Pancreas Cancer

Until now, pancreatic cancer has been unresponsive to both surgical and chemotherapeutic treatment, which explains why although the tumor is relatively rare, pancreas cancer ranks as the fourth most common cause of cancer mortality in the United States. Clinicians and patients know that afflicted patients rarely survive for 5 years. Smoking is the major known cause of pancreatic cancer, accounting for about 25 to 30 of all cases. Numerous studies confirm this finding (Table 19.2) (see Chapter...

Susceptibility To Environmental Toxins

A number of gene families determine the individual cellular settings of detoxifying enzymes and a person's capacity for enzymatic detoxification (see Chapter 7). This accounts for both an individual's susceptibility to environmental toxins and a predisposition for the development of environment-related diseases. The human super gene family of uridine 5'-diphosphate glucuronyl-transferases (UGT) is known to represent Phase II detoxifying enzymes that glucuronidate not only dietary by-products...

Conclusion

Fibrosis of the pancreas is observed in primary chronic pancreatitis or duct obstructing processes. At its beginning, there is a tissue injury that induces a process of fibrogenesis that is similar to the development of fibrosis in other organs (Table 16.2). Most likely of importance for the pattern of fibrosis in the pancreas is the site where the process of fibrogenesis is initiated. It is our working hypothesis that this depends on the factors that cause necrosis or apoptosis of pancreatic...

Pancreatic Acinar Cell Carcinoma

Rigaud et al.59 studied pancreatic acinar cell (PAC) carcinoma, which is a rare pancreatic tumor that lacks any information pertinent to chromosomal and gene anomalies. As part of a genomewide allelotyping of nine PACs, these authors found that the allelotype of PAC is markedly different from that of either ductal or endocrine tumors of the pancreas. Furthermore, the involvement of chromosomes 4q and 16q appears to be characteristic of this tumor type. High-resolution mapping of the 12...

Foreword

Although all pancreatic diseases have serious consequences and the pancreas appears to be sensitive to a variety of chemicals, this tissue has not been a subject of toxicology. The reason for this could be the unreachable location of the pancreas deep in the abdomen and the lack of experimental models. The development of animal models for acute pancreatitis was initiated during the last decade and focused primarily on the normal and abnormal function of acinar cells. The data gained from...

Drug Metabolism In Pancreatic Diseases

Based on the histology of most human pancreatic cancers, which are generally detected at later stages due to their late clinical symptoms, it is commonly believed that these carcinomas derive from the exocrine tissue, especially ductal cells. Animal models, however, made it possible to examine the histogenesis of the induced pancreatic tumors at all stages of carcinogenicity. The Syrian Golden Hamster (SGH) is the only species thus far that produces pancreatic tumors that mimic the human tumors...

General Topography

The pancreas is a retroperitoneal, yellowish-white lobulated organ, which weighs approximately 100 g in adult males and 85 g in adult females.1 It is enveloped by retroperitoneal connective tissue, which forms a poorly defined capsule, and the peritoneum of the posterior wall of the lesser sac covers the anterior surface of the pancreas. The dimension of the pancreas is generally reported as between 15 to 25 cm in length, 1.4 to 4 cm in thickness, and 3 to 9 cm in height. Surgical access to the...

Vasoactive Intestinal Polypeptide

VIP is widely distributed in central and peripheral nervous systems including the intrapancreatic nerves. Electrical vagal stimulation of isolated and perfused porcine pancreas resulted in the release of VIP and increased PES both of which were inhibited by infusion of SS and galanin. Thus, VIP appears to mediate PES in response to vagal efferent stimulation. Intravenous infusion of VIP in rats resulted in increase PES of water and bicarbonate, but little protein. Nevertheless, the...

Insuloacinar Portal System

The pancreas is part of the splanchnic circulation, where the celiac and superior mesenteric arteries supply blood by and venous drainage empties into the portal vein. The superior mesenteric artery supplies the head of the pancreas, while the celiac supplies the body and tail via the splenic artery.14 The microcirculation of the pancreas usually divides into that of the acini and duct and the islets, but remains interconnected (see also Chapter 4). Wharton first described these microvascular...

