Seiji Kawamata

Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesis

Background: Both chronic inflammation and somatic mutations likely contribute to the pathogenesis of ulcerative colitis (UC)‐associated dysplasia and cancer. On the other hand, both tumor suppression and oncogenesis can result from transforming growth factor (TGF)‐&bgr; signaling. TGF‐&bgr; type I receptor (T&bgr;RI) and Ras‐associated kinases differentially phosphorylate a mediator, Smad3, to become C‐terminally phosphorylated Smad3 (pSmad3C), linker phosphorylated Smad3 (pSmad3L), and both C‐terminally and linker phosphorylated Smad3 (pSmad3L/C). The pSmad3C/p21WAF1 pathway transmits a cytostatic TGF‐&bgr; signal, while pSmad3L and pSmad3L/C promote cell proliferation by upregulating c‐Myc oncoprotein. The purpose of this study was to clarify the alteration of Smad3 signaling during UC‐associated carcinogenesis. Methods: By immunostaining and immunofluorescence, we compared pSmad3C‐, pSmad3L‐, and pSmad3L/C‐mediated signaling in colorectal specimens representing colitis, dysplasia, or cancer from eight UC patients with signaling in normal colonic crypts. We also investigated p53 expression and mutations of p53 and K‐ras genes. We further sought functional meaning of the phosphorylated Smad3‐mediated signaling in vitro. Results: As enterocytes in normal crypts migrated upward toward the lumen, cytostatic pSmad3C/p21WAF1 tended to increase, while pSmad3L/c‐Myc shown by progenitor cells gradually decreased. Colitis specimens showed prominence of pSmad3L/C/c‐Myc, mediated by TGF‐&bgr; and tumor necrosis factor (TNF)‐&agr;, in all enterocyte nuclei throughout entire crypts. In proportion with increases in frequency of p53 and K‐ras mutations during progression from dysplasia to cancer, the oncogenic pSmad3L/c‐Myc pathway came to be dominant with suppression of the pSmad3C/p21WAF1 pathway. Conclusions: Oncogenic Smad3 signaling, altered by chronic inflammation and eventually somatic mutations, promotes UC‐associated neoplastic progression by upregulating growth‐related protein. (Inflamm Bowel Dis 2011)

Involvement of Smad3 phosphoisoform-mediated signaling in the development of colonic cancer in IL-10-deficient mice

Chronic inflammation predisposes to cancer. Transforming growth factor (TGF)-beta, a multifunctional protein, suppresses the growth of normal colonic epithelial cells, whereas it stimulates the proliferation of cancer cells. Interleukin (IL)-10-deficient mice, which develop colitis and colorectal cancer, show an increased level of plasma TGF-beta. Although TGF-beta may be a key molecule in the development of colon cancer arising from chronic colitis in IL-10-deficient mice, the role of TGF-beta still remains unclear. TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), which converts the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). We studied C57BL/6-IL-10-deficient mice (n=18) at 4 to 32 weeks of age. We investigated histology, and pSmad2/3L, pSmad2/3C, and p53 by immunohistochemistry. pSmad3L staining was detected in the cancer cells in all 10 mice with colonic cancer and in the epithelial cells in 7 of 12 mice with colonic dysplasia, but not in the normal or colitic mice. pSmad3c was detected without any significant difference between stages. p53 was weakly stained in a few cancer cells in 5 out of 10 mice. Smad3L signaling plays an important role in the carcinogenesis of chronic colitis in IL-10-deficient mice.

