Pancreatic Polypeptide Cell Proliferation in the Pancreas and Duodenum Coexisting in a Patient With Pancreatic Adenocarcinoma Treated With a GLP-1 Analog.

A partial pancreaticogastrodudenectomy was performed on a 66-year old man with type 2 diabetes mellitus because of an invasive, moderately differentiated adenocarcinoma in the head of the pancreas. In the adjacent grossly normal tissue of the uncinate process, there was a massive proliferation of pancreatic polypeptide (PP) cells confined to this region and showed invasive pattern. Strikingly, in the heaped area of his duodenum, there was a strikingly large number of PP, glucagon, a few insulin cells in a mini-islet-like patterns composed of glucagon and insulin cells.

Effects of porcine pancreatic enzymes on the pancreas of hamsters. Part 2: carcinogenesis studies.

Context: Our previous study suggested that porcine pancreatic extract in hamsters with peripheral insulin resistance, normalizes insulin output, islet size and pancreatic DNA synthetic rate. It also inhibited the growth of human pancreatic cancer cells in nude mice.

Objective: To examine the potential value of the porcine pancreatic extract in controlling pancreatic carcinogenesis in this model, the present experiment was performed.

Effects of porcine pancreatic enzymes on the pancreas of hamsters. Part 1: basic studies.

Context: Porcine pancreatic enzymes (PPE) extracted from glandular stomach has been used for the treatment of pancreatic cancer patients. Unfortunately, no information is available on the in vitro and in vivo effect on the pancreas and other tissues.

Objective: We used Syrian Golden hamsters, a unique pancreatic cancer model, to obtain basic information on PPE for its eventual use for the treatment of pancreatic cancer.

A novel tissue for islet transplantation in diabetics.

Background: Islet transplantation for diabetes therapy has remained a challenge. None of the currently used transplantation sites have provided satisfactory results as islets seem to require a specific tissue for survival and growth. Since the submandibular gland (SMG) shares physiological and anatomical similarities with the pancreas, we attempted to use this tissue as the transplantation site.

The pattern of neural elements in the islets of normal and diseased pancreas and in isolated islets.

Context: The association between islet cells and neural elements, the so-called "neuro-insular complex", has been known for centuries.

Objective: We examined the expression of beta-III tubulin, in normal pancreases from organ donors, surgical specimens of chronic pancreatitis, surgical specimens of ductal type carcinoma, isolated and purified islets of a 57-year-old male and the pancreases of adult Syrian golden hamsters by immunohistochemistry using a monoclonal antibody to beta-tubulin.

Results: In the normal pancreas of humans and hamsters, beta-III tubulin was expressed in alpha- and beta-cells, but not in PP cells, neural fibers and gangliae.

Morphometric studies in human pancreatic cancer argues against the etiological role of type 2 diabetes in pancreatic cancer.

Background: To understand the role of islet amyloid polypeptide (IAPP) in type 2 diabetes and pancreatic cancer (PC), we investigated the patterns of its expression and its ratio to insulin, glucagon, somatostatin and pancreatic polypeptide cells by morphometry in tissues from these two diseases in comparison to the normal pancreas.

Materials And Methods: Pancreatic tissues from 11 donors (five without pancreatic disease and six with type 2 diabetes) and 11 surgical specimens from PC patients obtained from the cancer area (zone A) and the adjacent tumor-free area (zone B) were examined immunohistochemically. The size of islets, the number on beta-, alpha-, delta- pp- and IAPP-expressing cells and their ratios in the islets of these tissues were determined.

Pancreatic cancer and glucose metabolism.

Background/aims: The mechanism of impaired glucose metabolism that develops in most patients with pancreatic cancer is obscure. The association between pancreatic cancer and diabetes is controversial. Impaired glucose tolerance or diabetes mellitus may develop as a clinical manifestation of pancreatic cancer; however, diabetes may be a predisposing risk factor for pancreatic cancer.

Diabetes mellitus in pancreatic cancer: is it a causal relationship?

The relationship between type 2 diabetes mellitus and pancreatic cancer (PC) is not clear. It has been reported that the increased release of islet amyloid polypeptides (IAPPs) is responsible for the impaired glucose tolerance in PC patients. However, no information exists on the patterns of IAPP expression in PC tissue in comparison with tissue from the normal pancreas and that of a patient with type 2 diabetes.

MUC4-expressing pancreatic adenocarcinomas show elevated levels of both T1 and T2 cytokines: potential pathobiologic implications.

