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Yuki Nakanishi,
Hiroshi Seno,
Ayumi Fukuoka, Taro Ueo,
Yuichi Yamaga,
Takahisa Maruno,
Naoko Nakanishi,
Keitaro Kanda,
Hideyuki Komekado,
Mayumi Kawada,
Akihiro Isomura,
Kenji Kawada,
Yoshiharu Sakai,
Motoko Yanagita,
Ryoichiro Kageyama,
Yoshiya Kawaguchi,
Makoto M Taketo,
Shin Yonehara,
Tsutomu Chiba
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ABSTRACT: There is great interest in tumor stem cells (TSCs) as potential therapeutic targets; however, cancer therapies targeting TSCs are limited. A drawback is that TSC markers are often shared by normal stem cells (NSCs); thus, therapies that target these markers may cause severe injury to normal tissues. To identify a potential TSC-specific marker, we focused on doublecortin-like kinase 1 (Dclk1). Dclk1 was reported as a candidate NSC marker in the gut, but recent reports have implicated it as a marker of differentiated cells (for example, Tuft cells). Using lineage-tracing experiments, we show here that Dclk1 does not mark NSCs in the intestine but instead marks TSCs that continuously produce tumor progeny in the polyps of Apc(Min/+) mice. Specific ablation of Dclk1-positive TSCs resulted in a marked regression of polyps without apparent damage to the normal intestine. Our data suggest the potential for developing a therapy for colorectal cancer based on targeting Dclk1-positive TSCs.
Nature Genetics 12/2012; · 35.53 Impact Factor
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ABSTRACT: Notch signaling regulates intestinal development, homeostasis and tumorigenesis, but its precise downstream mechanism remains largely unknown. Here we found that inactivation of the Notch effectors Hes1, Hes3 and Hes5, but not Hes1 alone, led to reduced cell proliferation, increased secretory cell formation and altered intestinal structures in adult mice. However, in Apc mutation-induced intestinal tumors, inactivation of Hes1 alone was sufficient for reducing tumor cell proliferation and inducing differentiation of tumor cells into all types of intestinal epithelial cells, but without affecting the homeostasis of normal crypts owing to genetic redundancy. These results indicated that Hes genes cooperatively regulate intestinal development and homeostasis and raised the possibility that Hes1 is a promising target to induce the differentiation of tumor cells.
Development 03/2012; 139(6):1071-82. · 6.60 Impact Factor
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Yuki Nakanishi,
Masato Nakatsuji,
Hiroshi Seno,
Shoko Ishizu,
Reiko Akitake-Kawano,
Keitaro Kanda, Taro Ueo,
Hideyuki Komekado,
Mayumi Kawada,
Manabu Minami,
Tsutomu Chiba
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ABSTRACT: Macrophages are a major component of tumor stroma. Tumor-associated macrophages (TAMs) show anti- (M1) or protumor (M2) functions depending on the cytokine milieu of the tumor microenvironment. Cyclooxygenase-2 (COX-2) is constitutively expressed in a variety of tumors including colorectal cancer. TAMs are known to be a major source of COX-2 in human and mice intestinal tumors. COX-2 inhibitor reduces the number and size of intestinal adenomas in familial adenomatous polyposis patients and Apc(Min/+) mice. Although COX-2 inhibitor is thought to regulate cancer-related inflammation, its effect on TAM phenotype remains unknown. Here, we examined the effects of COX-2 inhibition on TAM phenotype and cytokine expression both in vivo and in vitro. Firstly, the selective COX-2 inhibitor celecoxib changed the TAM phenotype from M2 to M1, in proportion to the reduction in number of Apc(Min/+) mouse polyps. Concomitantly, the expression of M1-related cytokine interfron (IFN)-γ was significantly upregulated by celecoxib, although the M2-related cytokines interleukin (IL)-4, IL-13 and IL-10 were not significantly altered. Secondly, IFN-γ treatment attenuated M2 phenotype of mouse peritoneal macrophages and oriented them to M1 even in the presence of M2-polarizing cytokines such as IL-4, IL-13 and IL-10. Thus, our results suggest that COX-2 inhibition alters TAM phenotype in an IFN-γ-dependent manner and subsequently may reduce intestinal tumor progression.
Carcinogenesis 08/2011; 32(9):1333-9. · 5.70 Impact Factor
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Rheumatology (Oxford, England) 04/2010; 49(8):1602-4. · 4.24 Impact Factor
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Gastroenterology 11/2007; 133(4):1076, 1395. · 11.68 Impact Factor
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Taro Ueo,
Shujiro Yazumi,
Syunsuke Okuyama,
Yorihisa Okada,
Takashi Oono,
Motoki Watanabe,
Yasuko Umehara,
Hajime Honjo,
Yasuhide Mitumoto,
Takahiro Mori,
Hideo Tomioka,
Taturo Mugitani,
Shigeto Mizuno,
Tsutomu Chiba,
Seiji Shimizu
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ABSTRACT: We report a unique case of acute cholecystitis due to strangulation of a floating gallbladder by the lesser omentum, which could be detected by abdominal ultrasonography. We believe this case to be the first case of reported literatures in English.
Abdominal Imaging 10/2006; · 1.73 Impact Factor
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Kaori Wada,
Masahiko Shirotani,
Tomoko Okamoto,
Akira Hashimoto,
Tetsuro Inokuma, Taro Ueo,
Mitsushige Shibatouge,
Toshinao Itani,
Jun Mimura,
Hideshi Komori,
Akio Todo
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 11/2002; 99(10):1231-5.
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Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 09/2002; 99(8):956-61.
