CXCR4-expressing Mist1\u3csup\u3e+\u3c/sup\u3e progenitors in the gastric antrum contribute to gastric cancer development

Mist1 was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express Mist1. The relevance of Mist1 expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using Mist1-CreERT mice, we revealed that Mist1+ antral cells, distinct from the Mist1+ population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above Lgr5+ or CCK2R+ cells. Mist1+ antral progenitors can serve as an origin of antral tumors induced by loss of Apc or MNU treatment. Mist1+ antral progenitors, as well as other antral stem/progenitor population, express Cxcr4, and are located in close proximity to Cxcl12 (the Cxcr4 ligand)-expressing endothelium. During antral carcinogenesis, there is an expansion of Cxcr4+ epithelial cells as well as the Cxcl12+ perivascular niche. Deletion of Cxcl12 in endothelial cells or pharmacological blockade of Cxcr4 inhibits antral tumor growth. Cxcl12/Cxcr4 signaling may be a potential therapeutic target

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting–purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Results: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB–IL34/CCL8 signaling that promotes macrophage chemotaxis. Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC

Modernisation des temples bouddhiques et société locale : le Nanzō-in de Sasaguri

This paper studies the modernization of a Buddhist temple, Nanzō-in located at Sasaguri town, Fukuoka prefecture in Kyūshū, and its socio-religious relationship with the local society. This temple belongs to the Shingon sect and is the first stop of the 88 pilgrimage sites, fudasho, replicas of the Shikoku Reijyō based upon Kōbō Daishi belief. According to legend, Sasaguri pilgrimage sites had been founded in 1835, and they flourished until the Meiji Restoration in 1868. According to the Meiji government's political order of the separation of Buddhism and deity belief, the socio-religious system of pilgrimage in Sasaguri had radically changed and gradually declined. Local people introduced the new idea of making requests to the headquarters of the Shingon sect located at Mt. Kōya. In 1898, Nanzō-in temple has migrated to Sasaguri and was afforded the supreme status of pilgrimage site. During the Meiji period, Nanzō-in was supported by local society and outsiders, including laborers of the coal-mining industry, so that this temple eventually passed through the process of modernization. The main topics of this paper are the history of temple, socio-economic background, the change in belief systems, the leadership of the main monk, and the transformation of the relationship between the temple and local society. Nanzō-in temple is a complicated religious site, comprising a main temple, Daishi-dō dedicated to the religious founder, small shrines, a large statue of Fudō-myōō and stone images of numerous bodhisattvas. We discuss radical changes in the temple's character from the supplication and prayer in this world to the appeasing of dead spirits in the other world. After the construction of the large bronze image of the 'Lying Buddha' in 1995, Nanzō-in transformed itself into a commercial temple and focused on conducting religious services for the storage hall of the bones of the dead, the nōkotsudō. This is a new business for the temple. Nanzō-in encompasses various believers from ascetics to pilgrims and is beginning to align itself with the 'Engaged Buddhism' movement. This study will highlight the 'invention of tradition' and modernization of Buddhism supported by the local society to establish the function of the temple's social capital. In conclusion, we discuss the negotiation of external and internal society and its inhabitants.Suzuki Masataka, Quiros Ignacio, Iyanaga Nobumi, Bouchy Anne. Modernisation des temples bouddhiques et société locale : le Nanzō-in de Sasaguri. In: Cahiers d'Extrême-Asie, vol. 22, 2013. Le vivre ensemble à Sasaguri, une communauté de Kyūshū. Dans l'entrelacs des dynamiques du dedans et du dehors. pp. 351-421

