2017 Group 2 Project

From CellBiology

2017 Projects: Group 1 - Delta | Group 2 - Duct | Group 3 - Beta | Group 4 - Alpha

Ductal Cells header.png

Introduction

Pancreas Drawing.png

The pancreas is a glandular organ located in the upper left abdomen, behind the stomach. It functions as both an exocrine and endocrine gland. Acinar cells are responsible for the exocrine function of the pancreas and secrete digestive hormones to aid the breakdown of proteins, lipids, nucleic acids and carbohydrates in food. [1] They are organised within a ductal network, where the pancreatic juices and bile are released into the duodenum [2]. The ductal cells surrounding the lumen of the ducts are epithelial cells and are involved in, not only forming the network delivering enzymes, but neutralising the fluid the enters the small intestine from the stomach by bicarbonate secretion [3]. The endocrine component of the pancreas consists of a clustered group of pancreatic cells known as Islets of Langerhans, and is composed of alpha and beta cells. It secrete hormones directly into the bloodstream. The two main pancreatic hormones are insulin, which decreases blood glucose levels; and glucagon, which increases blood glucose levels.

Dysfunction in the pancreatic ductal cells can lead to diseases such as Pancreatic Ductal Adenocarcinoma (PDAC) which is a fast moving cancer with a high mortality rate and little treatment [4], therefore understanding pancreatic ductal cells in more depth could lead to future therapies or targets for this disease. This project focuses on pancreatic ductal cells and their function, history, signalling interactions, abnormalities, current characteristics and potential protein targets.


Structure

Micro 2.png

[5]

Human Pancreas

The human pancreas is a clear-cut, solitary organ approximately around 14-18cm long. There are three main parts visible to the naked eye - the head, body and tail. The head of the pancreas is a C-shaped part, running with the upper curvature of the duodenum. The pancreas body is flat and narrow, and continues almost horizontally in the medial plane. It crosses with the superior mesenteric artery, abdominal aorta, portal vein and inferior vena cava. The tail of the pancreas is in close contact with the hilum of the spleen. The organ is enclosed by a fibrous capsule from which connective tissue septa extend into the gland separating its parenchyma into well defined lobes and lobules. [6] In the diagram, A shows the structure of the human pancreas.

Mouse Pancreas

The mouse pancreas is as distinct as the human pancreas. It is diffusely dispersed within the mesentery of the proximal small intestine in a dendritic manner. There are three major parts that can be identified - the duodenal, the splenic, and the gastric lobe. The splenic lobe is the largest lobe, continues horizontally between the duodenum and the spleen and is similar to the body and tail of the human pancreas. The duodenal lobe is equivalent to the head of the human pancreas, and is infused in the mesentery encapsulating the duodenum. The gastric lobe is the smallest of the three, and can be seen as an obvious section of the splenic love from which it develops during ontogeny. It is a changeable structure and exists in almost half of adult humans at the inferior margin of the transition of the head to the body and protruding toward the stomach.[7] In the diagram, B shows the structure of the mice pancreas.

Pancreatic ductal cells

Ductal cells are stimulated by the hormone secretin and are responsible for the maintenance of the duodenal pH and prevention of duodenal injury from acidic chyme. Ductal cells mix their production with acinar cells to make up the pancreatic juice.

Macro 1.png

[8]

The epithelial lining of the branched tubes that deliver enzymes produced by pancreatic acinar cells into the duodenum are formed by pancreatic duct cells. These cells secrete bicarbonate and mucins, which neutralize stomach acidity. During development, a complex branched network is formed from the rearrangement of the endodermal origin epithelium from the future duodenum area, thus invading the mesenchyme. In this structure, all acinar, endocrine and ductal cells originate from common precursors. Adult ductal cells have similar characteristics to embryonic primitive ducts and are able to continue generating endocrine cells in the adult. Ductal cells form about 10% of the pancreas in number and 4% in volume. In normal conditions of an adult, their proliferation rate is approximately 0.5%. In a damaged pancreas, mitotic activity increases. [9]

Structural organization of duct cells.png

A physiologically based mathematical model of the structural organization of duct cells and pancreatic duct cell secretion. [10]

Classification

Pancreatic ductal cells are classified into 4 main types, beginning with the terminal branches which extend into acini. The acini connect to individual intercalated ducts, which join to form larger intralobular ducts. These drain into interlobular ducts, which empty into the main excretory ducts.

