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Page 2 of 15 Sawayama et al. J Cancer Metastasis Treat 2018;4:10 I http://dx.doi.org/10.20517/2394-4722.2017.79

[2-4]
GC is reportedly gastrectomy with D2 dissection . However, distant metastasis or disseminated relapses
are experienced even after curative resection. Multidisciplinary treatment, perioperative chemotherapy and
radiotherapy are other treatment options, and immunonutritional support is effective supportive care for
GC. Prognosis of GC patients has been improved by multidisciplinary treatment. However, some patients
experience recurrence after curative resection with perioperative therapy. Patients with unresectable GC also
suffer from tumor progression and metastasis, even if they are treated with stronger therapeutic agents.

Trastuzumab and ramucirumab [targeting human epidermal growth factor receptor 2 (HER2) and vascular
endothelial growth factor receptor 2, respectively] have been approved for treating GC [5-7] and these
molecular targeting agents improve GC patients’ survival; however, many molecular targeting drugs that have
entered clinical trials for GC failed. Therefore, more effective treatment, which targets other mechanisms,
should be sought for these patients. The efficacy and safety of nivolumab, a human immunoglobulin
[8]
G-4 monoclonal antibody inhibitor of programmed death-1, were confirmed in GC patients . Recent
studies have revealed that programmed death-ligand-1 (PD-L1) expression is associated with the
microenvironments in GC. The Cancer Genome Atlas project demonstrates that GC cases can be divided
into four subtypes: tumors positive for Epstein-Barr virus (EBV), tumors with microsatellite instability (MSI),
genomically stable (GS) tumors and tumors with chromosomal instability (CIN). EBV positive tumors are
associated with phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha mutations, extreme
DNA hypermethylation, and amplification of Janus kinase 2 (JAK2), PD-L1 and PD-L2. Tumors with MSI
exhibit elevated mutation rates. GS tumors are enriched for the diffuse histological variant and mutations
of Ras homolog gene family member A (RHOA) or fusions involving RHO-family GTPase-activating
[9]
proteins. Tumors with CIN show marked aneuploidy and focal amplification of receptor tyrosine kinases .
Identification of these subtypes can prove to be valuable for developing strategies for targeted therapies for
cancer.

Increasing recent evidence has shown that tumor microenvironments of GC, as well as gene expression
pattern, are deeply implicated in tumor progression and metastasis. Tumor microenvironments consist
of cancer cells and various types of stromal cells, bone marrow-derived cells (BMDCs), mast cells (MCs),
tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs) and cancer associated
fibroblasts (CAFs). Interactions between cancer cells and their microenvironment with cytokines and
microRNA (miRNA) in extracellular vesicles, such as the exosome, can have a substantial impact on
tumor characteristics. Alterations in the tumor microenvironment may play a crucial role in facilitating the
progression of tumor cells as well as the activation of cell signaling pathways by the genetic or epigenetic
alteration of cancer cells.

In this review, important molecular insights into clinical impacts of the tumor microenvironment of GC will
be discussed.

BONE MARROW-DERIVED CELLS
BMDCs which are recruited to tissue injury sites are thought to represent a potential source of malignancy.
Chronic infection with Helicobacter felis induces the intensity of bone marrow-derived inflammation and
repopulation of the stomach with BMDCs. Metaplasia and dysplasia to intra-epithelial cancer progress
[10]
through the recruitment and accumulation of BMDCs . Helicobacter pylori infection leads to development
of chronic inflammation as well as the recruitment and accumulation of BMDCs in the gastric epithelial
mucosa. Nearly 20%-25% of dysplastic lesions include cells that originate from the bone marrow [11,12] . Bone
marrow cells may be associated with GC initiation and proliferation.

Recent studies have demonstrated the mechanism of BMDCs. Infection of gastrointestinal epithelial cells
by Helicobacter pylori stimulates the migration of BMDCs. The nuclear factor-kappa B (NF-kB) signaling