In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL- ;-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL- ;LSL- ;-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Subdiaphragmatic vagotomy or knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. .

ObjectiveLong-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression.DesignWe crossed LSL-Kras+/G12D;Pdx1-Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples.ResultsKC-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras+/G12D pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8+ T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1β pancreata, and depletion of IL-35 decreased the number of PD-L1+ B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival.ConclusionWe show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a two-stage carcinogenesis model in CD109-deficient mice with chronic skin inflammation. Immunohistochemical analysis revealed a higher level of TGF-β protein expression in the dermis of CD109-deficient mice than in that of wild-type mice. Additionally, immunofluorescence analysis showed that Smad2 phosphorylation and Nrf2 expression were enhanced in primary keratinocytes from CD109-deficient mice compared with in those from wild-type mice. Although no significant difference was found in conversion rates from papilloma to carcinoma between wild-type and CD109-deficient mice in the carcinogenesis model, we observed fewer and smaller papillomas in CD109-deficient mice than in wild-type mice. Apoptosis and DNA damage marker levels were significantly reduced in CD109-deficient skin compared with in wild-type skin at 24 h after 7, 12-dimethylbenz (α) anthracene treatment. Furthermore, mutation-specific PCR revealed that the mutation frequency of the H-ras gene was less in CD109-deficient skin than in wild-type skin in this model. These results suggest that CD109 deficiency suppresses skin tumorigenesis by enhancing TGF-β/Smad/Nrf2 pathway activity and decreasing the mutation frequency of the H-ras gene.

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Background The necessity of a specific T classification for extrahepatic intraductal papillary neoplasm of the bile duct (IPNB) type 2, one of the precursors of cholangiocarcinoma (CC), remains unclear. Methods Patients who underwent resection for extrahepatic biliary tumors were reviewed. Relapse‐free survival (RFS) was compared between IPNB type 2 and CC, stratified by T classification. Results The cohort involved 443 patients with IPNB type 2 (n = 57) and CC (n = 386). In 342 patients with perihilar tumors, 5‐year RFS of IPNB type 2 and CC group was 49.8% versus 34.5% (p = .012), respectively. The RFS was 54.6% versus 47.2% (p = .110) for pT1‐2 tumors and 28.6% versus 22.7% (p = .436) for pT3‐4 tumors, respectively. In 92 patients with distal tumors, 5‐year RFS was 47.4% versus 42.1% (p = .678). The RFS was 68.2% versus 49.6% (p = .422) for pT1 tumors and 18.8% versus 38.3% (p = .626) for pT2‐3 tumors, respectively. Multivariate analysis identified that poor histologic grade (HR, 2.105; p < .001), microscopic venous invasion (HR, 1.568; p = .002), and nodal metastasis (HR, 1.547; p < .001) were independent prognostic deteriorators, while tumor type (IPNB type 2 vs. CC) was not. Conclusions Prognostic impact of IPNB type 2 was limited, suggesting unnecessity of a specific T classification for IPNB type 2 with invasive carcinoma.

A 46-year-old female underwent total gastrectomy with a combined resection of the pancreatic tail, spleen, and lateral segment of the liver surgery after conservative medical management for a perforated advanced gastric cancer. The histological findings showed poorly differentiated adenocarcinoma, and the tumor was Stage IIIC. S-1 and "Kampo-Juzen-taiho-to" were administered as postoperative adjuvant chemo-immunotherapy. A Krukenberg tumor was identified 4 years later. The histological findings strongly suggested the presence of peritoneal dissemination, and S-1-based combined chemotherapies using key drugs such as CDDP, CPT-11, and taxane with the biochemical response modifier "Lentinan" was administered. However, the Krukenberg tumor rapidly increased in size after 4 years and she complained of abdominal distension. Therefore, it was removed with neither difficulties nor apparent recurrent disease, which was thought to be due to the S-1-based combined chemotherapy and the immunological agents are likely to have contributed to her long survival and good quality of life.