Intercalated ducts The intercalated ducts receive secretions from acini and leads directly from the acinus to a striated duct. It forms part of the intralobular duct. They have flattened cuboidal epithelium, the thinnest epithelium of any part of the duct system, that extends up into the lumen of the acinus to form centroacinar cells. [11]

Intralobular ducts As the name implies, intralobular ducts are located within lobules. They lead directly from the acinus to interlobular duct. It is composed of the intercalated duct and the striated duct. They are lined with simple cuboidal epithelial cells, which are also lined by myoepithelial cells. The intralobular ducts of the lobules drain into the interlobular ducts between lobules. They receive secretions from intercalated ducts. Cells in the intralobular ducts are important because they may have the ability to differentiate into islet and/or acinar cells.[12]

Interlobular ducts Interlobular ducts connect lobules and are found between lobules, within the connective tissue septae. They vary considerably in size. The smaller forms have a cuboidal epithelium, while a columnar epithelium lines the larger ducts. Intralobular ducts transmit secretions from intralobular ducts to the major pancreatic duct. [13] Cells in the interlobular and main pancreatic duct are believed to play a major role in carcinogenesis.

Main pancreatic duct The main pancreatic duct joins the pancreas to the common bile duct prior to entering the intestine. It supplies pancreatic juice, which aids in digestion. It receives secretion from interlobular ducts and penetrates through the wall of the duodenum. Some people have an additional accessory pancreatic duct.


Function

Ductal Cells.PNG

Image showing pancreatic ductal cells performing its function of secreting bicarbonate. A ductal network in the pancreas, joins the duodenum and the main pancreatic duct in order to transport enzymes produced by the acinar cells to the duodenum, the ductal cells form the lining of the tubal network. [14] One of the main functions of the pancreatic ductal cells is to regulate the pH of the fluid passing down from the stomach to the duodenum, this fluid is acidic due to the partial digestion from enzymes in the stomach. [15] The ductal cells secrete bicarbonate in response to activation from the hormone secretin. [16] Secretin is a protein which belongs to the Growth Hormone Releasing Hormone peptide family and promotes ductal cells to release bicarbonate by activating via specific receptors. [17] Once secretin is bound to the secretin receptor on the surface of the ductal cell, an intracellular cascade is activated. The secretin receptor, firstly activates the intracellular adenylate cyclase which causes an increase in cyclic AMP and subsequently the activation of protein kinase A [18].Protein Kinase A (PKA) phosphorylates and hence activates the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), transporting chloride ions out of the cell. This consequently activates an Cl-/HCO3- anion exchanger , pumping bicarbonate into the lumen of the ducts [19]. The secretin binding to the Secretin Receptor has also been seen to activate the Inositol Phosphate pathway which causes intracellular stores in the ductal cells to release Ca2+ ions [20] Acetylcholine has also been seen to stimulate the secretion of bicarbonate from ductal cells, the intracellular calcium concentration increases and this triggers bicarbonate secretion [21]. Neutralising the digested contents of the duodenum is not the only function of the bicarbonate secreted from the ductal cells – it also takes part in preventing the aggregation of digestive enzymes and mucins [22].


Exocrine Pancreas
Endocrine Pancreas


History

History of the discovery of pancreas and the pancreatic duct begins back in time, during 16th and 17th centuries. There have been a number of controversies on who discovered the parts first and comes first in priority. Many scientists in 19th century who dedicated most of their efforts to investigate the physiology of pancreatic secretion [23]

