The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and ß-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.

Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis.

The gene encoding the receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in many human cancers. However, it is unclear whether RHAMM plays a causal role in tumor initiation or progression. Using somatic gene transfer in a mouse model of islet cell tumorigenesis, we demonstrate that RHAMM isoform B (RHAMM(B)) promotes tumor growth and metastases to lymph nodes and the liver. The propensity of RHAMM(B)-expressing cells to metastasize to the liver was confirmed using an experimental metastasis assay in which cells were injected into the tail vein of immunodeficient mice. However, RHAMM(B) did not increase cell migration or proliferation in culture. In initial efforts to identify signaling pathways activated by RHAMM(B), we found that RHAMM(B) induced phosphorylation of epidermal growth factor receptor (EGFR), Erk1/2, and STAT3 and conferred susceptibility to apoptosis after treatment with an EGFR inhibitor, gefitinib. Taken together, the results indicate that RHAMM(B) promotes hepatic metastasis by islet tumor cells, perhaps through growth factor receptor-mediated signaling.

Islet cell tumours.

Pancreatic endocrine tumours can cause hormonal symptoms by over-secretion of hormones. They are less aggressive than exocrine pancreatic cancer, but carry a variable prognosis. The tumours are either sporadic or hereditary, as part of the multiple endocrine neoplasia type 1 syndrome. Despite the rarity of these tumours, they evoke significant interest in the research community and important advances have been made over the past years. This chapter provides an overview of the tumours and recent advances in the field. Hereditary forms of pancreatic endocrine tumours are caused by mutations in the MEN1 gene. Menin, the protein encoded by this gene, has been shown to interact with numerous transcription factors and proteins involved in cell-cycle control, shedding some light on the importance of the protein. Several genes have been shown to be up- or down-regulated, suggesting candidates to be further evaluated for a role in tumourigenesis. Several advances have been made in prognostication; a tumour-node-metastasis system has been evaluated and seems to have prognostic value, and several new molecular prognostic markers are under evaluation. It is hoped that the tumour-node-metastasis system and other prognostic markers will be adopted in clinical routine and improve prognostication and treatment choices. Surgery is still the only cure, but several new palliative drugs and interventions are in use or under investigation. Radiofrequency ablation is increasingly used for liver metastases, and a number of new chemotherapy drugs are being tested. Despite improvements in treatment, no clear improvement in survival has been demonstrated.

Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models.

Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature.

Long-term follow-up of patients with multiple endocrine neoplasia type 1.

Whether early surgical treatment of non-functioning pancreas islet cell tumor (NFPT) provides a favorable quality of life and life expectancy in patients with multiple endocrine neoplasia type 1 (MEN1) remains controversial. We analyzed the long-term clinical courses and surgical outcomes of 14 Japanese patients with MEN1-associated NFPTs. NFPTs smaller than 20 mm in diameter did not show any apparent growth over a long monitoring period. Furthermore, these small NFPTs did not metastasize to regional lymph nodes or the liver. On the other hand, the development of additional NFPTs or metastasis was found in five of six patients with large (35 mm or larger) NFPTs. Among the seven patients who underwent a partial pancreatectomy, six patients developed impaired glucose tolerance or diabetes. The accumulation of more prospective data is needed to clarify the optimal surgical indications for patients with NFPTs, especially among the Japanese population, which has a relatively low insulin secretion potency compared with non-Hispanic white and African-American populations.

Gastrointestinal manifestations of endocrine disease.

The hormonal interactions among the systems throughout the body are not fully understood; many vague clinical symptoms may in fact be manifestations of underlying endocrine diseases. The aim of the following review is to discuss gastrointestinal manifestations of surgically correctable endocrine diseases, focusing on abnormalities of thyroid function, cancer and finally autoimmune diseases. We also review manifestations of pancreatic endocrine tumors, and multiple endocrine neoplasia.

[Non-functional islet-cell tumor: analysis of 237 cases].

