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Page 6 of 13 Matsuoka et al. J Cancer Metastasis Treat 2018;4:6 I http://dx.doi.org/10.20517/2394-4722.2017.85

which are closely associated with cancer invasion, has been regarded as one of the useful tools in the early
detection of peritoneal metastasis. Matrix metalloproteinase 7 (MMP-7), also called matrilysin, is a familiar
member in the MMP family due to its excessive proteolytic activity for a broad range of molecules and is
selectively produced from gastric cancer cells . Moreover, a previous study found that an MMP-7 RT-
[50]
PCR assay of PLF detected cancer cells at densities of as low as < 10 cells/sample and was an independent
predictor of peritoneal recurrence . A quantitative RT-PCR analysis of the CEA and MMP-7 transcripts in
[25]
the PLF effectively predicted peritoneal relapse in gastric cancer in multivariate analysis, and combination
analysis of them enhanced the sensitivity and specificity compared with conventional PLC (71.1% and 74.6%,
[51]
respectively) . Trypsin is a member of the serine protease family which consists of 3 trypsinogen genes
(trypsinogen 1, 2 and 4) and has a potential role in cancer invasion . As a major digestive enzyme, trypsin has
[52]
high proteolytic activity, and its unsuitable activation may result in peritoneal dissemination of infiltrative
gastric cancer. Trypsinogen may be a good candidate for the early detection of peritoneal recurrence in
gastric cancer, because trypsinogen-1 mRNA was positive in a patient who did not show macroscopic or
cytological peritoneal dissemination . Th17 cells have been identified as having a distinct Th cell lineage
[53]
and have been found in several types of human cancers, including gastric cancer . Increasing evidence
[54]
suggests that IL-17 promotes tumor growth through angiogenesis and inflammation. On the other hand,
it contributes to the reduction of tumor growth by promoting dendritic cells, cytotoxic T lymphocyte, and
NK cells. Patients with high expression of IL-17 mRNA detected by real-time RT-PCR in peritoneal lavage
showed significantly prolonged survival compared with patients with low expression of IL-17 mRNA in
peritoneal lavage, suggesting that low IL-17 gene expression in PLF may correlate with cancer development
[55]
and poor prognosis in patients with gastric cancer . Telomerase is a ribonucleoprotein polymerase that
adds TTAGGG repeats to telomeric ends. Telomerase regulates cellular immortality and is reactivated in
[56]
approximately 85% of human malignancies . A recent study using a telomeric repeated amplification
protocol - enzyme-linked immunosorbent assay found that telomerase activity in PLF can be detected
in patients with peritoneal metastasis, and found the positive rate of telomerase activity was significantly
associated with the positive rate of telomerase activity and the presence of peritoneal recurrence, although
these methods were not superior to conventional cytology by itself .
[57]

Other candidates for genetic marker in PLC
The approaches mentioned above focus on the detection of already known genetic changes, whereas full
genome sequencing can be used for the detection of new candidates, and expression profiling may provide
the detection of previously unknown markers for PLC. With regard to peritoneal metastasis, malignant
features of tumor cells such as altered expression of growth factors, immuno-insufficiency, decreased
intercellular adhesion, increased cell-to-matrix adhesion, and resistance to apoptosis are considered to be
pivotal characteristics. The results of this comprehensive gene expression analysis of gastric cancer with
peritoneal metastasis may provide new insight into the detection of micrometastasis in PLF. A previous
study using a global analysis of the differential gene expression showed the relative mRNA levels of genes
expressed in gastric cancer cell lines established from primary tumors and of other cell lines established
from metastasis to the peritoneal cavity . Twenty-four genes including CD44, dopa decarboxylase (DDC),
[58]
keratin family genes, aldehyde dehydrogenase, CD9 and IP3 receptor type 3 were up-regulated while 17 genes
including CD4, IL4 Stat, IGFBP2, and histon deacetylase 3 were down-regulated in the metastatic cell lines
based on results of a high-density cDNA microarray method . Among them, the precise roles of DCC
[58]
in peritoneal metastasis have been investigated. DDC is an enzyme for the metabolism of dopamine, and
is also responsible for the production of neurotransmitters, such as serotonin . DCC was one of these
[59]
upregulated genes. DDC-specific RT-PCR may become a novel marker for peritoneal dissemination of
gastric cancer . CD44-positive gastric cancer cells have been said to show properties of self-renewal and
[60]
[61]
the capability to generate differentiated progeny, in line with the CSC . CD44 mRNA of separated CD45
EpCAM-positive cell fraction of peritoneal washes using the Auto-MACS system may be a useful genetic
[62]
marker for predicting high-risk individuals among stage II and III gastric cancer patients . Phenotype L3-