Year Discovery Section
310 BC The pancreas was first described by the Greek anatomist and surgeon Herophilus (335BC to 280 BC) [24] Pancreas
100 AD Ruphos of Ephesus named the organ ‘pancreas’, meaning ‘all flesh’ [25] Pancreas
129-216 AD Galen, a physician compared pancreatic juice to saliva and had a vague idea of the digestive process. His another concept of the pancreas as a protective cushion for the mesenteric vessels was accepted by all authors as indisputable until the 17th century, blocking the research on pancreatic physiology for centuries. [26] Pancreas
15th Century Giacomo Berengario da Carpi (1470-1550) produced the first illustrated textbook of anatomy where he described the bile duct and wrote of the pancreas as a secretory gland [27] Pancreas
1543 Andreas Vesalius (1515-1564) published a famous text book of anatomy, De Humani corporis fabrica libri VII. The book corrected a number of Galen’s errors and returned society to the local thought and observational methods of the ancient Greeks. He pictured the pancreas as a U-shaped gland attached to mesentery. [28] Pancreas
1642 The main duct of the pancreas was first described by Johann Georg Wirsung, during an autopsy of a 30 year old man executed for a crime. After this discovery, it was understood that the pancreas was a secretory gland. The first cannulation of pancreatic ducts was conducted in dogs by Reignier de Graaf [23] Main pancreatic duct
1681 - 1737 The accessory pancreatic duct was discovered by Diovanni Domenico Santorini [23] Accessory Pancreatic Duct
1724 Santorini wrote his 'Observationum Anatomicarum', where he clearly described a pancreatic duct [23] Accessory Pancreatic Duct
1755 Santorini's 'Observationum Anatomicarum' was published [23] Accessory Pancreatic Duct
1796 German G.Sommering first used the word ‘Bauchspeicheldruse (abdominal salivary gland) to indicate the pancreas’ excretory function [23] Main Pancreatic Duct
1859 Santorini was forgotten for a period of time and was re-evaluated by Claude Bernard with his physiologic studies 1859. However, the discovery of the second duct was already been observed by other scientists then. One explanation of the overlooked previous discoveries might be due to the fact that the language of the texts was Latin and perhaps contemporary anatomists did not make special efforts on reading it [23] Accessory Pancreatic Duct


Development

The Formation of the Pancreatic Ducts.jpeg

At the foregut junction the septum transversum generates [29] three pancreatic buds (1 dorsal, 2 ventral). Of these, one dorsal and at least one ventral bud develop to fuse to form the pancreas in response to signals from the adjacent mesodermal tissues such as notochord, aorta and cardiac mesoderm.

The dorsal bud arises first and forms most of the pancreas and the ventral bud generates the posterior part of the head and the uncinated process. During week 6 about day 41 the stomach and duodenum rotate, the ventral bud and the pancreatic biliary orifice move around, leading the ventral and dorsal buds to fuse. The main pancreatic duct, Wirsung is the result of the fusion of the ventral duct with the distal part of the dorsal duct. [30].

As they develop, anatomical variations in the adult pancreatic duct could occur. There are about 5 classifications and they are, common, ansa pancreatica, branch fusion, looped and separated [31].

To form the main duct that transverse the pancreas to the duodenum, delivering fluid laden with digestive enzymes, first, the intercalated ducts merge to form intralobular ducts and these in turn merge to form interlobular ducts, which then finally merge to become the main duct.

There are a number of markers and transcription factors that are critical and important in its development. Ductal Cells express markers including cytokeratin19, cystic fibrosis and DBA lectin. Some of its transcriptional factors include Pdx1and HNF6. They all contribute in processes of proliferation, differentiation, and endocrine lineage commitment.

Pdx1:

- for the specification for all pancreatic lineages

- non-islet Pdx1-positive cells display physical traits of ductal branching

- involved temporally in a program of gene expression sufficient to facilitate the biochemical and morphological changes necessary for branching ductal morphogenesis

HNG6:

- develops cysts in interlobular and intralobular pancreatic ducts but not in intercalated ducts

- maybe restricted to distinct ductal segments [32].


