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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-
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