Long-lived intestinal tuft cells serve as colon cancer-initiating cells

Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker that has been proposed to identify quiescent and tumor growth-sustaining stem cells. DCLK1+ tuft cells are increased in inflammation-induced carcinogenesis; however, the role of these cells within the gastrointestinal epithelium and their potential as cancer-initiating cells are poorly understood. Here, using a BAC-CreERT-dependent genetic lineage-tracing strategy, we determined that a subpopulation of DCLK1+ cells is extremely long lived and possesses rare stem cell abilities. Moreover, genetic ablation of Dclk1 revealed that DCLK1+ tuft cells contribute to recovery following intestinal and colonic injury. Surprisingly, conditional knockdown of the Wnt regulator APC in DCLK1+ cells was not sufficient to drive colonic carcinogenesis under normal conditions; however, dextran sodium sulfate-induced (DSS-induced) colitis promoted the development of poorly differentiated colonic adenocarcinoma in mice lacking APC in DCLK1+ cells. Importantly, colonic tumor formation occurred even when colitis onset was delayed for up to 3 months after induced APC loss in DCLK1+ cells. Thus, our data define an intestinal DCLK1+ tuft cell population that is long lived, quiescent, and important for intestinal homeostasis and regeneration. Long-lived DCLK1+ cells maintain quiescence even following oncogenic mutation, but are activated by tissue injury and can serve to initiate colon cancer

Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1+ stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12+ endothelial cells and Cxcr4+ gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche

Enteric Infection with Citrobacter rodentium Induces Coagulative Liver Necrosis and Hepatic Inflammation Prior to Peak Infection and Colonic Disease

Acute and chronic forms of inflammation are known to affect liver responses and susceptibility to disease and injury. Furthermore, intestinal microbiota has been shown critical in mediating inflammatory host responses in various animal models. Using C. rodentium, a known enteric bacterial pathogen, we examined liver responses to gastrointestinal infection at various stages of disease pathogenesis. For the first time, to our knowledge, we show distinct liver pathology associated with enteric infection with C. rodentium in C57BL/6 mice, characterized by increased inflammation and hepatitis index scores as well as prominent periportal hepatocellular coagulative necrosis indicative of thrombotic ischemic injury in a subset of animals during the early course of C. rodentium pathogenesis. Histologic changes in the liver correlated with serum elevation of liver transaminases, systemic and liver resident cytokines, as well as signal transduction changes prior to peak bacterial colonization and colonic disease. C. rodentium infection in C57BL/6 mice provides a potentially useful model to study acute liver injury and inflammatory stress under conditions of gastrointestinal infection analogous to enteropathogenic E. coli infection in humans.United States. Army Research Office (Institute for Soldier Nanotechnology grant 6915539 (SRT))National Institutes of Health (U.S.) (Grant P01 CA026731)National Institutes of Health (U.S.) (Grant P30 ES02109)National Institutes of Health (U.S.) (Toxicology Training grant ES-070220

Combining isotopic signatures of n(87Sr)/n(86Sr) and light stable elements (C, N, O, S) with multi-elemental profiling for the authentication of provenance of European cereal samples

The aim of this work (from the FP6 project TRACE) was to develop methods based on the use of geochemical markers for the authentication of the geographical origin of cereal samples in Europe (cf. EC regulations 2081/92 and 1898/06). For the first time, the potential usefulness of combining n(87Sr)/n(86Sr) and δ13C, δ15N, δ18O and δ34S isotopic signatures, alone or with key element concentrations ([Na], [K], [Ca], [Cu] and [Rb], progressively identified out of 31 sets of results), was investigated through multiple step multivariate statistics for more than 500 cereal samples collected over 2 years from 17 sampling sites across Europe representing an extensive range of geographical and environmental characteristics. From the classification categories compared (north/south; proximity to the Atlantic Ocean/to the Mediterranean Sea/to else; bed rock geologies) the first two were the most efficient (particularly with the ten variables selected together). In some instances element concentrations made a greater impact than the isotopic tracers. Validation of models included external prediction tests on 20% of the data randomly selected and, rarely done, a study on the robustness of these multivariate data treatments to uncertainties on measurement results. With the models tested it was possible to individualise 15 of the sampling sites

Millets: A Nutritional Powerhouse With Anti-cancer Potential

Millets are important food crops widely grown by smallholder farmers in the arid and semi-arid regions of the world. Millets are rich in protein, dietary fiber, micronutrients, and have a low glycemic index (GI) and desirable bioactive compounds. Due to their higher nutritional content, millets are popularly known as "nutricereals". Coinciding with the United Nations and the Food and Agriculture Organization's declaration of 2023 as the "International Year of Millets," this review underscores the nutritional value of these grains from the Poaceae family. The consumption of nutricereals is associated with several health benefits including lowering of blood sugar levels (diabetes), controlling blood pressure, and providing protection against thyroid, cardiovascular, and cancer diseases. A review of the literature from PubMed and Google Scholar was done focusing on the health benefits and anti-cancer properties of different millets. Millets have a rich content of macronutrients like carbohydrates and proteins, as well as micronutrients and bioactive compounds, including dietary fibers, essential fatty acids, and phytochemicals. This article explores millets' nutritional elements, i.e., macronutrients, micronutrients, and bioactive compounds, and provides insights into the types of carbohydrates present, the prebiotic function of dietary fibers, and millets' low GI. The study identified the mechanisms by which millets may deter cancer growth, focusing on the roles of dietary fibers, plant protease inhibitors, and bioactive peptides. Additionally, it compared the mineral and vitamin content of millets to other common grains, such as rice and wheat, and explored the potential health advantages of millets over other cereal crops. This review systematically investigated the health advantages of millets, particularly, their anti-cancer capabilities. Dietary fibers, plant protease inhibitors, and bioactive peptides present in millets have the capacity to induce apoptosis, inhibit cell proliferation, and interact with gut microbiota leading to potential anti-cancer effects. This review also identified existing challenges in the bioavailability and effective delivery of millets' bioactive peptides, advocating for further research to maximize their health benefits