OBJECTIVE: To summarize the clinical aspects of nonfunctional islet-cell tumor (NIT) reported in Chinese periodicals. METHODS: Articles in Chinese on NIT were screened from the Chinese Bio-Medical Database (1981.1 - 1999.10). Data of epidemiology, clinical manifestations, diagnosis, defferential diagnosis, and treatment of NIT were analyzed. RESULTS: 60 articles and 237 cases of NIT were selected. The female to male ratio was 2.9:1. Abdominal mass was the most common clinical symptom. It was difficult for the pre-operative diagnosis of NIT and differentiation from pancreatic tumor or retroperitoneal mass. The malignant rate of NIT was 35%. The five-year survival rate of malignant NIT was 53.1%. CONCLUSION: NIT is rare. It occurs more often in female than in male. The preoperative diagnostic rate is rather low. The prognosis of malignant NIT is favorable. Active treatment is strongly recommended.

The effects of ad libitum overfeeding and moderate and marked dietary restriction on age-related spontaneous pancreatic islet pathology in Sprague-Dawley rats.

This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on aged-related degenerative and proliferative changes of the endocrine pancreas in Sprague-Dawley (SD) rats. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72-79% of AL (group 2), DR at 68-72% of AL (group 3) or DR at 47-48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Before each necropsy, glucose and serum insulin levels were measured. In addition to the routine histopathologic examination performed in both sexes, determination of 9 pancreatic islet stereologic parameters was done in males at 13, 26, and 53 weeks. In AL-fed rats, early changes in the islet morphology occurred, which resulted in a high incidence of islet fibrosis, focal hyperplasias and adenomas by two years. DR was dose-proportionally associated with decreased glucose and serum insulin levels, and delayed the onset, and decreased the incidence and severity of islet fibrosis and hyperplasia. Results of the stereology supported the histopathologic and clinical chemistry findings. It demonstrated that, compared to AL-fed rats, DR-fed rats had smaller pancreas, smaller pancreatic islets, smaller insulin secreting cell volumes, a lower degree of islet fibrosis and a lower islet cell BrdU labeling index, which correlated with a lower incidence of islet adenoma and carcinoma at study termination. Moderate and marked degrees of DR delayed the onset and severity of islet hyperplasia and fibrosis in a temporal- and dose-related manner. In contrast to marked DR, which dramatically prevented these changes, moderate DR delayed but not prevented onset of islet tumors. These findings support the concept that moderate DR results in a better-controlled animal model with a lower incidence or delayed onset of chronic spontaneous endocrine diseases in the rat bioassay.

The pancreatic renin-angiotensin system: does it play a role in endocrine oncology?

The characterization of a local renin-angiotensin system in the pancreas has attracted much attention because of its potential clinical applications. A pancreatic renin-angiotensin system may be present in humans and may interact with islet cells. Nevertheless, our knowledge of the renin-angiotensin system in the human pancreas is still in its infancy, especially in the field of endocrine oncology. Much of our knowledge stems from the study of the pancreas and pancreatic endocrine tumors of rodents. Thus, the direction of future research should be based on in-depth and collaborative efforts between researchers in the various disciplines in order to apply the newly acquired scientific knowledge to the patient.

Evaluation of PCNA, p53, K-ras and LOH in endocrine pancreas tumors.

BACKGROUND/AIMS: The object of this study was to evaluate the characters of the endocrine pancreas tumors including proliferative activity, p53 mutation, K-ras mutation and microsatellite instability. METHODOLOGY: The 13 endocrine tumors of the pancreas were enrolled in this study. There were 8 hypervascular tumors and 4 normo- or hypovascular tumors. All cases were immunohistochemically characterized in paraffin sections for the presence of proliferating cell nuclear antigen and p53 protein. Mutation in K-ras at codon 12 was detected by the Mutant-allele-specific amplification system. Microsatellite instability was examined by using frozen tissues in the 2 cases. RESULTS: Proliferating cell nuclear antigen labeling index range was 0.00-0.62 (0.26 +/- 0.23). p53 was positive in 4/13 tumors. K-ras codon 12 mutation was not detected in any tumors. PCNA LI was significantly lower in hypervascular tumors (0.16 +/- 0.20) than normo- or hypovascular tumors (0.44 +/- 0.17) (P < 0.05). PCNA LI was significantly lower in the p53-positive tumors (0.48 +/- 0.17) than the p53-negative tumors (0.17 +/- 0.18) (P < 0.05). K-ras codon 12 mutation was not detected in any tumors. Loss of heterozygosity in 3p was detected in 1 tumor. CONCLUSIONS: Hypervascular endocrine pancreas tumors have low proliferative activity. p53 mutation influences proliferation as the late event of tumor progression.

Mechanism of gastric acid hypersecretion in patients with islet cell tumor without hypergastrinemia: studies in rats.

BACKGROUND & AIMS: A nongastrin acid-stimulating peptide (NGASP) has been found in ulcerogenic pancreatic tumor syndrome without hypergastrinemia. The mechanism of gastric acid hypersecretion by NGASP was investigated in rats. METHODS: In vivo, gastric acid secretion and in vitro histamine release from enterochromaffin-like (ECL) cells in responses to tumor extract (TE) and synthetic human gastrin-17 I or pentagastrin (PG) were studied. Whether the 2 secretagogues potentiate each other was determined. RESULTS: TE dose-dependently stimulated histamine release, which was not blocked by a cholecystokinin (CCK)-B receptor antagonist. When TE was incubated with trypsin, the activity was abolished but was not affected by antibody. However, when rats were pretreated with antigastrin serum or CCK-B receptor antagonist, the acid secretion by TE was virtually abolished. The dose response of acid secretion to TE in the rats receiving PG in a threshold dose was significantly greater than that achieved by TE alone. Similarly, the dose response to PG combined with a threshold dose of TE was significantly greater than that produced by PG alone. CONCLUSIONS: NGASP stimulates histamine release from ECL cells, but the release is not mediated via CCK-B/gastrin receptor. NGASP and gastrin may potentiate each other to produce acid hypersecretion in ulcerogenic pancreatic tumor syndrome.

Islet cell tumors.

Although quite rare, the islet cell tumors present an important challenge to the clinician because of their protean manifestations and potential lethality. Early diagnosis is essential and depends on recognition of the classic and variant clinical syndromes followed by confirmation of elevated peptide levels by radioimmunoassay. Medical control of the hormonal syndrome with agents such as diazoxide for insulinoma, omeprazole for gastrinoma, and octreotide for vipoma and glucagonoma allows an orderly and thorough investigation for associated endocrinopathies and comorbid medical conditions. Localization and staging of the tumors are important because they may be small and occult, widely metastatic, or multifocal in the context of multiple endocrine neoplasia type I (MEN I) syndrome. Computed tomography, visceral angiography, endoscopic ultrasonography, and indium-labeled octreotide scanning are the most useful preoperative imaging techniques. Surgical exploration that includes intraoperative ultrasonography remains an essential localization technique for occult tumors, particularly insulinomas and gastrinomas. For all patients other than some with advanced metastatic disease or MEN I syndrome, an aggressive surgical approach with the intent of complete and curative tumor excision is indicated. Surgical cure is possible in most insulinomas, a substantial proportion of gastrinomas, and some patients with the other more rare and malignant islet cell tumors. At present, adjuvant medical therapies for unresectable malignant disease have limited efficacy. However, a variety of newer and innovative tumor localization techniques, operative strategies, and nonoperative treatment modalities hold considerable promise for the attainment of higher cure rates and improved palliation.

[The endocrine pancreas]. / Pâncreas endócrino.

The islets of Langerhans provide energy storage and disposal, and protection from plasma glucose excursions, especially hypoglycemia. Insulin-dependent diabetes mellitus (IDDM) results from autoimmune beta-cell damage. Prevention of IDDM has already been achieved in animal investigation and some centers are now screening and treating individuals at high risk for developing IDDM. Immunosuppressive drugs can induce transient remission of recent-onset IDDM. Intensive insulin treatment of IDDM delays the onset and slows the progression of long-term complications. Non-insulin dependent diabetes mellitus (NIDDM) is the result of beta-cell malfunction and is strongly associated with X syndrome. Diet and exercise are of undoubted importance in NIDDM prevention and treatment. Functional endocrine tumors of the pancreas (FET) are rare hormone and peptide-secreting neoplasms. These peptides may or may not occur naturally in the islets. FETs often occur with multiple endocrine neoplasia 1 (MEN 1) so that MEN-1 screening should always be performed, and extended to family members whenever diagnosed. Drugs--alcohol, insulin and sulfonilureas--are the main cause of hypoglycemia. Insulinoma is the main cause of post-absorptive organic hypoglycemia. Non islet-cell tumors seldom cause hypoglycemia. Insulinoma often is a solitary tumor, but it may be multicentric and may coexist with cell hyperplasia and nesidioblastosis. Symptoms of neuroglycopenia may be mistaken for neuropsychiatric disease. The diagnosis is based on confirmation of post absorptive hypoglycemia and hyperinsulinism. Gastrinoma causes Zollinger-Ellison syndrome (ZES) which is characterized by fulminating peptic ulcer disease. The tumor is often malignant, and it may be multicentric and may occur with cell hyperplasia and nesidioblastosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-tumor action of dietary restriction is lesion-dependent in male Fischer 344 rats.

The effects of dietary restriction (DR) on spontaneous oncogenesis in male Fischer 344 rats were analyzed. Previously reported analyses of studies carried out in our laboratory demonstrated that DR reduces the incidence and delays the onset, but not the progression, of leukemia in male F344 rats. In this report, the influence of DR on pituitary tumors, adrenal pheochromocytoma, pancreatic islet cell tumors, and interstitial cell tumors of the testis was analyzed. DR reduced the relative incidence (relative onset rates) and delayed the onset of the four tumors. DR also retarded the progression (duration from onset to death) of pituitary tumors and pheochromocytoma. DR has delayed the onset of all tumors of the male F344 rat so far analyzed, but its effect on tumor progression appears to be lesion-dependent.

Is there a prognostic difference between functional and nonfunctional islet cell tumors?

BACKGROUND: Pancreatic islet cell tumors are categorized as either functioning or nonfunctioning. Functioning islet cell tumors (FIT) elaborate a variety of hormones, producing dramatic symptoms, while the initial presentation of non-functioning islet cell tumors (NIT) is commonly an abdominal mass or symptom complex related to invasion of adjacent structures. As a result, NIT are purported to present at a later stage, with lower resectability rates, and an overall poorer prognosis, when compared to FIT. In addition, a number of reports have indicated that the incidence of NIT has increased significantly in recent years. PATIENTS AND METHODS: Twenty-eight patients were studied retrospectively. All had islet cell tumors of the pancreas and were seen at the University of Nebraska Medical Center and affiliated Nebraska Methodist Hospital during a 19-year period. RESULTS: There were 9 patients (32%) in the NIT group and 19 (68%) in the FIT group. The mean ages at presentation were 61 years for the NIT and 52 years for the FIT group. In the NIT group, all presented with either abdominal pain (n = 7) or jaundice (n = 2). In contrast, over 90% of the patients with FIT had symptoms referable to the specific hormone elaborated by the tumor. Primary tumor size for NIT was 4.1 +/- 0.7 cm versus 5.0 +/- 0.6 cm for the FIT group. No significant difference was found for NIT versus FIT with respect to the incidence of metastatic disease at presentation (44% versus 53%), resectability rate with curative intent (44% versus 53%), or disease-free survival at 2 years (67% versus 40%). CONCLUSIONS: This series, in contrast to earlier reports, suggests that nonfunctioning islet cell tumors do not present at a more advanced stage, have lower resectability rates, or an overall poorer long-term prognosis when compared to functioning tumors.

Functional coupling between the cyclic adenosine monophosphate pathway and cholecystokinin secretion in RIN cells.

The cellular events associated with cAMP-dependent cholecystokinin (CCK) release were investigated with an X-ray induced rat pancreatic tumor cell line (RIN 1056 E). Forskolin dose-dependently stimulated the release of CCK. Agents that increase [Ca2+]i (thapsigargin, Bay K 8644, ionomycin) also stimulated the release of CCK. Conversely, absence of extracellular Ca2+ or cell treatment with various calcium channel blockers strongly reduced the forskolin-induced CCK release. Finally, the cAMP-kinase inhibitor H89, the calmodulin antagonist W7 and the Ca/calmodulin-dependent protein-kinase II inhibitor KN62 strongly inhibited the forskolin-evoked CCK secretion. We conclude that the release of CCK via a cAMP-dependent pathway is dependent on the activation of voltage-dependent calcium channels and may implicate protein kinase A, calmodulin and the Ca/calmodulin-dependent protein kinase II.

Cell lines derived from pancreatic tumors of Tg(Ela-1-SV40E)Bri18 transgenic mice express somatostatin and T antigen.

Continuous cell lines have been isolated from islet cell, small cell anaplastic and acinar cell carcinomas arising in the pancreas of transgenic mice, line Tg(Ela-1-SV40E)Bri18. These mice carry the pseudogene construct composed of elastase-1 promoter linked to the SV40 T antigen. Cells derived from islet cell or small cell anaplastic tumors secreted insulin and somatostatin during the early period of culture. Phenotypic alterations occurred during culture, whereby insulin secretion ceased and cells instead secreted somatostatin, indicating a change from beta-cell to delta-cell phenotype. Acinar cell lines did not secrete amylase or lipase.

Doppler color flow imaging in the detection and quantitative measurement of the gastroduodenal artery blood flow.

The purpose of this article was to investigate the detection rate of gastroduodenal artery blood flow (GDABF), and to measure its velocity and volume flow rate using Doppler color imaging. The GDABF was detected in 40 of 41 (98%) normal subjects with longitudinal scanning and in 36 (88%) with transverse scanning. The velocity of the GDABF was 21 +/- 8 cm/sec (m +/- SD) and the volume flow rate was 67 +/- 20 mL/min. Without color Doppler, the vascular lumina of the GDA was demonstrated in 27 (66%) subjects by longitudinal scanning and in 26 (63%) by transverse scanning. The hemodynamics of the GDA were revealed noninvasively using Doppler ultrasonography in a patient with a malignant islet cell tumor of the pancreas and one with a ductal cell carcinoma of the pancreas.

A study of biological behavior based on the expression of a proliferating antigen in neuroendocrine tumors of the digestive system.

The expression of a proliferating antigen by Ki-67 immunohistochemistry was evaluated in 32 gastrointestinal carcinoids and in 5 pancreatic islet cell tumors. In the tissue sections the number of labelled nuclei was calculated per tumor area. The tumors were classified as low proliferating (less than 0.3 labelled cells/mm2), medium proliferating (0.3-1 labelled cells/mm2), and high proliferating (greater than 1 labelled cell/mm2). In 26 tumors obtained from patients receiving antitumor therapy (alpha-interferon) the proliferative activity was decreased. In treated midgut carcinoids the proliferative activity in metastatic tissue was significantly reduced (p less than 0.05). Though not statistically significant, primary midgut carcinoids collected from untreated patients displayed a lower proliferative activity than liver metastases. A survival analysis revealed that patients with tumors displaying low proliferative activity had a better survival than those with high proliferative activity (p less than 0.05). Single cell cytofluorometric DNA analyses showed regular diploid stem cell lines in the majority of tumors from untreated patients (9/11 cases). No correlation was found between the calculated proliferative activity and the DNA profile. The obtained results indicate that the expression of a proliferation antigen by Ki-67 immunohistochemistry can be used to evaluate the biological behavior of neuroendocrine tumors of the digestive system and predict survival.