Apc遺伝子欠損マウスにおいて、塩素水は遺伝子不安定性と腸内細菌環境を介して結腸直腸腫瘍の発育を調節する。

This work was supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (http://www.jsps.go.jp/j-grantsinaid/) (Grant Number 22390257) TH, and The Japanese Society of Gastroenterology (http://www.jsge.or.jp/english/english.html) Grant-in-Aid 2010 TH, and Japan Science and Technology Agency (JST) A-STEP (http://www.jst.go.jp/) (Grant Number AS231Z04862F) TH.広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

A case of HER-2-positive recurrent breast cancer showing a clinically complete response to trastuzumab-containing chemotherapy after primary treatment of triple-negative breast cancer

We report a case of HER-2-positive recurrent breast cancer showing a clinically complete response to trastuzumab-containing chemotherapy 6 years after primary treatment of triple-negative breast cancer. The primary tumor was negative for HER-2 as determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) (1+, and ratio, 1.1), but examination of the recurrent lymph node metastasis showed positivity for HER-2 by FISH (ratio, 5.2). No lesions were detected in either her left breast or in other organs, and the patient was diagnosed as having HER-2-positive recurrent disease. Combination chemotherapy using weekly paclitaxel and trastuzumab was initiated, and a clinically complete response was achieved. This report suggests the benefit of routine evaluation of HER-2 status in recurrent breast cancer with the introduction of HER-2-targeting agents

Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice.

The gastrointestinal tract is continuously exposed to a variety of chemicals and commensal bacteria. Recent studies have shown that changes in gut microbial populations caused by chlorine or other chemicals in the drinking water influence the development of human colorectal cancer, although the mechanism of tumorigenesis in the gut epithelium is obfuscated by the diversity of microflora and complexity of the tumor microenvironment. In this regard, mouse models that recapitulate human colorectal cancer are an invaluable tool. In this study, we used two conditional adenomatous polyposis coli (Apc) knockout mouse models to investigate the effect of chlorinated water on tumorigenesis in the digestive tract. Mice with colon-specific carcinoma--caused by either chromosomal (CDX2P 9.5-NLS Cre;Apc(+/flox), abbreviated to CPC;Apc) or microsatellite (CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox)) instability, respectively--were administered chlorinated (10.0 mg/L chlorine) or tap (0.7 mg/L chlorine) water and evaluated for colon polyp formation. In CPC;Apc mice given chlorinated drinking water, tumors tended to develop in the colon, whereas in those that drank tap water, tumors were mostly observed in the small intestine. There was no difference in the rate of tumor formation of CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox) mice consuming chlorinated as compared to tap water, suggesting that microsatellite instability in the Apc gene does not significantly affect tumorigenesis. Chlorinated water altered the enteric environment by reducing the fecal populations of the obligatory anaerobes Clostridium perfringens and C. difficile, as well as species belonging to the Atopobium cluster, including Enterobacteriaceae and Staphylococcus sp., which was associated with colon tumorigenesis in CPC;Apc mice. These results suggest that differences in tumorigenesis among CPC;Apc mice consuming chlorinated versus tap water may be due to differences in gastrointestinal commensal populations

Cdx2 Regulates Multidrug Resistance 1 Gene Expression In Malignant Intestinal Epithelium

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MSI in tumors from <i>CPC;Apc</i> and <i>CDX2P9</i>.<i>5-G19Cre;Apc</i>^{<i>flox/flox</i>} mice.

<p>Tumors from <i>CDX2P9</i>.<i>5-G19Cre;Apc</i>^{<i>flox/flox</i>} mice showed a hypermutable phenotype (arrowhead and black bar) for two (<i>D7Mit91</i> and <i>GA29)</i> of four markers investigated, suggesting that tumor development occurs via MSI. The 600 LIZ size standard (Eurofins GeneScan, Frieburg, Germany) was used as a marker for sizing DNA fragments.</p

Polyp number and volume in the colon, cecum, and small intestine.

<p>A greater number of polyps was detected in the colon than in the ileum of the chlorinated water group (black columns), whereas more polyps occurred in the small intestine in the tap water group (white columns). Polyp volume was correlated with polyp number, and colon polyp volume differed significantly between the two groups. ch; chlorinated water group, ta; tap water group. *P < 0.05 (Student’s t test).</p

Tumorigenesis and body weight in <i>CPC;Apc</i> mice.

<p><b>A,</b> Tumorigenesis in 40-week-old <i>CPC;Apc</i> mice. Left, mouse administered chlorinated water (10.0 mg/L chlorine). Right, mouse administered tap water (0.7 mg/L chlorine). Tumors were mainly detected in the colon and at the end of the ileum in the chlorinated and tap water groups, respectively. st, stomach; je, jejunum; ce, cecum; co, colon; an, anus. Bar, 10 mm. <b>B,</b> Tumor histology in <i>CPC;Apc</i> mice. H&E staining of a colonic tumor from a chlorinated water-treated mouse (left) and a small intestinal tumor from a tap water-treated mouse (right). Bar, 500 μm. <b>C,</b> Body weight gain in the chlorinated water group (black box) was the same as in wild-type C57B/6 mice, while the tap water group (white box) had significantly lower weight gain. *P < 0.05 (ANOVA).</p