Peribiliary Glands as the Cellular Origin of Biliary Tract Cancer

The identification of the cellular origin of cancer is important for our understanding of the mechanisms regulating carcinogenesis, thus the cellular origin of cholangiocarcinoma (CCA) is a current topic of interest. Although CCA has been considered to originate from biliary epithelial cells, recent studies have suggested that multiple cell types can develop into CCA. With regard to the hilar and extrahepatic bile ducts, peribiliary glands (PBGs), a potential stem cell niche of biliary epithelial cells, have attracted attention as the cellular origin of biliary tract cancer. Recent histopathological and experimental studies have suggested that some kinds of inflammation-induced CCA and intraductal papillary neoplasms of the bile duct are more likely to originate from PBGs. During inflammation-mediated cholangiocarcinogenesis, the biliary epithelial injury-induced regenerative response by PBGs is considered a key process. Thus, in this review, we discuss recent advances in our understanding of cholangiocarcinogenesis from the viewpoint of inflammation and the cellular origin of CCA, especially focusing on PBGs

Clinicopathological Features of Gastric Cancer with Autoimmune Gastritis

Most gastric cancers develop in patients with chronic gastritis. Chronic gastritis can be classified into two major subtypes: Helicobacter pylori (H. pylori)-induced gastritis and autoimmune gastritis (AIG). Whereas H. pylori-related gastric cancers are more common and have been extensively investigated, the clinicopathological features of gastric cancer with autoimmune gastritis are unclear. Patients diagnosed with gastric cancer and hospitalized in the University Tokyo Hospital from 1998 to 2017 were enrolled. Diagnosis of autoimmune gastritis was based on positivity for serum anti-parietal cell antibody (APCA). We evaluated mucin expression and immune cell infiltration by immunohistochemical staining for MUC5AC, MUC6, PD-L1, CD3, CD11, Foxp3, and PD1. We also examined the presence of bacterial taxa that are reportedly enriched in AIG. Survival analyses of recurrence and 5-year mortality were also performed. In total, 261 patients (76 APCA-positive and 185 APCA-negative) were analyzed. Immunohistochemical staining in the matched cohort showed that AIG-related gastric cancer had higher MUC5AC expression (p = 0.0007) and MUC6 expression (p = 0.0007). Greater infiltration of CD3-positive (p = 0.001), Foxp3-positive (p < 0.001), and PD1-positive cells (p = 0.001); lesser infiltration of CD11b-positive (p = 0.005) cells; and a higher prevalence of Bacillus cereus (p = 0.006) were found in AIG-related gastric cancer patients. The cumulative incidences of gastric cancer recurrence were 2.99% at 2 years, 15.68% at 6 years, and 18.81% at 10 years in APCA-positive patients; they were 12.79% at 2 years, 21.35% at 6 years, and 31.85% at 10 years in APCA-negative patients. The cumulative incidences of mortality were 0% at 3 years and 0% at 5 years in APCA-positive patients; they were 1.52% at 3 years and 2.56% at 5 years in APCA-negative patients. We identified molecular differences between AIG and non-AIG gastric cancer. Differences in T-cell populations and the gastric microbiota may contribute to the pathogenesis of gastric cancers and potentially affect the response to immunotherapy

Efficacy of triple therapy with esomeprazole, amoxicillin, and sitafloxacin as a third-line Helicobacter pylori eradication regimen

Objective: To examine the efficacy of third-line Helicobacter pylori eradication therapy with esomeprazole, amoxicillin, and sitafloxacin for patients with clarithromycin- and metronidazole-based first- and second-line therapy failure. Methods: Thirty patients with first- and second-line H. pylori eradication failure were treated prospectively with esomeprazole 20 mg twice daily, amoxicillin 750 mg twice daily, and sitafloxacin 100 mg twice daily for 7 days. After 8–12 weeks, the outcome of eradication therapy was assessed by 13C-urea breath test or stool antigen test. Results: All 30 patients completed the study. Eradication was successful in 25 patients and the eradication rate was 83% in the intention-to-treat and per-protocol analyses. No specific or significant adverse events were recorded in the 30 patients. Patient characteristics such as sex, body mass index, and pepsinogen I/II ratio did not differ between patients who were treated successfully and those who were not treated successfully. Conclusions: Third-line H. pylori eradication therapy with esomeprazole, amoxicillin, and sitafloxacin is as safe and effective as previously reported sitafloxacin-based triple therapy