The proximal part of the dorsal duct, Santorini is preserved with its own opening into the duodenum [33]. In the adult it has been further classified as either: - Long-type (joins main pancreatic duct at pancreas neck portion) or - Short-type (joins main pancreatic duct near first inferior branch) [34]

Development in Mouse

In the mouse, at 8.5 dpc, the homeobox transcription factors Pdx1 and Hlxb9 mark regions of the forming duodenum where the pancreas buds form (one dorsal and two ventralateral). One dorsal and one ventral bud expand and fuse to form one organ. All the endocrine cells including duct cells derive from common progenitors expressing Pdx1 but each start a unique differentiation program. During 9.5 and 11.5 dpc, selective labelling of cells that express Pdx1 at particular developmental stages show that duct progenitors express Pdx1. Permanent expression of activated Notch allows the expression of several ductal markers. The mechanism where branches form is still not clear and certain. However several gene deletions affect the number of branches and the factors produced by the mesenchyme of the pancreas control branching [35]


Signalling and Interactions

Signalling in Pancreatic ductal cells

One of the most important signalling pathways in ductal cells is the Ras signalling pathway. Integrins such as SR,VEGF, EGFR, HGF and IGF bind to receptors on the surface of the cell, causing Ras proteins to swap GDP for GTP. The binding of GTP to Ras proteins results in the protein turning ‘on’ and activating other intracellular proteins such as Raf, MAPK and the PI3-Akt cascades. Once the PI3K-Akt pathway is activated, cellular processes such as transcription, translation, cell cycle progression, cell survival, cell motility and adhesion and cell proliferation are started. These pathways can also be upregulated by the EGFR pathway. When a ligand binds to the transmembrane tyrosine kinase it leads to a phosphorylation of tyrosine on the intracellular domain of the protein, this recruits PI3-Akt proteins and STAT proteins. [36].

Another important signalling cascade in ductal cells is Hedgehog signalling, responsible for the formation of cells and the ductal epithelial cells being of the appropriate orientation and size [37]. If the Ptch ligand is present, a transmembrane receptor, SMO, is activated and subsequently hedgehog signalling is activated. There are 3 Gli proteins transcription factors, Gli1 only acts as an activator, Gli2 has 2 forms – activator and repressor but the activator form is more stable and therefore is higher activating activity, and Gli3 which is a repressor protein. The results of the hedgehog signalling depend on the ratio of the different Gli proteins, inducing different transcriptional targets [38].

Signalling interactions between the ductal cells

One of the main functions of pancreatic duct is to deliver the enzymes produced by the acinar cells to the duodenum, therefore the ductal epithelial cells are required to form an impermeable barrier in order to stop the enzymes from leaking out into the intracellular space. In order to do this, the ductal cells interact with each other and form tight junctions with properties that inhibits water and solute flow through the paracellular space. The junctions are also involved in the formation of the cells polarity. The junction is made up of claudins and occludins [39], which are integral membrane proteins responsible for maintaining and regulating membrane polarity [40]. In order to secrete bicarbonate, the ductal cells have a paracellular pathway which means the tight junctions are permeable to Na2+. Ductal hypertension can disrupt the properties of the tight junction and this is regularly seen as an early event in pancreatitis [41].

ZO-1 is a protein present in specific tights junctions in the embryo from day 10.5 to day 15.5, found around the cells facing the lumen of the ducts it is partly responsible for the polarization of the peripheral cells in the pancreatic buds. At days 9.5 the epithelial cells start forming layers, although the cells in these layers lacks the tight junctions and ZO-1 protein, but where the ZO-1 is present on the lumen buds start to form seen at day 10.5. At day 11.5 some cells in the multilayered mass of epithelial cells start forming polarity and secondary lumina form due, ZO-1 protein is present around these cells. Progression of these secondary lumina forms towards to main lumen which results in the ductal network.

Dysregulation of signalling in diseases

One feature of PDAC is that it is unresponsive to radio- and chemotherapy and the reason for this is that lesions formed in the pancreatic duct result in the pancreas releasing pro-inflammatory factors, activating pancreatic stellate cells and there is a build-up of myofibrolasts who are responsible for synthesis and deposition of extracellular matrix. If this response is altered the cells that make up the extracellular matrix will form a barrier around the lesion protecting it from the therapies. Hedgehog signalling is involved in activating the pancreatic stellate cells, disruption in this can be responsible for this accumulation [42].

