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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 3 of 15

[13]
pathway may play a major role in the ability of infected epithelial cells to induce BMDC migration .
Bone marrow-derived myofibroblasts secrete high levels of murine IL-6 and hepatocyte growth factor
(HGF), which activate transforming growth factor-b1 (TGFb1) and signal transducers and activators of
transcription (STAT3) in GC cells. Bone marrow-derived myofibroblasts that increase IL-6/HGF and cancer
cell-derived TGFb1 mediate the interactions between bone marrow-derived myofibroblasts and GC cells,
[14]
which regulate promotion of tumorigenesis and cancer stemness . NF-kB is regulated by miRNAs. miRNA-
155-5p downregulation induces BMDCs to acquire a GC mesenchymal stem cell (MSC)-like phenotype.
The function depends on NF-kB p65 activation. This mechanism is the cancer associated MSC remodeling
[15]
in the tumor microenvironment . The association between BMDCs and chemokines has been analyzed
to evaluate the chemotaxis-stimulating factor from diffuse-type GC cells using BMDCs in an in vitro assay.
CXCL1 from GC cells stimulates the recruitment of BMDCs into tumor stroma via CXCR2 signaling of
[16]
BMDCs .
Some markers, including CD13, CD15, CD73, CD140b, CD144, CD146, CD164 and CD271, have been used
to identify MSCs [17,18] . Neural crest nerve growth factor receptor (CD271) was reported as a marker of bone
marrow-derived stromal cells [18,19] . The role of bone marrow-derived stromal cells expressing CD271 has
been evaluated in GC patients. CD271 expression in stromal cells is significantly associated with macroscopic
type-4 cancers, diffuse type tumors and depth of invasion. In one study, patients (n = 279) with CD271-
[20]
positive stromal cells had a worse prognosis than patients with CD271-negative stromal cells .
Some studies have demonstrated that the interaction between BMDCs and GC cells is an important factor in
cancer development and progression and may be associated with the survival of GC patients.

MAST CELLS
MCs play an important role in immunity and defend the body against viruses and bacteria. MCs are also
known for causing uncomfortable symptoms due to their release of histamine and other mediators which
cause allergic responses. MCs constitute a long-lived, heterogeneous cellular population originating from
[21]
the bone marrow . Mast cell density (MCD) in GC was found to be higher than that in the control.
Moreover, MCD in well-differentiated adenocarcinoma was higher than that in poorly-differentiated
[22]
adenocarcinoma . MCs were recognized by their modulatory activities in inflammation and angiogenesis.
Tryptase was used as a marker for MCs. The expression of tryptase and Foxp3 were positively correlated.
[23]
Infiltration of MCs was found to be significantly associated with an advanced stage of GC . MCs density
[24]
increased with an increase in malignancy grade and was highly correlated with the extent of angiogenesis .
However, increased tryptase expression was associated with better survival outcome in early-stage GC
patients after surgical resection. These opposing effects may indicate the possibility of two mast cell
[25]
phenotypes (MC1 and MC2) . MCs were associated with angiogenesis and tumor progression in diverse
[21]
tumors , however contradictory results were also reported in other cancers [25,26] . The relation between MCs
and GC remains largely unknown and further investigations regarding MCs, including other factors, are
needed.

TUMOR-INFILTRATING LYMPHOCYTES
TILs consist of T cells, B cells, and NK cells. The subset of T cells is represented by CD8+ cytotoxic T cells,
CD4+ T helper cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells and NK cells. These cells can
infiltrate stroma and tumor cells, and are considered a manifestation of the host immune response against
[27]
tumor cells .
Thirty-one studies (incorporating 4,185 patients) were conducted to evaluate the relationship between TILs
and GC prognosis. The amount of CD8+, FOXP3+, CD3+, CD57+, CD20+, CD45RO+, Granzyme B+ and