Progastrin stimulates colonic cell proliferation via CCK2R- and b-arrestin-dependent suppression of BMP2

BACKGROUND & AIMS: Progastrin stimulates colonic mucosal proliferation and carcinogenesis through the cholecystokinin 2 receptor (CCK2R)-partly by increasing the number of colonic progenitor cells. However, little is known about the mechanisms by which progastrin stimulates colonic cell proliferation. We investigated the role of bone morphogenetic proteins (BMPs) in progastrin induction of colonic cell proliferation via CCK2R. METHODS: We performed microarray analysis to compare changes in gene expression in the colonic mucosa of mice that express a human progastrin transgene, gastrin knockout mice, and C57BL/6 mice (controls); the effects of progastrin were also determined on in vitro colonic crypt cultures from cholecystokinin 2 receptor knockout and wild-type mice. Human colorectal and gastric cancer cells that expressed CCK2R were incubated with progastrin or Bmp2; levels of β-arrestin 1 and 2 were knocked down using small interfering RNAs. Cells were analyzed for progastrin binding, proliferation, changes in gene expression, and symmetric cell division. RESULTS: The BMP pathway was down-regulated in the colons of human progastrin mice compared with controls. Progastrin suppressed transcription of Bmp2 through a pathway that required CCK2R and was mediated by β-arrestin 1 and 2. In mouse colonic epithelial cells, down-regulation of Bmp2 led to decreased phosphorylation of Smads1/5/8 and suppression of inhibitor of DNA binding 4. In human gastric and colorectal cancer cell lines, CCK2R was necessary and sufficient for progastrin binding and induction of proliferation; these effects were blocked when cells were incubated with recombinant Bmp2. Incubation with progastrin increased the number of CD44+ bromodeoxyuridine+, and NUMB+ cells, indicating an increase in symmetric divisions of putative cancer stem cells. CONCLUSIONS: Progastrin stimulates proliferation in colons of mice and cultured human cells via CCK2R- and β-arrestin 1 and 2 -dependent suppression of Bmp2 signaling. This process promotes symmetric cell division.Guangchun Jin, C. Benedikt Westphalen, Yoku Hayakawa, Daniel L. Worthley, Samuel Asfaha, Xiangdong Yang, Xiaowei Chen, Yiling Si, Hongshan Wang, Yagnesh Tailor, Richard A. Friedman And Timothy C. Wan

CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis

Objective: Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. Design: We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. Results: Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5neg or low cell population but was distinct from typical antral Lgr5high stem cells. Treatment with progastrin interconverts Lgr5neg or low CCK2R+ cells into Lgr5high cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. Conclusions: CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.Yoku Hayakawa, Guangchun Jin, Hongshan Wang, Xiaowei Chen, Christoph B Westphalen, Samuel Asfaha, Bernhard W Renz, Hiroshi Ariyama, Zinaida A Dubeykovskaya, Yoshihiro Takemoto, Yoomi Lee, Ashlesha Muley, Yagnesh Tailor, Duan Chen, Sureshkumar Muthupalani, James G Fox, Arthur Shulkes, Daniel L Worthley, Shigeo Takaishi, Timothy C Wan

Impact of headwater hydrological deficit on the downstream flood-based farming system in Northern Ethiopia

Flood-based farming is a means of improving crop production in rain-deficit lowlands. Such spate irrigation systems are growing in importance, although the effects of headwater hydrological deficit on downstream flood farming are lacking evidence. This study investigates the impacts of headwater hydrological deficit on the extent of spate-irrigated agriculture in the Guguf spate system. The length of canals and area of spate-irrigated agriculture to the right and left of the Guguf River for the 1980s and 2010s were tracked using a global positioning system and mapped in a geographic information system interface, while climate data were collected from National Meteorological Agency. Trends of selected hydroclimatic variables were analysed using linear regression and the Pettitt test. The flash floods have shrunk by 7.36 x 10(6) m(3), as a result of which the length of canals and area of spate-based farms declined by 1.37 km and 1540 ha, i.e. 35 and 57.5%, respectively, in only three decades. This corresponds to an average withdrawal of -44.0 ha yr?(1). A single 1 million m(3) decline in flash floods caused a 366.4 ha decline in spate-based farms. Moreover, farm fields located next to the river course are less affected, compared to those at the tail of the scheme. If the current trend continues, there is a high risk that the remaining farms currently receiving floods may find themselves outside of the spate systems. Therefore, we suggest that flood management technologies are needed to optimize the efficiency of soil moisture in the spate system. (c) 2020 John Wiley & Sons, Ltd