Paul Drillenburg

Cyclooxygenase‐2 expression during carcinogenesis in the human stomach

The prolonged use of non‐steroidal anti‐inflammatory drugs (NSAIDs) has been associated with a reduced risk of gastric cancer. The best‐known target of these drugs is cyclooxygenase (COX); the COX‐2 isoform is frequently up‐regulated in gastric adenocarcinomas. Using the post‐gastrectomy stomach as a model, the expression of COX‐2 mRNA and protein has been investigated during tumour progression in the human stomach. COX‐2 expression was comparable in gastric stump carcinomas and conventional gastric carcinomas and localized primarily to the cytoplasm of the neoplastic cells. COX‐2 mRNA was elevated in biopsies containing intestinal metaplasia, as determined by reverse transcriptase polymerase chain reaction (RT‐PCR). COX‐2 immunopositivity became more frequent during progression from reactive epithelium to high‐grade dysplasia, both in the epithelial and in the stromal cell compartment. Co‐localization of COX‐2‐positive stromal cells was seen with CD68, α‐smooth muscle actin (α‐SMA), vimentin, and HLA‐DR, but an as yet unidentified subpopulation of stromal cells remained. Co‐localization with the macrophage marker CD68 was only observed in a minority of COX‐2‐positive cells. These data show that COX‐2 expression is a relatively early event during carcinogenesis in the stomach. COX‐2 expression increases during tumour progression in the stomach, suggesting a role for COX‐2 expression in gastric tumourigenesis. Copyright

Aberrant expression and reverse signalling of CD70 on malignant B cells

In normal lymphoid tissues the tumour necrosis factor‐receptor family member CD27 and its ligand CD70 have a restricted expression pattern. Previously, we reported that expression of CD27 is deregulated in B‐cell leukaemias and lymphomas. Here we show that, although infrequently expressed by normal human B cells in vivo, CD70 is found on 50% of B‐CLLs, 33% of follicle centre lymphomas, 71% of large B‐cell lymphomas, and 25% of mantle cell lymphomas. Interestingly, in the majority of leukaemias and lymphomas examined, CD70 was found to have a capped appearance, a feature that coincided with co‐expression of CD27. Functional analysis showed that a subset of B‐CLLs could proliferate vigorously in response to CD70 mAb but not to CD27 mAb. This response was synergistically enhanced by ligation of CD40 but inhibited by the presence of IL‐4. Additional experiments indicated that the proliferative response was due to an agonistic signal delivered via CD70, rather than blocking of negative signalling by CD27. Thus, next to its role as ligand, in a subset of malignant B cells CD70 can operate as receptor and as such might contribute to progression of these B‐cell malignancies.

K-ras oncogene mutations in osteoclast-like giant cell tumors of the pancreas and liver: genetic evidence to support origin from the duct epithelium.

Osteoclast-like giant cell tumors (OCGTs) of the pancreas and liver are enigmatic tumors. Despite their striking morphologic resemblance to certain mesenchymal tumors of bone and tendon sheath, it has been suggested that these tumors may, in fact, arise from epithelial precursors. It is also unclear whether the osteoclast-like giant cells in OCGTs are neoplastic or nonneoplastic. We identified OCGTs of the pancreas and liver that were associated with atypical intraductal epithelial proliferations or mucinous cystic neoplasms. To determine the relationship between the noninvasive epithelial proliferations and the infiltrating OCGTs, each individual component was analyzed for mutations at codon 12 of the K-ras oncogene. Four of the five-duct epithelial lesions harbored activating mutations of the K-ras oncogene. In each case, the same K-ras mutation was also present in the mononuclear cells from the paired OCGT. Moreover, these same mutations were detected when the osteoclast-like giant cells were individually microdissected and analyzed. A panel of immunohistochemical stains was performed, and the osteoclast-like giant cells demonstrated macrophage differentiation. These cells were consistently reactive for the monocyte/macrophage marker KP1, but showed absent staining for a panel of epithelial markers. The infiltrating mononuclear cells lacked strong staining for epithelial markers and monocyte/macrophage markers. These findings suggest that OCGTs of the pancreas and liver are undifferentiated carcinomas that arise directly from intraductal epithelial precursors. The finding of K-ras mutations in the osteoclast-like giant cells may reflect their propensity to phagocytize tumor cells.

Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis

Background: Crohns disease is characterised by a chronic relapsing inflammation of the bowel in which proinflammatory cytokines play an important perpetuating role. Mitogen activated protein kinase p38 (p38 MAPK) has been established as a major regulator of the inflammatory response, especially with regard to production of proinflammatory cytokines, but its role in inflammatory bowel disease is unexplored. In this paper we describe the effects of a specific p38 MAPK inhibitor, SB 203580, in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice. Results: SB 203580 had a dichotomal effect in TNBS mice. Weight loss of TNBS mice treated with SB 203580 was significantly worse and colon weight on sacrifice was significantly increased in MAPK inhibitor treated TNBS mice (229.2 mg and 289.1 mg, respectively). However, the total number of cells in the caudal lymph node decreased to 188.8×104 cells in SB 203580 treated TNBS mice compared with 334×104 cells in vehicle treated mice. CD3/CD28 double stimulated caudal lymph node cells of SB 203580 treated mice showed decreased interferon γ production but increased tumour necrosis factor α production. The concentration of interleukin 12p70 in colon homogenates was significantly decreased in SB 203580 treated mice whereas concentrations of interleukin 12p40, tumour necrosis factor α, and interleukin 10 were similar in vehicle and SB 203580 treated TNBS mice. Conclusion: Our results reveal a dichotomy in p38 MAPK action during experimental colitis.