Introduction

Most injuries to the pancreas are caused by chemicals that reach the pancreas through arteries. Consequently, knowledge of the vascular structure of the pancreas is of immense importance in understanding the site and the extent of the damage. The pancreas receives its blood supply from branches of the celiac artery (CEA) and the superior mesenteric artery (SMA) (Figure 4.1). The gas-troduodenal artery (GDA) generally departs from the common hepatic artery Figure 4.1 Pancreatic arterial anatomy,...

Microcirculation Of The Pancreas

The microcirculation system of the pancreas is studied by electron microscopic examination of vascular casts of human pancreas. The results are schematically illustrated in Figure 4.13.11 The vascular bed of the exocrine lobules (lobular plexus) consists of fine capillaries (Figure 4.7) that receive one or more afferent vessels (lobular arteries) from the interlobular arteries and issue one or more efferent vessels (lobular veins) continuous with the interlobular veins (Figure 4.8 and Figure...

Alloxan

Alloxan (2,4,5,6-tetraoxyprimidine 5,6-dioxyuracil), a uric acid derivative, was isolated in 1818 as the first pyrimidine derivative and was named by Wohler and Liebig who described its synthesis by uric acid oxidation.119 The diabetogenic action of alloxan was shown by Dunn and coworkers in 1943,120 who demonstrated its selective islet cell necrosis in rabbits. Since then, alloxan has been widely used as an experimental diabetes model together with STZ. In initial studies, it was observed that...

References

Gastard J., Joubaud F., Farbos T., Loussouarn J., Marion J., Pannier M., Renaudet F., Valdazo R., and Gosselin M. 1973. Etiology and course of primary chronic pancreatitis in Western France. Digestion 9 416-428. 2. Durbec J.P. and Sarles H. 1978. Multicenter survey of the aetiology of pancreatic diseases, relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion 18 337-350. 3. Goebell H., Hotz J., and Hoffmeister H. 1980....

Fammm Syndrome And Pc

Historically, the first detailed report of a family with cutaneous features consistent with the FAMMM was by Norris in 1820.35 Lynch et al.36 and Clark et al.37 provided the first detailed descriptions of the clinical and genetic (autosomal dominant) features of the FAMMM BK mole syndrome. Table 25.2 Clinical and Pathologic Features of PJS Patients with Pancreatic Tumors Clinical Presentation and Initial Detection of Histopathology of Age3 Gender Latencyb Pancreatic Tumors Pancreatic Tumors...

Occupation

A number of occupational cohort and case-control studies have evaluated occupation and pancreatic cancer mortality and incidence. Exposure is usually assessed by job title. One of the main weaknesses of these studies has been a lack of precision because of the small number of observed cases of pancreatic cancer. In general, the evidence linking occupations with pancreatic cancer has not been strong. However, a number of occupations and specific occupational exposures have emerged as potentially...

The Transforming Growth Factor p Family In Pancreatic Diseases

Transforming growth factor (TGF-p) was originally discovered as a secreted factor that induces malignant transformation in vivo.62 Now it is known that the TGF-p superfamily of ligands consists of a large family of polypep-tide growth factors that exert a wide range of biological effects, including cell growth and differentiation, angiogenesis, cell invasion, extracellular matrix composition, local immune function, and apoptosis.63,64 The mammalian TGF-p superfamily includes the TGF-p family...

Effects Of Ethanol On The Pancreas

Ethanol consumption results in various effects on pancreatic exocrine secretion (Table 15.1) (reviewed in Reference 30), and ethanol and its metabolites have additional damaging effects on the pancreas (Table 15.2) (reviewed in Reference 26). Thus, these different effects of ethanol on the pancreas have to be considered separately. 15.4.1 Alcohol and Pancreatic Exocrine Secretion The pancreatic secretory response to intestinal nutrients is mediated by a highly complex interplay of neural and...

Cationic Trypsinogen

The report in 1996 of a mutation in the cationic trypsinogen gene on Chromosome 7 in families with HP was a first success in the effort to understand the pathophysiology of acute and chronic pancreatitis on a molecular level.10 This mutation leads to a substitution of the amino acid histidine (H) to arginine (R) at Position 122 and is now the most common (of several) mutation in the cationic trypsinogen in patients with HP. To determine whether a specific mutation is of clinical relevance, it...

