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Page 4 of 8 Hu et al. J Cancer Metastasis Treat 2018;4:39 I http://dx.doi.org/10.20517/2394-4722.2018.08

cancers, the PI3K/Akt [48-50] and PTEN/PI3K/NF-κB/FAK pathways [51,52] are involved in the formation of PD
and anoikis resistance. FAK is a key integrin signaling molecule involved in cell survival pathways [51,52] .
Moreover, the CXCL12/CXCR4 pathway can induce EMT [53,54] and is associated with PD and anoikis
resistance [55,56] in multiple human cancers.

THE ATTACHMENT OF FREE TUMOR CELLS TO PERITONEAL MESOTHELIAL CELLS AND

TUMOR GROWTH
Cancer cells seeded in the peritoneal cavity attach directly to the peritoneal surface. However, the mesothelium,
a membrane composed of simple squamous epithelium that forms the lining of peritoneum, prevents the
cancer cells from penetrating into the submesothelial space. The connective tissue under the mesothelium
contributes to the formation of a microenvironment (niche) for seeding cancer nodules in the process of
PD [6,57,58] . The production of MMPs and integrin is important for the penetration into the submesothelial
space . Notably, MMP-7 functions as a key factor in the degradation of ECM, promoting the penetration
[59]
of cancer cells into the submesothelial space and the formation of PD. Integrins, transmembrane receptors
that facilitate cell-ECM adhesion, were found to be overexpressed in GC cell lines with high PD potential .
[60]
Takatsuki et al. reported that inhibition of integrin a3b1 reduced the number of disseminated nodules in
[61]
GC cells. Laminin-5, a ligand with a high affinity for integrin a3b1, is a major ECM glycoprotein. Inhibition
of laminin-5 reduced the adhesion of free cells to parietal peritoneum, suggesting that integrin a3b1 plays a
key role in cell penetration into the submesothelial space . Recently, it was reported that mesothelial cells
[61]
create a novel tissue niche that facilitates GC invasion, resulting in PD .
[62]
Cancer cells that have attached to connective tissue underlying the mesothelium induce angiogenesis for
tumor growth through high expression of vascular endothelial growth factor (VEGF) . VEGF is a well-
[59]
known signaling protein that stimulates formation of blood vessels. Previous studies suggest that VEGF is
associated with PD in GC [63-65] . VEGF receptor antisense therapy inhibited angiogenesis and PD in GC .
[65]
Targeting VEGF is considered an attractive strategy to inhibit PD in GC.

NEW TOPICS IN GC
Immune checkpoint inhibitors enhance antitumor T-cell activity through inhibition of immune
checkpoints such as the programmed death-1 (PD-1) receptor. Recent trials showed that anti-PD-1 receptor
antibodies (pembrolizumab evaluated inKEYNOTE-012 and nivolumab in ONO-4538-12) exert antitumor
activity in patients with advanced GC or gastro-esophageal junction cancer [66,67] . In a subgroup analysis
of theONO-4538-12 trial, there are no interactions between PD and nivolumab treatment, indicating that
nivolumab is effective for treatment of GC patients with or without PD. Immune checkpoint inhibitors are
expected to improve the outcome of GC patients with PD.

With the accumulation of genomic/epigenomic data, many public data and online analysis tools are now
available. The Cancer Genome Atlas (TCGA) is a large cancer genome project that has accumulated RNA
sequencing, exome sequencing, SNP array, DNA methylation, reverse-phase protein lysate microarray,
and clinical data across multiple cancers, and these data sets can be downloaded easily. Recently, TCGA
reported a molecular classification that divides GC into four subtypes [Epstein-Barr virus (EBV)-positive,
microsatellite instability (MSI), genomically stable (GS), chromosomal instability (CIN)] based on
integrated genomic/epigenomic data (copy number analysis, whole exome sequencing, DNA methylation
arrays, RNA sequencing, microRNA arrays, protein arrays) . This classification provides a consistent and
[68]
unified framework for further clinical and preclinical translational research. Elucidation of the molecular
characterization of PD in GC is still needed but is expected to promote the development of novel treatments
for GC patients with PD.