mTORC1 in the Paneth cell niche couples intestinal stem cell function to calorie intake

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.National Institutes of Health (U.S.) (CA103866)National Institutes of Health (U.S.) (CA129105)David H. Koch Institute for Integrative Cancer Research at MIT (Initiator Award)Ellison Medical FoundationNational Cancer Institute (U.S.) (NCI (T32CA09216) fellowship support)Academy of FinlandFoundations’ Postdoc PoolNational Institutes of Health (U.S.) (NIH (1F32AG032833-01A1))Jane Coffin Childs Memorial Fund for Medical Researc

Superior Prognostic Importance of Perineural Invasion vs. Lymph Node Involvement After Curative Resection of Duodenal Adenocarcinoma

Background: Unlike other gastrointestinal tumors, lymph node involvement has not consistently been a negative prognostic factor for survival in patients with duodenal adenocarcinoma. Our aim is to examine prognostic factors in patients who underwent a curative resection of their duodenal adenocarcinoma. Methods: A retrospective review of 169 patients diagnosed with primary duodenal lesions between 1982 and 2010 was performed, of whom 103 were treated with curative intent. Clinico-pathologic factors were evaluated. Results: A potentially curative resection was performed in 103 patients with a median age of 67 years (range, 22-91). Perineural and lympho-vascular invasion were identified in 30 (29. 1%) and 39 patients (37. 9%), respectively. Median follow-up was 26. 5 months. The 5-year overall survival was 62% vs. 25% for patients with or without nodal metastases (p < 0. 001) and 56% vs. 19% for patients with or without perineural invasion (p < 0. 001), respectively. Lymph node ratio, type of resection, and size of tumor failed to stratify prognosis. By multivariate analysis, perineural invasion was the most powerful independent predictor of survival (HR, 2. 520; CI, 1. 361-4. 664). Conclusions: Perineural invasion is a stronger predictor for recurrence and survival than tumor size, depth of infiltration, lymph node involvement, and type of resection in patients with duodenal adenocarcinoma. © 2011 The Society for Surgery of the Alimentary Tract