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


               Table 1. The association between the tumor microenvironments and survival of GC patients
               Factors            Marker         HR      95% CI      P value   Year         Journal
               CAFs
                             IL1A, IL1B and TNF  1.41    1.11-1.78   0.004     2017   Gastroenterology [63]
               BMDCs
                             CD271               1.82    1.08-3.07   0.025     2015   Br J Cancer [20]
               TILs
                             CD3+ TILs (intra-tumoral)  0.52  0.43-0.63  < 0.001  2017  Oncotarget [28]
                             FOXP3+ TILs (intra-tumoral)  1.57  1.04-2.37  0.033
                             FOXP3+ TILs (extra-tumoral)  0.76  0.60-0.96  0.022
               TAMs
                             Total TAM           1.71    1.19-2.45   0.004     2016   Genet Mol Res [41]
                             M1 macrophage       0.46    0.33-0.65   < 0.001
                             M2 macrophage       1.71    1.39-2.09   < 0.001
               Chemokines
                             CXCR4               2.63    1.69-4.09   < 0.001   2014   Tumour Biol [74]
                             CXCL12              2.08    1.31-3.33   0.002     2017   Br J Cancer [73]
               MMPs
                             MMP-2               1.92    1.48-2.48   < 0.001   2014   Cancer Biother Radiopharm [101]
                             MMP-7               2.01    1.62-2.50   < 0.001   2015   PLoS One [102]
                             MMP-9               1.69    1.29-2.23   < 0.001   2014   Hepatogastroenterology [103]
               GC: gastric cancer; HR: hazard ratio; CI: confidence interval; CAF: cancer associated fibroblast; IL: interleukin; TNF: tumor necrosis
               factor; BMDC: bone marrow-derived cell; TIL: tumor-infiltrating lymphocyte; TAM: tumor-associated macrophage; MMP: matrix
               metalloproteinase


               liver-like microenvironment [118] . GC cell-derived exosomes stimulate the activation of the NF-kB pathway
               in macrophages, which promotes cancer progression in the tumor microenvironment [119] . The expression
               of miRNAs in exosomes of the peripheral blood has been investigated. High expression of miRNA-221 is
               associated with poor clinical prognosis in GC patients. Exosomes originating from BMDCs, which were
               transfected with miRNA-221 mimics, promote proliferation, invasion, migration and adhesion to the matrix
               of GC cell lines [120] . CD97 knockdown reduces the metastatic capacity of GC cells. Exosomes or conditioned
               medium from the SGC-L cells (GC cell line) activate proliferation and invasion as compared with that from
               SGC-L/CD97-knockdown cells. Exosomal CD97 is associated with CD55, CD44v6, a5b1 and CD31, and the
               exosome-dependent CD97 plays a role in premetastatic niche formation [121] .


               Investigating exosomal miRNA secretion provides novel insight into communication among
               microenvironments of cancer cells. Dysregulation of miRNAs in CAFs, NFs and cancer cells can affect the
               secretory phenotype of cancer cells.


               CONCLUSIONS AND PERSPECTIVE
               This review describes the importance of the microenvironment of GC for cancer progression and metastasis.
               Major components of the microenvironments of GC consist of BMDCs, TILs, TAMs and CAFs. GC cells
               are also affected by these components, with chemokines and miRNA in extracellular vesicles such as the
               exosome. The accumulation of BMDCs is associated with Helicobacter pylori infection. Cytokines and growth
               factors secreted by BMDCs lead to cancer progression and metastasis. The amount of CD3+ TILs in the
               intra-tumoral compartment is the most significant prognostic marker. PD-L1 expression was significantly
               associated with the prognosis of GC patients owing to the interaction between PD-L1 and TILs.  Increased
               levels of total TAM and M2 macrophage infiltration in GC patients are associated with worse overall survival.
               In contrast, elevated M1 macrophage density is associated with better overall survival. M2 macrophages
               might activate PD-L1 expression in tumor cells. Interleukins and miRNAs produced by CAFs are associated
               with cancer progression and metastasis of GC cells. CXCR4 and CXCL12 are associated with prognosis of
               GC patients.  CXCL12 strongly activates the Akt pathway and upregulates the expression of MMP-2 and
               MMP-7 to assist EMT. These MMPs are capable of degrading ECM proteins and trigger the loss of the
               basement membrane.
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