The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17.

Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130(F/F) mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130(F/F) mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rorγt, IL-23), were augmented compared to wild-type gp130(+/+) mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17-related factors in gp130(F/F) mice were reduced to wild-type levels in gp130(F/F) :Stat3(-/+) mice displaying normalized STAT3 activity, and also in gp130(F/F) :IL-6(-/-) mice. Importantly, genetic ablation of IL-17A in gp130(F/F) :IL-17a(-/-) mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis.

An immunohistochemical profile of the so-called bile duct adenoma: clues to pathogenesis.

The so-called bile duct adenoma and peribiliary glands are characterized by the expression of two foregut antigens (designated D10 and 1F6) and secretion of acid mucin. On account of this similarity in phenotype and their frequent close association with a large caliber bile duct, it was earlier suggested that bile duct adenoma represent a peribiliary gland hamartoma. Here, we compare the expression of 13 tissue antigens in bile duct adenomas, other benign bile duct lesions, and various foregut-derived tissues, to further investigate the bile duct adenoma phenotype and pathogenesis. Antibodies to 4 intestinal mucins, 3 cytokeratins, and CDX2, were not informative. Five foregut antigens (D10, 1F6, MUC6, MUC5AC, and TFF2) and secretion of acid mucin were of use in distinguishing bile duct adenoma from other hepatic lesions. 1F6 and MUC6 were normally present in bile ductules and canals of Hering, whereas the epithelium lining the larger bile ducts stained focally for D10, MUC5AC, MUC6, or TFF2 in, respectively, 21%, 36%, 43%, and 100% of the livers examined. Thirty-six bile duct adenomas examined were distinguished by expression of MUC6 (94% of bile duct adenoma), MUC5AC (90%), TFF2 (80%), D10 (67%), and 1F6 (61%), and varying degrees of acid mucin secretion (100%). Of 30 bile duct adenoma tested for all 5 antigens, 40% expressed all 5, 27% expressed 4, 17% expressed 3, 13% expressed 2, and 1 expressed only MUC6. Peribiliary glands invariably expressed D10, 1F6, MUC6, and TFF2, and showed acid mucin secretion, with MUC5AC present in the inflamed peribiliary glands of 3/4 livers with recurrent pyogenic cholangitis, but none of the glands of the other 23 normal or diseased livers tested. The acini of pyloric gland metaplasia in gallbladder and terminal ileum also stained for D10, 1F6, MUC6, and TFF2, with MUC5AC focally present in the gastric foveolar metaplasia overlying the pyloric gland metaplasia but not in the metaplastic glands. MUC6 was expressed in 92% of ductular reactions, 1F6 in 42%, and D10 in 25%. Focal expression of MUC6, or TFF2 was observed in 1 or 2 examples of 14 von Meyenburg complexes and 6 polycystic livers, with staining for acid mucin generally obvious only in the glycocalyx of the epithelium of these two types of lesions. The distinguishing feature of so-called bile duct adenoma is their display of the same phenotype as pyloric gland metaplasia. It is concluded that they develop as a localized biliary healing response equivalent to the function of a peribiliary gland or pyloric gland metaplasia in the foregut.

STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice.

Deregulated activation of STAT3 is frequently associated with many human hematological and epithelial malignancies, including gastric cancer. While exaggerated STAT3 signaling facilitates an antiapoptotic, proangiogenic, and proproliferative environment for neoplastic cells, the molecular mechanisms leading to STAT3 hyperactivation remain poorly understood. Using the gp130(Y757F/Y757F) mouse model of gastric cancer, which carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and is characterized by hyperactivation of the signaling molecules STAT1 and STAT3, we have provided genetic evidence that IL-11 promotes chronic gastric inflammation and associated tumorigenesis. Expression of IL-11 was increased in gastric tumors in gp130(Y757F/Y757F) mice, when compared with unaffected gastric tissue in wild-type mice, while gp130(Y757F/Y757F) mice lacking the IL-11 ligand-binding receptor subunit (IL-11Ralpha) showed normal gastric STAT3 activation and IL-11 expression and failed to develop gastric tumors. Furthermore, reducing STAT3 activity in gp130(Y757F/Y757F) mice, either genetically or by therapeutic administration of STAT3 antisense oligonucleotides, normalized gastric IL-11 expression and alleviated gastric tumor burden. Surprisingly, the genetic reduction of STAT1 expression also reduced gastric tumorigenesis in gp130(Y757F/Y757F) mice and coincided with reduced gastric inflammation and IL-11 expression. Collectively, our data have identified IL-11 as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1.

Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss.

The effect of significant weight loss on nonalcoholic fatty liver disease remains unclear. In this case series of 36 selected obese patients, we examined the effect of weight loss on nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. These 36 patients (11 males, 25 females) had paired liver biopsies, the first at the time of laparoscopic adjustable gastric band placement and the second after weight loss. Second biopsies were obtained from two groups: those requiring a subsequent laparoscopic procedure (n = 19) and those with index biopsy score of 2 or greater for zone 3-centric hepatic fibrosis (n = 17). All biopsies were scored, blinded to the patient's identity and clinical condition, for individual histological features and for NASH stage and grade. Initial biopsies demonstrated NASH in 23 patients and steatosis in 12 patients. Repeat biopsies were taken at 25.6 +/- 10 months (range, 9-51 months) after band placement. Mean weight loss was 34.0 +/- 17 kg, and percentage of excess weight loss was 52 +/- 17%. There were major improvements in lobular steatosis, necroinflammatory changes, and fibrosis at the second biopsy (P <.001 for all). Portal abnormalities remained unchanged. Only four of the repeat biopsies fulfilled the criteria for NASH. There were 18 patients with an initial fibrosis score of 2 or more compared with 3 patients at follow-up (P <.001). Those with the metabolic syndrome (n = 23) had more extensive changes before surgery and greater improvement with weight loss. In conclusion, weight loss after surgery provides major improvement or resolution of obesity and metabolic syndrome-associated abnormal liver histological features in severely obese subjects.

Biliary adenofibroma: a rare neoplasm of bile duct origin with an indolent behavior.

We report a case of biliary adenofibroma in a 47-year-old woman, who presented with right upper quadrant pain for several months. Abdominal imaging revealed a 16-cm solid and cystic mass in the left hepatic lobe. Histologically, the tumor showed two distinct components: 1) cystic and tubular structures lined by low columnar to cuboidal biliary-type epithelium, and 2) a dense fibrous stroma composed of spindle-shaped cells with only mild nuclear pleomorphism and inconspicuous nucleoli. Mitoses and stromal invasion were absent. The glandular epithelium stained positively for keratin AE.3/Cam 5.2, cytokeratin 7, cytokeratin 19, carcinoembryonic antigen, and epithelial membrane antigen and had a low Ki-67 proliferative index. In addition, the epithelium was positive for D10 but did not stain for 1F6 or acid mucin with alcian blue stain. This staining pattern, similar to bile duct hamartoma (von Meyenburg complex) with which this tumor shares morphologic similarity, suggests that biliary adenofibroma originates from interlobular or larger bile ducts. Three years after a subtotal resection no metastasis or significant tumor growth was noted. However, given the marked nuclear p53 immunoreactivity and tetraploidy status observed in this tumor, we cannot exclude that biliary adenofibroma may represent a premalignant process that warrants complete resection and thorough histopathologic examination.