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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 7 of 15

[67]
tensin homolog . In CAFs, miRNA-143 overexpression is derived from diffuse type GC compared with
NFs. miRNA-143 promotes GC cell invasion by regulating the expression of collagen type III in CAFs,
[68]
and miRNA-143 expression serves as a prognostic marker of GC . The expression of miRNA-200b is
downregulated by CAFs. miRNA-200b downregulates zinc finger E-box-binding homeobox expression and
[69]
upregulates E-cadherin expression in GC cells to repress tumor cell invasion and peritoneal dissemination .
Expression of miRNA-328 mediated by macrophages regulates CD44 signaling and may promote tumor
[44]
progression by enhancing ROS defense .
At least 20% of CAFs originate from the bone marrow and are derived from MSCs. Those MSC-derived
CAFs were recruited to the tumor in a TGF-b- and stromal-derived factor (SDF)-1a-dependent manner in
mouse models of inflammation-induced gastric dysplasia (21316604). SDF-1a produced by myofibroblasts
promotes gastric epithelial proliferation, partly through CXCR4-positive gastric tissue stem progenitor
[11]
cells, and plays a key role in gastric carcinogenesis . CXCL12 is also associated with CAF-induced cancer
progression. CXCL12 and Twist1 expression are correlated in CAFs present in gastric tumor specimens.
Ectopic expression of Twist1 in NFs suppresses premature senescence, whereas Twist1 attenuation accelerates
senescence in CAFs [70,71] .

Interleukins and miRNAs produced by CAFs are associated with cancer progression and metastasis of GC
cells. Interactions between cancer cells and CAFs with interleukins or miRNAs can have a substantial impact
on tumor characteristics and alteration of signaling pathways associated with proliferation and invasion of
GC cells.

CHEMOKINES
Fibroblasts are a major component of the tumor stroma, and activated fibroblasts regulate solid tumor
progression. The interaction between cancer cells and CAFs by chemokines has been suggested to be
important for the progression of GC. Chemokines, more than 40 of which have been identified, are
8-10-kDa secreted proteins with 20%-70% homology in structure. They share the common functional activity
as being chemotactic for leucocytes. Pro-inflammatory stimuli, such as IL-1, TNF-a, lipopolysaccharide
or pathogens produce inflammatory chemokines, which determine the migration of inflammatory cells.
Chemokines bind to G protein-coupled receptors on leukocytes and stem cells, and they function through
guanine nucleotide-binding proteins to control intracellular signaling that promotes the migration ability
[72]
toward the chemokine source .
CXCR4 and CXCR7 are important chemokine receptors that share the same ligand CXCL12. The association
of CXCR4 and CXCL12 with GC patient prognosis was evaluated in a meta-analysis [CXCR4; 13 studies (n
= 1936 patients) and CXCL12; 38 studies (n = 5807 patients)]. High expression of CXCL12 is associated with
[73]
reduced overall survival in GC patients (HR 2.08; 95% CI = 1.31-3.33; P = 0.0002) . CXCR4 expression is
[74]
associated with shorter overall survival (HR 2.63; 95% CI = 1.69-4.09; P < 0.001) .

Many studies have demonstrated that CXCR4 is the major chemokine receptor expressed in diverse cancer
[75]
cells . Previous studies had shown that the CXCL12/CXCR4 axis plays an important role in invasion and
metastasis. CXCL12, which is a ligand for CXCR4, activates the CXCR4 and attracts circulating CXCR4-
expression cells to peripheral tissues by regulating a wide variety of downstream signal pathways related
[76]
to proliferation, migration, chemotaxis and cell survival . CXCR4 levels in GC are also significantly
higher than those in the normal mucous membrane. CXCR4 expression is significantly related to poor
differentiation, high tumor stage and lymph node metastasis [77,78] . CXCR4 activates actin polymerization
[79]
to induce cell motility and the EMT after binding its ligand CXCL12 . CXCL12 rapidly and strongly
phosphorylates Akt. Mammalian target of rapamycin (mTOR) pathways, which are located downstream of
Akt, activate p70S6K (S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). CXCL12/CXCR4