Short double-balloon enteroscope for previously failed colonoscopy

1. American Society for Gastrointestinal Endoscopy. Multi-society guideline for reprocessing flexible gastrointestinal endoscopes. Gastrointest Endosc 2003;58:1-8. 2. Nelson D, Jarvis W, Rutala W, et al, Society for Healthcare Epidemiology of America. Multi-society guideline for reprocessing flexible gastrointestinal endoscopes. Infect Control Hosp Epidemiol 2003;24: 532-7. 3. Society of Gastroenterology Nurses and Associates. Standards of infection control in reprocessing of flexible gastrointestinal endoscopes. Gastroenterol Nurs 2000;23:172-87. 4. Alfa MJ, Howie R. Modeling microbial survival in buildup biofilm for complex medical devices. BMC Infect Dis 2009;9:56. 5. Pajkos A, Vickery K, Cossart Y. Is biofilm accumulation on endoscope tubing a contributor to the failure of cleaning and decontamination? J Hosp Infect 2004 58;3:224-9. 6. Muscarella LF. Evaluation of the risk of transmission of bacterial biofilms and Clostridium difficile during gastrointestinal endoscopy. Gastroenterol Nurs 2010 33;1:28-35. . Catalone B, Koos G. Avoiding reprocessing errors critical for infection prevention and control. 2005. Available at: http://www.olympusamerica. com/msg_section/files/mic0605p74.pdf. Accessed August 2010. . Muscarella LF. Inconsistencies in endoscope-reprocessing and infectioncontrol guidelines: the importance of endoscope drying. Am J Gastroenterol 2006;101:2147-54. . Martiny H, Floss H, Zuhlsdorf B. The importance of cleaning for the overall results of processing endoscopes. J Hosp Infect 2004;56:S16-22. oi:10.1016/j.gie.2010.09.028

Detection of ileal carcinoid tumor needs further investigations for other lesions.

To The Editor: We read with interest the article by Yarze et al. ( 1 ) on the detection of asymptomatic ileal carcinoid tumors during routine ileal intubation at screening colonoscopy. Th ey diagnosed six patients with a carcinoid tumor in the terminal ileum. Aft er surgical resection, metastatic lymph nodes were observed in those with the lesion ≥ 1 cm in size (four pateints). Although they recommended the routine ileal intubation at the time of screening colonoscopy, we believe that the detection of an ileal carcinoid tumor needs further investigations of small bowel for the possibility of multiple carcinoid tumors. Small bowel carcinoid tumors account for 15 – 29 % of all gastrointestinal carcinoid tumors, and account for 17 – 46 % of all malignant small bowel tumors ( 2 ). Although carcinoid tumors are slowly progressive and usually clinically silent, small bowel carcinoid tumors have a high rate of transmural invasion and are more likely to metastasize than carcinoid tumors in the rectum or appendix ( 3 ). Multicentricity has been reported as low as 2 – 4 % for rectal carcinoid tumors, but as high as 40 % for small bowel carcinoid tumors ( 4 ). Patients with multiple ileal carcinoid tumors are younger, have a greater risk of developing carcinoid syndrome, and have a poorer prognosis than patients with solitary tumors ( 5 ). Although carcinoid tumors of the rectum, stomach, and duodenum generally are found by endoscopy at an early stage, carcinoid tumors of the small bowel are diffi cult to be diagnosed by conventional imaging techniques, such as double-contrast barium study, computed tomography, and ultrasonography ( 2 ). Small bowel carcinoid tumors usually are discovered aft er resection of the small bowel in patients with obstructive symptoms, or during exploration of the small bowel for search of a primary tumor in patients with distant metastases ( 2 ). Multiple carcinoid tumors of the small bowel are extremely diffi cult to diagnose and localize before surgery ( 2 ). With the widespread use of capsule endoscopy and balloon-assisted endoscopy, management of small bowel lesions has become easier ( 2,4 ). Aft er failed detection with conventional imaging techniques, capsule endoscopy ( 4,6 ) and balloon-assisted endoscopy ( 2 ) can identify multiple carcinoid tumors in the small bowel. We therefore believe that the detection of a carcinoid tumor in the terminal ileum needs further investigations of the small bowel by capsule endoscopy or balloon-assisted endoscopy in the early diagnosis of multiple carcinoid tumors.

Colonoscopy with a transparent hood: simple technique for improved quality of colonoscopy.

To the Editor: We read with interest the article by Radaelli et al. (1) on the factors that influence the technical performance of colonoscopy. In nationwide quality improvement programs of colonoscopy in Italy, researchers set out to identify the factors in clinical practice. They concluded that the sedation/analgesic use, bowel preparation quality, endoscopist experience, and colonoscopy volume of centers influenced the quality of colonoscopy. We believe that a simple technique can improve the quality of colonoscopy.