The Ras signalling pathway is important in the tumour progression of PDAC. One way in which is involved is if there is a mutation in the KRAS protein – a member of the Ras family of genes. Ras proteins are GTPases, but some mutations in the KRAS gene can cause the protein to lock the GTP and therefore is always in its active form [43]. This means that the PI3K-Akt is sustained and therefore leads to a long term expression of proliferation and cell survival, hallmarks of cancer cells [44]. The mutations of KRAS are the most frequent mutations seen in the over activation of KRAS and invasive PDAC [45].


Pathology/Abnormalities

Disease Symptoms Causes/Risk Factors Histology Treatments
Non Disease Histology of Normal Pancreatic Tissue.png
Acute Pancreatitis Sudden abdominal pain, nausea, vomiting, high heart rate, rapid breathing, high blood pressure and hypothermia [46] Gallstones, ductal hypertension, alcoholism, genetic, trauma, infections [47] Histology of Acute Pancreatitis.png If mild -Enteral Nutriton (feeding through a tube), if severe – intensive care needed, fluid collected and removal of pancreatic necrosis [48]
Chronic Pancreatitis Constant abdominal pain, weight loss, development of Diabetes [49] Smoking, alcoholism, genetic, autoimmune, chronic renal failiure, recurrent acute pancreatitis, CFTR mutations, obstruction of pancreatic ducts, diet [50] Histology of Chronic Pancreatitis.png Surgery, whipple procedure (removing inflammation and mass of the pancreas), pancreatectomy [51]
Pancreatic Ductal Adenocarcinoma Hard to distinguish symptoms - very similar to pancreatitis symptoms [52] Pancreatitis, inherited, smoking, high fat diet, gender [53] Histology of Pancreatic Ductal Adenocarcinoma tissue.png Surgery, chemotherapy, radiation, palliation [54]
Cystic Fibrosis Pancreatitis, lung infections, diabetes, liver disease, salty sweat, gallstones, greasy stool, stomach pain [55] Genetic disease caused by mutations in the Cystic Transmembrane Conductance Regulator protein (CFTR) [56] Treatment for lung problems - exercise and medicine, oxygen therapy, pulmonary rehabilitation, treatment for digestive problems [57]

Pancreatitis

Pancreatitis is a variable disease; acute pancreatitis consists of inflammatory processes and can cause the patient pain which subsequently can lead to severe pancreatitis and organ failure [58]. Trypsin is an enzyme secreted by the Acinar cells which travels through the pancreatic ducts and travels to the duodenum to aid food digestion [59]. As Trypsin is a protease, it is secreted from the acinar cells in an inactive form of Trypsinogen. This is then activated once in the small intestine by enteropeptidase. An early event seen in acute pancreatitis is the activation of Trypsinogen in the lumen of the ducts, resulting in irritation of the pancreas. The present of Trypsin in the pancreatic duct is responsible for reduction in pancreatic secretion from the ductal epithelial cells and contributes to the development of chronic pancreatitis [60]. Acute necrotizing pancreatitis (ANP) can affect main pancreatic duct (MPD) as well as parenchyma [61]. Acute pancreatitis leads to changes in the cell permeability of epithelium cells – the ductal cells. This is due to the breakdown of the tight junctions between the cells, as mentioned before in signalling between the cells, these have an important function. This means that the digestive enzymes present in the pancreatic juice can pass through the gaps between the epithelium cells and into the interstitial space. Acute pancreatitis is usually a short term disease and can be caused by diet and environment. When the pancreatic ducts are blocked the pancreas becomes inflamed and this development of acute pancreatitis could be an indicator of gallstones. There are also risk factors associated with acute pancreatitis, such as drinking high volumes of alcohol. Acute pancreatitis could also be a symptom of other diseases such as pancreatic adenocarcinoma and Cystic Fibrosis [62].

Chronic pancreatitis is similar to acute pancreatitis but is longer term and can lead to loss of pancreatic function. The most significantly affected factor of chronic pancreatitis is the extracellular organisation and upregulation of cell adhesion proteins. In contrast enzymes related to digestion had a decreased expression in chronic pancreatitis tissues – this is due to a loss of acinar cells [63]. Chronic pancreatitis is an irreversible disease and leads to a increased risk of developing pancreatic cancer [64].

Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most common of pancreatic cancers and is fatal due to its ability of quickly metastasizing. [65]. It is the fourth leading cause of cancer death, and originates from either pancreatic duct cells or acinar cells. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and begin the process of transdifferentiation, called acinar-to-ductal-metaplasia (ADM). Here, duct cells are formed and then they are transformed into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC [66]. Early PDAC does not show specific symptoms and there is not much in terms of screening for the cancer. As a result, pancreatic ductal adenocarcinoma is difficult to diagnose [67]. Therefore, it is normally only identified at late stages, which in turn limits the therapies that can be used [68]. The treatment for pancreatic ductal adenocarcinoma remains challenging due to the absence of effective prognosis, diagnosis and therapy. [69]. PDAC is a complex multi factoral disease with risk factors ranging from family history, age, gender to smoking, diabetes, high fat diets, although the 2 most prominent risk factors are smoking and family history [70]. It is an important cancer to research further as identification of early stages of the cancer need to be developed, along with better therapies that are effective.

PDAC forms white yellow tumours which obstruct the pancreatic ducts and cause them to dilate, the surrounding tissues of the tumour appear to show atrophy and fibrosis [71]. The most common cysts in PDAC are pancreatic intraepithelial neoplasia (PanIN), these are where the tumours can develop from [72]. There is a lot of variation between PanINs from patient to patient and therefore they are hard to compare and understand further [73]. As PanINs develop they acquire genetic alterations, such as p53 mutations, which lead to them becoming invasive cancers[74]. Genetic abnormalities drive the progression of the cancer, the most frequent being activation of KRAS, inactivation of CDKN2A, TP53, SMAD4 and BRCA2 [75]. For example, if oncogeneic KRAS expression is knocked out in pancreatic ductal epithelial cells using Pdx1 during development there is an increased development of PanINs across the tissue [76].

Cystic Fibrosis

One of the roles of the bicarbonate secreted by the pancreatic ductal cells is to prevent aggregation of digestive enzymes and mucins in the ducts [77]. A characteristic of Cystic Fibrosis (CF) is the disruption of bicarbonate causing the aggregation and thickening of the digestive enzymes secreted from the acinar cells and therefore obstruction within the ducts [78].

Cystic Fibrosis is a genetic disease, inherited as an autosomal recessive trait due to a mutated gene carried on chromosome 7[79]. It caused by mutations in the Cystic Transmembrane Conductance Regulator protein (CFTR), an apical chloride channel that regulates active chloride transport across epithelial cell membranes.[80] CFTR is present in epithelial and blood cells, specifically pancreatic ductal epithelial cells [81]. The CFTR is involved in the secretion of bicarbonate as it functions as a channel for chloride ions to leave the cell and activates the anion exchanger which pumps bicarbonate out into the lumen of the duct [82]. The primary ductal cell chloride channel abnormality results in dehydrated protein-rich secretions that obstruct the proximal ducts, leading to secondary acinar cell destruction, fibrosis, and exocrine pancreatic insufficiency in 85% of the CF population.[83]

It has been found that the number of CFTR gene mutations and their severity are correlated with the rate of transepithalial transport and therefore patients that suffer from CF usually either carry loss of function mutations on both alleles of CFTR genes or at least one allele [84]. The obstructive build up caused by the failiure of CFTR protein leads to pancreatic insufficiency, causing patient to have abdominal pain, constipation, greasy stools, impaired nutritional status and complications can lead to cirrhosis and hepatic failure. These symptoms are all traits of CF and greatly decrease the quality of life for many patients [85].


Disconnected Pancreatic Duct Syndrome

Disconnected pancreatic duct syndrome (DPDS) begins from cellular necrosis that leads to a circumferential interruption of the pancreatic duct. Consequently, extraductal leakage of pancreatic secretions and the destruction of viable pancreatic tissue surrounding the duct occur. In more serious cases, DPDS can cause leakage of pancreatic fluid into the peritoneal cavity, causing chemical pancreatic ascites. The most common site of DPDS is within the head or body of the pancreas, though the disconnected part can happen anywhere in the duct. This disease is a management challenge in many patients who develop DPDS secondary to acute necrotising pancreatitis, chronic relapsing pancreatitis or pancreatic fisula. However, the two most major non-iatrogenic causes of DPDS is trauma and acute/chronic necrotising pancreatitis. Though the prevalence of DPDS is unclear, it has been demonstrated through research that acute necrotising pancreatitis can be complicated by DPDS in 1 in 5 cases. The diagnosis for this syndrome is most often made by MR cholangiopancreatography or endoscopic retrograde cholangiopancreatography (ERCP) with or without endoscopic ultrasound. DPDS is definitely one of the most interesting abnormality in pancreatic duct cells. I raised a challenge for the hospital team because of the associated persistent pain and prolonged hospitalisation. [86]