IL-10 gene therapy prevents TNBS-induced colitis.

The transfer of genes encoding immunomodulatory proteins to the intestinal mucosa is a promising new approach to the treatment of Crohns disease (CD). This study investigates the therapeutic efficacy of an adenoviral vector encoding IL-10 (AdvmuIL-10) in experimental colitis. BALB/c mice were treated with a single intravenous injection of AdvmuIL-10, empty cassette virus (Adv0) or PBS prior to the induction of trinitrobenzene sulphonic acid (TNBS) colitis. AdvmuIL-10 treatment prevented the severe loss of body weight associated with TNBS administration. In addition, AdvmuIL-10 therapy led to a significant reduction in both stool markers of inflammation (IL-1β and TNFR-II) and acute phase response (serum amyloid protein). Finally, the histological scores of mice with TNBS colitis treated with AdvmuIL-10 were significantly lower than Adv0- or PBS-treated controls. The therapeutic efficacy of AdvmuIL-10 was associated with a decrease in the IFN-γ and IL-6 levels detected in colonic homogenates from mice with TNBS colitis, whereas no effect was observed on cytokine release from stimulated systemic lymphocytes. Thus, AdvmuIL-10 is an effective therapy in the TNBS model of colitis. Gene therapy strategies using adenoviral vectors encoding IL-10 may prove to be a potent therapy for chronic inflammatory conditions such as CD.

Pancreatic intraepithelial neoplasia and pancreatic tumorigenesis: of mice and men.

CONTEXT Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease. OBJECTIVES To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis. DATA SOURCES A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models. CONCLUSIONS Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remain.

Expression of the mucosal homing receptor α4β7 in malignant lymphomatous polyposis of the intestine

Abstract Recent studies have identified the integrin α4β7 as a mucosal homing receptor that mediates lymphocyte migration to the intestinal mucosa by binding to MAdCAM-1, which is a vascular recognition molecule (adressin) selectively expressed on mucosal endothelium. The expression of the α4β7 mucosal homing receptor was studied in eight cases of malignant lymphomatous polyposis (MLP). This unusual presentation of non-Hodgkins lymphoma of mantle cell type is characterized by multifocal lymphomatous involvement of the gastrointestinal tract. Unlike nodal mantle cell lymphomas, cases of MLP showed expression of α4β7, suggesting that this homing receptor plays an important role in determining the characteristic mucosal dissemination pattern of MLP.

Differential Susceptibility of Multidrug Resistance Protein-1 Deficient Mice to DSS and TNBS-Induced Colitis

The molecular mechanisms underlying inflammatory bowel diseases (IBD) are incompletely characterized. MRP-1, normally expressed in the large and small bowel epithelium, serves as a multidrug resistance protein. In this report we explored the role of MRP1 in IBD. Mrp1-deficient mice (mrp1−/−) were subjected to two different models of IBD. The mrp1−/− mice and wild-type (WT) mice showed equal induction of TNBS colitis, a hapten-induced T-cell mediated disease. However, in DSS colitis more severe disease was observed in mrp1−/− mice. In a survival study, mortality of mrp1−/− mice was higher. In nonlethal DSS colitis, the mean histological colitis score was significantly higher in mrp1−/− mice and showed particularly severe epithelial damage. Although endogenous LTB4 levels were significantly increased in mrp1−/− mice, treatment with a LTB4 antagonist did not reduce disease. We conclude that MRP-1 has an important role in the intestinal epithelial resistance to exogenous injury, but MRP-1 does not affect T-lymphocyte mediated mucosal damage.

Report of an Amsterdam working group on Barrett esophagus.

More than 50 years have passed since Barrett described a case of peptic ulcer disease of the esophagus and the condition that would carry his name [1]. It is now generally accepted that Barrett esophagus is the result of long-standing gastroesophageal reflux disease leading to replacement of the normal stratified squamous epithelial lining of the esophagus by glandular epithelium of various types [24, 32]. The importance of a diagnosis of Barrett esophagus is its association with the development of an esophageal adenocarcinoma. In contrast to what Norman Barrett originally thought, Barrett esophagus is a premalignant condition, and the incidence of Barrett carcinoma has increased dramatically since his publication in 1950 [12]. Barrett adenocarcinoma is preceded by a well-defined premalignant lesion, i.e., dysplasia (intraepithelial neoG. J. A. Offerhaus · S. van Eeden · F. J. W. ten Kate · A. Bosma Department of Pathology, Academic Medical Center Amsterdam, The Netherlands

Intestinal Metaplasia of the Esophagus or Esophagogastric Junction Evidence of Distinct Clinical, Pathologic, and Histochemical Staining Features

Our purpose was to evaluate the clinical, histologic, and histochemical staining characteristics of intestinal metaplasia (IM) at an endoscopically normal-appearing esophagogastric junction (IM-EGJ) compared with IM in a columnar-lined esophagus (IM-CLE). A prospective study included 253 patients referred for elective upper gastrointestinal endoscopy. Biopsy specimens were obtained from 2 cm above and immediately distal to the squamocolumnar junction, the gastric corpus, and the antrum. Any red mucosa above the EGJ was sampled. IM-CLE (prevalence, 5.5%) typically occurred in white male smokers with a long history of reflux symptoms. IM-EGJ (prevalence, 9.1%) was associated with corpus and antrum gastritis and with IM at these sites. IM-CLE usually (13/14 [93%]) was the incomplete type IM, whereas only 12 (52%) of 23 patients in the IM-EGJ group had incomplete IM. IM-EGJ and IM-CLE should be considered as separate entities. Further research is needed to evaluate whether neoplastic progression of IM-EGJ is related to its mucin profile.