Metabolic Disorders

A variety of inborn errors of metabolism, such as disorders of specific amino acid transporters, branched chain amino acid degradation, or hemol-ysis, have been reported in some families to be associated with acute and chronic-recurrent episodes of pancreatitis. Although in most of these metabolic disorders, pancreatitis is not the most serious clinical manifestation of the underlying metabolic defect, some disorders are known to cause dramatically increased plasma concentrations of...

Nerves

The pancreas is supplied with sympathetic, parasympathetic, and visceral sensory nerves. The pancreatic nerves are mainly unmyelinated (Figure 3.9), although some myelinated fibers are present. Bundles of unmyeli-nated nerves that travel through the interlobular connective tissues innervate the acini and ducts. Islets are innervated by both sympathetic and parasympathetic fibers. Sympathetic fibers mainly travel the greater (originating from the T4 to T10 sympathetic ganglia) and lesser...

Streptozotocin

Glycogen Streptozotocin

STZ, derived from the soil microorganism Streptomycetes achromogenes in 1960, has been found to have a significant antimicrobial action for a wide spectrum of organisms.2,3 However, during the preclinical toxicology studies, it was found that this compound causes hyperglycemia when given by intravenous administration in rats and dogs within a few hours.4,5 Therefore, its use as an antimicrobial agent was abandoned. At the same time, its antitumor activity was demonstrated.6 Tumor studies in the...

Natural Course Of Alcoholic Chronic Pancreatitis

The majority of patients with alcoholic chronic pancreatitis are diagnosed between 35 and 40 years of age.15 Alcoholic chronic pancreatitis usually presents with an early phase of recurrent attacks of acute pancreatitis, followed by the late phase of the disease characterized by the development of chronic pain, pancreatic calcifications, and exocrine and later endocrine insufficiency. The pancreas demonstrates a large functional capacity so that exocrine and endocrine insufficiency develops...

Phase I Metabolizing Enzymes Cytochrome P450s

CYPs belong to the Phase I biotransforming enzymes and metabolize lipophilic substances, depending on the nature of the parent substrate, to toxic or nontoxic products.19,47 All of the presented enzymes have been linked to the activation of various nitrosamines and of a broad spectrum of xenobiotics, including carcinogens and therapeutic agents.13,17,20,22,23,48 The expression of CYP enzymes has been studied immunohistochemically and with molecular biological methods in cultured human ductal...

Acute Pancreatitis

There are multiple causes for acute pancreatitis, but two factors account for almost 90 of all attacks 1. Gallstones, which cause acute biliary pancreatitis and are especially common in females 2. Alcohol, which is the most common cause of acute pancreatitis in males Both of these forms of pancreatitis are related to environmental factors. Gallstones are extremely common in developed countries, but the prevalence of gallstones varies widely throughout the world. They are more common in females...

Insulin In Pancreatic Diseases

Insulin is an anabolic hormone with powerful metabolic effects. It is synthesized by the beta cells of the islets of Langerhans as a single chain precursor called proinsulin. Insulin consists of 2 dissimilar polypeptide chains, an A chain with 21 amino acids and a B chain with 30 amino acids, which are linked by 2 disulfide bonds. Chain A and Chain B are derived from a 1-chain precursor, proinsulin. Proinsulin is converted to insulin by the enzymatic removal of a segment that connects the amino...

Exogenous Sex Hormones

The risk of pancreatic cancer associated with the use of exogenous hormones such as oral contraceptives (OCs) and hormone replacement therapy (HRT) has been evaluated in a limited number of epidemiologic studies. Of the studies that evaluated use of HRT and pancreatic cancer risk, two studies found inverse associations,72,73 while two studies found positive associations with risk.74-76 In a network of case-control studies,76 HRT use for 2 or more years was associated with a decreased risk odds...