Current Research

Pancreatic Ductal Adenocarcinoma

As mentioned in ‘Pathologies/Abnormalities’, the survival rate of PDAC are very low due to lack of early diagnosis, effective treatments and knowledge of disease. Therefore it is important for current research to take place as to identify future targets for treatments and therapies or early diagnosis.

A study conducted by Sun et al. in 2016 investigated the effects of insulin on PDAC progression. One of the risk factors of PDAC is high fat diets and Type II diabetes. Analysing the effects of insulin on PDAC is important as diabetes plays an important role in PDAC and is results in an individual experiencing high sustained effect of elevated insulin levels – insulin is a powerful mitogen and therefore could cause increased growth on the surround pancreatic cells. The study performed aimed to determine the expression patterns of trangelin-2 in PDAC cells showing the mechanism that are involved in its deregulation and therefore possible genes involved in the progression of PDAC. Transgelin-2 is a protein involved in cell shape and translocation and has been seen to be overexpressed in some cancers – such as colorectal and renal cancer – which suggests it could be a potential biomarker for tumorigenesis. Because of its involvement in cell translocation it participates in cancer metastasis. Another protein involved in the study is Sterol Regulatory element binding protein (SREBP1), as it has roles in necessary for cell growth and when knocked down in flies, it induces cancer cell death.

Using various techniques and procedures, the results of the study found that; the Transgelin-2 gene had a high expression via SREBP-1 transcription in PDAC tissues and this upregulation of Transgelin-2 is associated with a poor prognosis of PDAC. This is linked to diabetes type II as the study also found that insulin causes an increased expression of Transgelin-2 in PDAC cells and is also required for proliferation of these cells. SREBP-1 is also responsible for the increased transcription of Transgelin-2 when the PDAC cells are treated with insulin. This information is important as it provides a deeper understanding of the relationship between insulin and PDAC – although as mentioned in the study further investigation needs to be done as the SREBP-1/transgelin-2 network could be potential therapeutic target for diabetes-associated PDAC [87].

Pancreatic Intraepithelial Neoplasia

The best chance of successful treatment for pancreatic cancer is when it is found early at precancerous stages, such as pancreatic intraepithelial neoplasia, or PanIN lesions, the most common form out of the few kinds. PanIn, together with carcinoma component share the genetic abnormalities and often it is observed in the pancreatic duct around the carcinoma component. However, there is only a little knowledge about PanIN and the relationship between the grade of PanIN and prognosis for patients with invasive ductal carcinoma. Having 124 people with ductal carcinoma involved, the grade and number of PanIN lesions in all slides of resected pancreas were examined and were put into either PanIN-low (PanIN-1A and PanIN-1B) or PanIN-high (PanIN-2 and PanIN-3) group according to the prevalence rates. The study shows that there were a greater total number of PanIN lesions in the PanIN-high group than the PanIN-low group, indicating a strong correlation between the grade and the number of PanINs. It was also found in both univariate and multivariate analyses for both disease free survival and overall survival, that the PanIN-high group had better prognoses than the PanIN-low group. The Pancreatic cancer without high-grade PanIN leads to a worse prognosis. Thus, it is critic to evaluate not only tumour histology but also the degree of dysplasia of PanINs [88].

Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells

Through the advancement of systems that reconstruct indications of human pancreatic intraepithelial neoplasia (the precursor to pancreatic ductal adenocarcinoma), it is possible that new strategies for early diagnosis will be on its way. Even though human cell-based PanIN models with clear mutations are unavailable, recent studies have shown that genetic modification of primary human pancreatic cells progresses to the growing advancement of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. