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Mechanisms concerning the growth effects of gastrin were studied using model systems in which rat cholecystokinin-B (CCK-B) receptors were transfected into Chinese hamster ovary (CHO) and Swiss 3T3 cells. It was observed that the activation of CCK-B receptors inhibited the growth of CHO cells. On the other hand, the activation of CCK-B receptors stimulated the growth of Swiss 3T3 cells. In the two models, CCK-B receptor activation were significantly influenced by cellular conditions such that differences in growth responses could be attributed to factors other than differences in receptor coupling.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare, heterogeneous group of tumors that originate from the endocrine system of the gastrointestinal tract and pancreas. GEP-NENs are subdivided according to their differentiation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Since GEP-NENs represent rare diseases, only limited data from large prospective, randomized clinical trials are available, and recommendations for treatment of GEP-NEN are in part based on data from retrospective analyses or case series. In this context, tractable disease models that reflect the situation in humans and that allow to recapitulate the different clinical aspects and disease stages of GEP-NET or GEP-NEC are urgently needed. In this review, we highlight available data on mouse models for GEP-NEN. We discuss how these models reflect tumor biology of human disease and whether these models could serve as a tool for understanding the pathogenesis of GEP-NEN and for disease modeling and pharmacosensitivity assays, facilitating prediction of treatment response in patients. In addition, open issues applicable for future developments will be discussed. [ABSTRACT FROM AUTHOR]

The tumor suppressor gene [p16.sup.INK4a] inhibits the kinase activity of the cyclin-dependent kinase 4-6/ cyclin D complexes and subsequent phosphorylation of critical substrates necessary for transit through the G1 phase of the cell cycle. Recent studies suggested that control of the G1/S boundary might not be the sole biological function of [p16.sup.INK4a]. We hypothesized that [p16.sup.INK4a] might influence hitherto unknown critical features of a malignant epithelial phenotype, such as anchorage dependence. Here we provide evidence that stable transfection of [p16.sup.INK4a] restitutes apoptosis induction upon loss of anchorage (anoikis) in a variety of human cancer cells. Anoikis in [p16.sup.INK4a]-transfected cells was evidenced by DNA fragmentation and poly(ADP-ribose) polymerase cleavage upon cultivation on polyhydroxyethylmethacrylate-coated dishes and was associated with suppression of anchorage-independent growth as well as complete loss of tumorigenicity. [p16.sup.INK4a]-mediated anoikis was due to selective transcriptional upregulation of the [[Alpha].sub.5] integrin chain of the [[Alpha].sub.5][[Beta].sub.1] fibronectin receptor as detected by FACS analysis, immunoprecipitation, Northern blotting, and nuclear run-on assays. Addition of soluble fibronectin and inhibitory as antibodies to nonadherent cells completely abolished [p16.sup.ISK4a]-mediated anoikis, whereas laminin was ineffective. Furthermore, antisense-induced downregulation of the [[Alpha]5] integrin chain in [p16.sub.INK4a]-transfected cells restored resistance to anoikis. These data suggest a novel functional interference between a cell cycle-regulating tumor suppressor gene and membrane-bound integrins, thus regulating a hallmark feature of an epithelial transformed phenotype: susceptibility to anoikis. Key words: tumor suppressor [p16.sub.INK4a] * anoikis * fibronectin * integrin * tumorigenicity

Background: Mesenteric fibrosis (MF) surrounding a lymph node metastasis is a known phenomenon in midgut neuroendocrine tumors (NETs) with characteristic radiological appearance. Its etiology is poorly understood as it affects some but not all midgut NET patients with lymphatic involvement. This study assessed a potential relationship of MF with carcinoid syndrome, urinary 5-hydroxyindoleacetic acid (5-HIAA), and carcinoid heart disease (CHD). Methods: A cohort of 81 patients with pathologically proven NETs with the primary site in the midgut and mesenteric lymphatic metastases on imaging were retrospectively included. Imaging characteristics of lymphatic and hepatic metastases at diagnosis (size, number, burden, and morphologic features, including presence of MF), Ki67 grading, 5-HIAA, functionality, and development of CHD were analyzed. Results: Overall, 54% of patients had MF. The presence of MF was more frequently associated with mesenteric vessel encasement (100 vs. 46% without MF; p < 0.001), presence of hepatic metastases (91 vs. 62%; p = 0.002), larger hepatic tumor burden (15 vs. 5%; p = 0.001), and functionality (86 vs. 43%; p < 0.001). Multivariate analysis revealed 5-HIAA ≥395 µmol/day (p = 0.020), age (p = 0.013), and largest lymphatic metastasis ≥24 mm (p = 0.009) as independent predictors of MF, while functionality (p = 0.098) and CHD (p = 0.070) showed a tendency towards significance. MF was associated with decreased time to development of CHD in functional midgut NETs (p = 0.043). Conclusions: We found a significant association of MF with metastatic patterns and with criteria of functionality. The association of MF with elevated 5-HIAA, and consecutively with carcinoid syndrome and potential development of CHD, suggests a linked pathophysiological mechanism, which might be similar to that of endocardial fibrosis. [ABSTRACT FROM AUTHOR]