Michihiro Narikiyo

Frequent and preferential infection of Treponema denticola, Streptococcus mitis, and Streptococcus anginosus in esophageal cancers

Multiple cancers frequently occur in the upper digestive tract. One possible explanation is that specific bacterial infection stimulates the normal epithelium to initiate inflammation and/or promotes carcinogenesis. This study was undertaken to determine which bacterial species is predominantly associated with esophageal cancer. We examined the bacterial diversity in this type of cancer and in the saliva from healthy people by using a culture‐independent molecular method. Here we report the preferential and frequent infection of the oral periodontopathic spirochete Treponema denticola (T. denticola), Streptococcus mitis (S. mitis), and Streptococus anginosus (S. anginosus) in esophageal cancer from different regions of the world, and we also describe the induction of inflammatory cytokines by infection of S. anginosus and S. mitis. Our present data suggest that these three bacteria could have significant roles in the carcinogenic process of many cases of esophageal cancer by causing inflammation and by promoting the carcinogenic process, and that eradication of these three bacteria may decrease the risk of recurrence.

Small interfering RNA expression vector targeting hypoxia-inducible factor 1 alpha inhibits tumor growth in hepatobiliary and pancreatic cancers

Hepatobiliary and pancreatic carcinomas are hypovascular tumors that can proliferate under hypoxic conditions. Recent reports have demonstrated that hypoxia-inducible factor 1 alpha (HIF1α) plays an important role in the survival of these cancers. Given these findings, the inhibition of the HIF1α pathway might prove to be a powerful tool in the treatment of these cancers. To inhibit HIF1α expression, we used small interference RNA (siRNA) expression vectors in this study. The transient transfection of siRNA expression vectors significantly reduced both HIF1α mRNA levels (13% of control) and protein levels (41% of control) and significantly inhibited the growth of cancer cell lines (P<0.05). VEGF, Glut1, and aldorase A expressions were also significantly reduced by transfection with these vectors (P<0.05), and we found that these vectors induced apoptosis but not cell cycle arrest. In a subcutaneous tumor model using nude mice, transfected MIA PaCa-2 cells, stably expressing siRNAs, barely formed tumors compared to control (P<0.05). This study thus demonstrates the usefulness of siRNA expression vector in targeting HIF1α and points to a potential clinical role in the treatment of pancreatic and hepatobiliary carcinomas.

Clinicopathological and prognostic significance of mucin phenotype in gastric cancer

Gastric and intestinal mucin phenotype cell markers are widely expressed in gastric carcinoma cells, irrespective of their tumor histological type. In the present study, we tried to reveal the clinicopathological significance of mucin phenotype in human gastric carcinomas. Moreover, we investigated the clinical significance of RUNX3 in association with mucin phenotype.

Different frequencies of Streptococcus anginosus infection in oral cancer and esophageal cancer

Multiple cancers frequently occur in the upper aerodigestive tract. The high incidence rate of multiple carcinomas in this region is often explained in terms of involvement of the same underlying risk factors. It has been reported that the oral bacterium Streptococcus anginosus (S. anginosus) is associated with esophageal, gastric, and pharyngeal cancer tissues. In this study, a highly specific quantification method for S. anginosus DNA using real‐time PCR was established. We employed this assay to determine whether S. anginosus is also associated with oral cancer tissues. This precise quantification method revealed different degrees of infection with S. anginosus in esophageal cancer and oral cancer. We assayed 10 ng of genomic DNA from cancer tissues, and found that eight of 18 samples (44%) from the esophagus contained a detectable level (>10 fg) of S. anginosus DNA, whereas this was the case for only five of 38 samples (13%) of oral cancer. The quantity of S. anginosus DNA in the esophageal cancer tissues was significantly higher than in oral cancer. The maximum amount of S. anginosus DNA was approximately ten times higher in esophageal than in oral cancer tissues. In addition, none of the five different oral cancer sites (floor of the mouth, mandibular gingival, maxillary gingival, buccal mucosal, and tongue) showed significant signs of S. anginosus infection. On the other hand, most non‐cancerous tissues of the esophagus and tongue showed an undetectable level of S. anginosus. These results suggest that S. anginosus is associated with esophageal cancer, but is not closely related with oral cancer.

Antisense epidermal growth factor receptor delivered by adenoviral vector blocks tumor growth in human gastric cancer

Epidermal growth factor receptor (EGFR) protein overexpression is commonly found in human gastric cancer, and its gene amplification is known to correlate with poor prognosis in gastric cancer patients. With regard to therapy trials targeting EGFR, it has been reported that stable transfection of EGFR antisense or treatment with antibody against EGFR results in growth suppression of human cancer cells that express high levels of EGFR. We have designed an adenovirus-expressing antisense EGFR and have investigated its effect on the growth of gastric cancer in vitro and in vivo. Following infection with EGFR antisense RNA-expressing adenovirus (Ad-EAS), the cell surface EGFR protein levels of infected cancer cells were markedly reduced, and the in vitro growth of Ad-EAS-infected cells was significantly inhibited relative to control-infected cells in all three gastric cancer cell lines (AGS, KKLS, and MKN28) studied here (P < .0002). In a nude mouse subcutaneous tumor system, in vivo tumor growth of MKN28 was significantly inhibited after Ad-EAS treatment, and inhibition on day 48 was 93% by volume compared with that of untreated controls. These results suggest that an adenoviral vector system targeting the down-regulation of EGFR could be a good candidate for the therapy of gastric cancers that overexpress EGFR.

Evaluation of Remnant Gastric Cancer Surgically Resected after EMR

はじめに: EMRは早期胃癌に対する治療法として広く普及しており, 胃癌治療ガイドラインでも標準的治療法として位置付けられている. しかし, EMR後の遺残・再発はまれではなく, また遺残・再発病変に対する追加治療法も一定していないのが現状である. 胃癌EMR後の遺残・再発病変に対する適切な追加治療法などについて検討した. 対象と方法: 胃癌EMR後の遺残・再発により胃切除術を行った症例27例29病変を対象とし, EMR施行目的別に, 1) EMR適応症例 (15例16病変), 2) 診断目的症例 (8例8病変), 3) EMR適応外症例 (5例5病変) に分けて検討した. 結果: 1) EMR適応症例では, 手術までに長期間経過した1例が深達度MPに進行しており, 1群リンパ節転移を認めた. 2) 診断目的症例では, 8例のうち6例は結果的にEMR 適応症例であったが, この6例はすべて多分割切除であった. 3) EMR適応外症例では, 未分化型癌の1例が手術時にはリンパ節転移を認め, 術後再発により死亡した. まとめ: 1) EMR適応基準を満たす症例のEMR後遺残に対しては, 長期間経過していなければ胃局所切除術を含めた縮小手術で良好な予後が期待できる. 2) 診断目的でEMRを行う場合でも, EMR術者は常に癌の場合を想定し, 一括切除を心掛けるべきである. 3) EMR適応拡大が議論されているが, 特に未分化型癌に対しては慎重に検討する必要がある.