Objective: The human MUC4 mucin plays an important role in the pathogenesis of pancreatic cancer. Recently, we have demonstrated that MUC4 expression in pancreatic tumor cells is regulated by interferon-gamma (IFNgamma) and by retinoic acid via transforming growth factor beta 2 (TGFbeta-2). In the present study, we established the pathobiological association of various cytokines and MUC4 in pancreatic tumor tissues and tumor cell lines.

Distribution of pancreatic endocrine cells including IAPP-expressing cells in non-diabetic and type 2 diabetic cases.

There is a lack of agreement on the distribution of islet amyloid polypeptide (IAPP) in the pancreases of healthy and diabetic subjects. Therefore, a detailed morphometrical and immunohistochemical study was performed to obtain information on the distribution of cells expressing insulin, glucagon, somatostatin, pancreatic polypeptide (PP), and IAPP in the pancreases of non-diabetic (n=4) and diabetic individuals (n=6). In the non-diabetic cases, beta-cells contributed to approximately 64%, alpha-cells to 26%, delta-cells to 8%, PP cells to 0.

Expression of Oct4, a stem cell marker, in the hamster pancreatic cancer model.

Background: Oct4 has been shown to present a stem cell marker that is expressed in embryonic cells and in germ cell tumors. Recently, its expression in a few human tissues and cancer cells has been reported. Because in the hamster pancreatic cancer model most tumors develop from within islets presumably from stem cells, we investigated the expression of Oct4 in this model.

Are there any stem cells in the pancreas?

A vast number of studies indicate the presence of stem/progenitor cells virtually in all tissues in adult organs, particularly in bone marrow. Recent studies, however, cast doubt about the existence of true stem cells in adult tissue. The complex integrity of several cells with distinct morphologic and functional properties in the mature pancreas confers an appropriate status for stem cell research.

Pancreatic hepatocellular tumor.

Background: Hepatocellular differentiation of pancreatic cells has been observed under certain conditions in several species, including humans. Their cell of origin and biology has remained controversial. Generally, these lesions have been considered a degenerative process.

High concentrations of retinoids induce differentiation and late apoptosis in pancreatic cancer cells in vitro.

Background: Our previous investigations showed that retinoids, at specific concentrations, can inhibit cell proliferation. In this investigation, we hypothesize that high concentrations of retinoids can induce phenotypic changes (differentiation) and late apoptosis in pancreatic cancer cells in vitro.

Materials And Methods: To test our hypothesis, retinoid-induced differentiation was assessed: (1) phenotypically by light and electron microscopy and (2) biochemically by measuring carbonic anhydrase, aerobic metabolic and mucin producing activities.

Natural retinoids inhibit proliferation and induce apoptosis in pancreatic cancer cells previously reported to be retinoid resistant.

Background: The anticancer ability of natural retinoids on pancreatic adenocarcinoma, an aggressive tumor, is still controversial. This investigation tested the hypothesis that all-trans retinoic acid can inhibit proliferation and induce apoptosis in pancreatic cancer cell lines.

Materials And Methods: Using our previously optimized conditions, the effect of all-trans retinoic acid (atRA, 0.

ErbB2 growth factor receptor, a marker for neuroendocrine cells?

Background/aims: The overexpression of ErbB2 in pancreatic cancer has been reported with a varying incidence ranging between 1 and 80%. Our routine examination, however, revealed a consistently strong immunoreactivity of three anti-ErbB2 growth factor receptor antibodies in pancreatic islets and intrapancreatic ganglia. To validate our findings and to understand the reasons for the reported differences in the frequency of ErbB2 overexpression in pancreatic cancer, the following studies were performed.

ErbB2 oncogene antibodies differentiate between the normal and diseased pancreas, and between chronic pancreatitis and pancreatic cancer.

Histological differentiation between chronic pancreatitis and pancreatic cancer, especially in biopsy material, remains challenging and the frequent association of 'secondary' chronic pancreatitis (due to ductal obstruction) with pancreatic cancer causes additional diagnostic problems. Our study, using anti-ErbB2 antibodies from Santa Cruz and Dako in tissues from the normal pancreas, chronic pancreatitis and pancreatic cancer showed that these antibodies discriminate between primary chronic pancreatitis and 'secondary' chronic pancreatitis due to pancreatic cancer. Tissues from 28 pancreatic cancer patients, 15 chronic pancreatitis patients and 12 organ donors or early autopsy cases were subjected to immunohistochemical studies using polyclonal ErbB2 antibodies from Santa Cruz and Dako.

The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) and Genistein is effective in inhibiting pancreatic cancer growth.

Objectives: Our previous studies have shown that, contrary to many other human pancreatic adenocarcinoma cell lines, AsPC1 cells are resistant to the apoptotic effect of the tumor necrosis factor-related apoptosis-inducing ligand, also called Apo2L (TRAIL/Apo2L). In our in vitro studies, the combination of TRAIL/Apo2L and protein synthesis inhibitor, genistein, but not genistein alone, was, however, effective in inducing apoptosis in AsPC1 cells. In the present study, we examined the effect of TRAIL/Apo2L with genistein on the growth of AsPC1 cells in vitro and in vivo.

Pancreatic enzyme extract improves survival in murine pancreatic cancer.

Objectives: The disappointing current therapeutic approaches for pancreatic cancer (PC) represent an urgent need for the development of novel methods to control the disease. Based on a recent report on the effectiveness of pancreatic enzyme therapy, we examined the effect of porcine pancreatic enzyme extracts (PPE) on human PC xenografts in nude mice.

Methods: The malignant human PC cell line AsPC1 was transplanted into the pancreas of male beige XID nude mice that were treated or not with PPE in drinking water.

Differences in immunohistochemical expression of xenobiotic-metabolizing enzymes between normal pancreas, chronic pancreatitis and pancreatic cancer.

Metabolic activation of many toxins, carcinogens, drugs, and anti-cancer agents is governed by the cytochrome P450 (CYP) drug-metabolizing enzyme system. To help elucidate the role of this enzyme system in the pathogenesis of chronic inflammatory and malignant pancreatic diseases, we compared the immunohistochemical expression pattern of 8 CYP-enzymes in 24 normal, 20 chronic pancreatitis, and 21 pancreatic cancer specimens using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, and 3A4, and the NADPH cytochrome P450 oxido-reductase (NA-OR). Compared to the normal pancreas, a higher frequency of immunopositivity for CYP 1A2, 2B6, 2C8/9/19, 2D6, and NA-OR was found in chronic pancreatitis, and of all CYPs but 1A2 in pancreatic cancer.

Diabetes and its relationship to pancreatic carcinoma.

Introduction: The mechanism of impaired glucose metabolism that develops in most patients with pancreatic cancer (PC) is obscure and the association between PC and diabetes is controversial. According to the published data, about 70% of patients with PC have an impaired glucose tolerance (IGT) or frank diabetes, whereas 30% do not. Up to 60% of the patients with IGT or diabetes show improvement in glucose metabolism after surgery, whereas other patients show only mild or no improvement.

Neural invasion in the staging of pancreatic cancer.

The natural history of pancreatic ductal adenocarcinoma makes it one of the most malignant human diseases. Unknown etiology, lack of early symptoms, explosive outcome, short survival, and resistance to therapy are hallmarks of this cancer. Although surgery has been shown to be an effective therapeutic approach, the inevitable tendency for recurrence, even after apparently curative operation, has remained a mystery.

What is the origin of pancreatic adenocarcinoma?

The concept of pancreatic cancer origin is controversial. Acinar, ductal or islet cells have been hypothesized as the cell of origin. The pros and cons of each of these hypotheses are discussed.

Expression of drug-metabolizing enzymes in the pancreas of hamster, mouse, and rat, responding differently to the pancreatic carcinogenicity of BOP.

Background/methods: N-nitroso-bis(2-oxopropyl)amine (BOP) induces pancreatic ductal adenocarcinoma in Syrian golden hamsters, but not in rats or mice. To examine whether this difference is due to the diversity in the presence and distribution of enzymes involved in the metabolism of BOP, the cellular expression of nine cytochrome P-450 isozymes (CYP1A1, CYP1A2, CYP2B6, CYP2C8,9,19, CYP2D1, CYP2E1, CYP3A1, CYP3A2, and CYP3A4) and of three glutathione S-transferase isozymes (GST-pi, GST-alpha, and GST-mu) was investigated in the pancreas of hamsters, rats, and mice by immunohistochemistry.

Results: We found a wide species variation in the presence and cellular localization of the enzymes and a lack of several enzymes, including GST-alpha in islets, CYP2B6, CYP2C8,9,19, CYP3A1 in acinar cells, and CYP3A4 in ductal cells, in the rat as compared with hamster and mouse.