNA
levels are selectively increased in response to EGFR activity in ovarian tumor cells [107] . FGF and STAT3
(Ser-727) are involved in the signaling leading to MMP-7 expression in prostate cancer [109] . In GC, IL-17A
is involved in the pathology of inflammatory diseases and the tumor microenvironment. It could promote
the invasion of GC cells by activating the NF-kB pathway, and subsequently upregulating the expression
of MMP-2 and MMP-9 [106] . IL-10-stimulated macrophages also induce MMP-2 and MMP-9 activities in
gastric and colorectal cancer cell lines [105] . Overexpression of HER2 is also associated with MMPs. HER2
overexpression is not only closely associated with tumor growth but is also related to tumor invasion. HER2
knockdown results in the downregulation of the expression of MMP-9 [111] .

EXOSOMES IN THE TUMOR MICROENVIRONMENT
Previous studies demonstrated that CAFs and cancer cells communicate by secreting a variety of cytokines,
chemokines and ECM [112] . The mechanism underlying the communication among CAFs, NFs and cancer
cells has been investigated. Recent extracellular vesicle assessments have demonstrated that cancer cells
interact with the neighboring cells via soluble factors secreted into the extracellular space [113] . Extracellular
vesicles can be classified into three main types according to size and biogenesis: exosomes (30-100 nm),
microvesicles (100-1000 nm), and oncosomes (1-10 mm) [114] . These three extracellular vesicle types play roles
in cancer biology through vesicular transport.

Recent studies have demonstrated that exosomes are associated with GC progression and metastasis. GC
cell-derived exosomes induce injury of peritoneal mesothelial cells through apoptosis and mesothelial-to-
mesenchymal transition, resulting in mesothelial barrier destruction and peritoneal fibrosis. GC-derived
exosomes can facilitate peritoneal dissemination and a novel mechanism for GC peritoneal metastasis
has been identified [115] . Next-generation sequencing technology provides more complete data and allows
even deeper analyses of RNA transcriptomes. Exosomes from different GC cell lines and an immortalized
normal gastric mucosal epithelial cell line were extracted and the amounts of exosomal proteins and RNAs
were evaluated. According to the miRNA profiles of exosomes, miRNA-21-5p and miRNA-30a-5p were
two of the most abundant sequences [116] . In another study, exosomal miRNA profiles in peritoneal fluid of
peritoneal dissemination in GC were investigated. miRNA-21 was also identified as having the highest signal
intensity and another five miRNAs (miRNA-1225-5p, miRNA-320c, miRNA-1202, miRNA-1207-5p and
miRNA-4270) were identified [117] .

EGFR in exosomes secreted from GC cells can be delivered into the liver. The translocated EGFR on the
plasma membrane of liver stromal cells activates HGF. The upregulated paracrine HGF, which binds the
c-MET receptor on the migrated cancer cells, promotes liver metastases to favor the development of a