Pancreatic Pathways Molecular Epidemiology And The Study Of Geneenvironment Interactions

Research on the role of common inherited mutations (polymorphisms) in genes for biochemical pathways that may be important in exposure-related pancreatic carcinogenesis has been expanding. (See also Chapter 24 and Chapter 25.) Certain polymorphisms in genes within biochemical pathways with functional relevance to the pancreas may have subtle effects on protein function or gene expression, and these effects in combination with exposures (gene-environment interactions) such as carcinogens in...

Effects Of Toxic Agents To The Exocrine Pancreas

There are some toxic agents that cause damage to the exocrine pancreas resulting in acute or chronic pancreatitis or cancer.44 The toxic agents include toxic chemicals (see Chapter 22), therapeutic drugs, hormones, and bile salts. Chemicals toxic to the pancreas included alcohol (see Chapter 15), alloxan, streptozotocin, azaserine, dimethylbenzo a anthracene, ethio-nine, methanol, oleic acid, 4-hydroxyaminoquinoline-1-oxide, beta-oxidized derivatives of dipropylnitrosamine, and chloroform that...

Brca2 Mutations In Familial Pancreatic Cancer

Murphy et al.53 investigated the role of germ line mutations in the etiology of PC in the search for mutations in four tumor suppressor candidate genes, namely MAP2K4, MADH4, ACVR1B, and BRCA2, through direct sequencing of constitutional DNA. The samples were selected from families containing three or more PC affecteds, wherein at least two were first-degree relatives. No mutations were identified in MAP2K4, MADH4, or ACVR1B, from which the authors conclude that, It is unlikely that germ-line...

The Role Of Enzymes In Pancreatic Diseases

Chronic pancreatitis appears to be the result of exposure to xenobiotics too. Finding an increased expression of the Phase II enzyme GST-n in the islets of human patients with chronic pancreatitis compared with normal pancreas and secondary chronic pancreatitis due to duct obstruction in pancreatic cancer supported this hypothesis (see Chapter 7). 38 Lacking an animal model of chronic pancreatitis, Rutishauser et al.39 fed SGHs with a low or high fat diet that was supplemented with a prototype...

Abnormal Glycosylation Of Mucins In Pancreatic Cancer

Aberrant glycosylation is common in many pathological conditions including cancers. Many glycosyl epitopes constitute tumor-associated antigens (TAAs) and have been used as a target for immunotherapy and diagnosis. Aberrant glycosylation as a result or a cause of cancer remains enigmatic. Many recent studies indicate that some, if not all, cases of aberrant glycosylation are the results of initial oncogenic transformation and represent key events in the induction of invasion and metastasis. The...

The Role Of Islet Cells In Drug Metabolism

Interestingly, in all investigated species, the primary localization of the enzymes was the pancreatic islet.9 In each species, an average of nine enzymes were expressed in the islets, eight enzymes within ductal cells, and seven within acinar cells. The exclusive expression of isozymes in the islet cells was seen in hamsters (CYP 2E1), mice (CYP 1A1, CYP 1A2, GST-a, GST- ), rats (CYP 2C8, CYP 2C9, CYP 2C19), rabbits (CYP 1A2, CYP 2B6, GST-n), and pigs (CYP 1A1) (Figure 8.1). These findings,...

Functional Analysis Of Recombinant Psti Proteins With Amino Acid Substitution

We hypothesized that mutation of the PSTI gene may promote predisposition to pancreatitis, possibly by lowering the function of inhibiting trypsin activity. Based on the hypothesis, we developed a producing system of PSTI recombinant proteins and performed a biochemical analysis. Trypsin inhibitory activity of recombinant protein was analyzed using human and bovine trypsin.10 The activity of PSTI protein with a point mutation of the most common type, N34S, was compared to that of the wild type....

Physical Activity

Physical activity influences insulin levels and is a factor of interest for its independent association with pancreatic cancer and for its potential modifying effects with dietary factors and obesity. Comprehensive evaluations of physical activity and pancreatic cancer in humans have not been published and the experimental results are confusing. As stated earlier, in the hamster pancreatic cancer model, physical exercise had no effect on pancreatic carcinogenesis.23 Most human studies have...

Regulation Of Pancreatic Secretion

Anatomically, the exocrine and endocrine pancreas each are innervated by the parasympathetic and sympathetic branches of the autonomic nervous system (see Chapter 2 and Chapter 6). Parasympathetic inner- vation via the vagus nerves potentiates hormone- and meal-stimulated exocrine pancreatic secretion and glucose-stimulated insulin and glucagon secretion. Sympathetic innervation via the splanchnic nerve inhibits glucose-stimulated insulin and somatostatin secretion, as well as basal- and...

Suggested Physiological Function Of Centroacinar Cells

Our findings, supported, in part, by earlier studies, strongly suggest that the centroacinar cells play a crucial role in the secretion process of pancreatic enzymes. We hypothesize the following scenario. The two types of acinar cells may indicate that the secretion process in acinar cells is random (i.e., a certain percentage of acinar cells function simultaneously at a given time, while the other group rest or recover). It also questions the possible differences in the machinery of enzyme...

Pathology Of Centroacinar Cells

Striking changes in the number, size, and topography of the centroacinar cells occur during pancreatic carcinogenesis in the hamster model. In the normal pancreas of hamsters, the centroacinar cells are confined within the acinar lumen, although in aged hamsters, occasionally, tiny cytoplasmic processes covering a small part of the neighboring acinar cells can be Figure 5.7 Centroacinar-like cells within an acinus of a hamster pancreas containing a few endocrine granules and several lysosomes....

Type Of Pancreatitis Initial Damage In The Pancreas And Fibrosis Pattern

The etiological classification of chronic pancreatitis distinguishes between alcoholic, hereditary, autoimmune, idiopathic, tropical, and other rare types (Table 16.1).16,17 Here the mechanisms that may lead to certain patterns of fibrosis in the pancreas will be discussed for alcoholic chronic pancreatitis, hereditary pancreatitis, and autoimmune pancreatitis. Figure 16.2 Development of fibrosis in relapsing severe acute pancreatitis caused by alcohol abuse. A Interlobular fatty tissue...

NTs in CP

In CP, recurrent abdominal pain, which occurs in approximately 80 to 90 of the patients, is the dominant clinical symptom. It is reported that the NGF TrkA pathway is activated in CP and that this activation might influence nerve growth and the pain syndrome. NGF and its high-affinity TrkA receptor are increased in CP samples in comparison to the normal pancreas.179 In CP, enhanced NGF expression is present in metaplastic ductal cells, in degenerating acinar cells, and in acinar cells...

Pancreatic Duct 251 Anatomy

Congenital Cyst Common Bile Duct

The pancreas develops from both ventral and dorsal pancreatic anlages, which arise from the endodermal epithelium of the duodenum. The ventral anlage becomes the dorsocaudal portion and uncinate process of the head of the pancreas, and the dorsal anlage becomes the ventrocephalic portion of the head and body and tail of the gland. The duct of the ventral anlage and of the dorsal anlage distal to the junction of both ducts serve as the main pancreatic duct (duct of Wirsung). The duct of the...

Disease Manifestations

Major complications of the CF disease occur in the respiratory tract, causing sinusitis and respiratory failure. Severe bacterial infestation of the respiratory passage is also a major problem in CF patients. The second most common complications arise in the gastrointestinal tract. Other organ systems that are involved and show complications are the sweat glands (salt loss syndrome) and reproductive system (male infertility and reduced female fertility) (Table 26.3). The disease presentation...

Phylogeny Of Vertebrate Pancreas

Consideration of invertebrate and lower vertebrate organisms provides enormous insight into the evolution of the pancreas.6 Although no islets of Langerhans exist in any invertebrate, the insulin signaling pathway itself is highly conserved across a broad phylogenetic range. A range of invertebrates, from arthropods7 to worms8 to mollusks,9 have been found to express genes orthologous to mammalian insulins in these invertebrates, insulin orthologs are typically expressed within cells of the...

Expression Profiles Of Human Mucins In The Pancreas

Mucins are produced by a variety of epithelial cells. They are commonly encountered at, although not restricted to, the interface between epithelial tissues lining ducts or lumens and the adjoining external milieu.1,3 Mucins are characterized by a well-defined expression pattern, which may be disrupted in response to a variety of environmental insults, or following intrinsic changes e.g., epigenetic modifications that alter gene expression or secretion rate. Different organs serving specific...