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Page 8 of 15 Sawayama et al. J Cancer Metastasis Treat 2018;4:10 I http://dx.doi.org/10.20517/2394-4722.2017.79

activation also mediates integrin b1 clustering at the cell surface and promotes the invasive ability of GC
[81]
[80]
cells . In addition, CXCL12/CXCR4 upregulates the expression of MMP-2 and MMP-7 to assist EMT .
Runt-related transcription factor 2 (RUNX2) directly binds to the promoter region of the gene coding
area for the chemokine receptor CXCR4 to enhance its transcription, as well as that of CXCL12. RUNX2
is a regulator of embryogenesis and development, and promotes the invasion and metastasis of GC by
[82]
transcriptionally upregulating the chemokine receptor CXCR4 .
CXCR7 is expressed in embryonic neuronal and heart tissue, some hematopoietic cells, and the activated
[83]
endothelium . It is a receptor specific to SDF-1, and SDF-1 expression is strongly chemotactic for
[84]
lymphocytes. It is also associated with lymph nodes in GC patients . CXCR7 expression is upregulated
[85]
in GC tissues. Overexpression of CXCR7 promotes cell proliferation, migration and invasion and it is
[86]
associated with peritoneal dissemination and poor prognosis .
Other chemokine receptors are also associated with GC progression and survival. CXCR1 is a class-A,
rhodopsin-like G-protein-coupled receptor, which takes charge of cellular signal transduction and is targeted
[87]
as a drug receptor . CXCR1 functions as a high-affinity receptor for IL-8, which is a major mediator of
[88]
inflammatory responses and tumorigenesis . High expression of CXCR1 is associated with poorer overall
survival in stage II and III GC patients. Importantly, stage II GC patients with higher CXCR1 expression have
been shown to significantly benefit from 5-fluorouracil (5-FU) based adjuvant chemotherapy [89,90] . CXCR2
expression strongly correlates with CXCR4 expression. CXCR2 expression changes according to the activity
[91]
of CXCR4 signaling. CXCR4 and CXCR2 cross-activate each other to promote the metastasis of GC . The
co-expression of CXCR2 and IL-22 receptor 2 is associated with poor prognosis in GC. CXCR2 is involved in
[92]
complex mechanisms and roles, and indicates a poor outcome in GC .
Analysis of the expression levels of CXCR4 and CXCR7 revealed that these chemokine receptors are
associated with the activation of the oncogenic pathway in GC. CXCL12, which is the ligand of CXCR4 and
CXCR7 chemokines, is associated with poor prognosis in GC patients.

MATRIX METALLOPROTEINASES
MMPs are a family of endogenous calcium- and zinc-dependent proteolytic enzymes. Cancer cells in a
microenvironment escape from the primary lesion through the surrounding ECM and intravasate into the
lumina of blood vessels during metastatic progression. MMPs probably contribute to metastasis by secretion
[93]
of pro-angiogenic and ECM-remodeling factors . MMPs are capable of degrading ECM proteins and drive
the loss of the basement membrane. The activation of MMPs and urokinase-type plasminogen activator
[94]
(uPA) are required for expression of transcription factor Snail-1, which finally inhibits E-cadherin .
MMPs degrade most ECM components, and regulate other enzymes, chemokines and even cell receptors.
[95]
Twenty-three types of MMPs have been described so far . MMP-7, named matrilysin, is a distinct family
member with proteolytic activity against a wide range of biomolecules including proteoglycans, laminin,
fibronectin, casein and, more importantly, basement membrane collagen type IV. It is recognized as pivotal
[96]
in the MMP family because it activates other MMPs (e.g. MMP-2 and MMP-9) for ECM degradation and
[97]
possesses the highest activity in the MMP family . MMP-7 regulates the activity of other biomolecules and
MMP-7 degrades ECM protein. MMP-7 may play a central role in the stromal invasion of GC cells during
[99]
[98]
the formation of peritoneal dissemination . MMP-9 is known as type-IV collagenase or gelatinase B .
Systematic reviews and meta-analyses have demonstrated the prognostic effects of MMP2, MMP7 and
MMP9 in GC patients [100] . A meta-analysis of 10 studies (incorporating 1669 patients) was conducted to
evaluate the relationship between MMP-2 and GC prognosis. Overexpression of MMP-2 is associated with
TNM stage, depth of invasion, lymph node metastasis and distant metastasis. Overexpression of MMP-2
significantly predicts poor overall survival of GC patients (HR = 1.92, 95% CI = 1.48-2.48; P < 0.001) [101] .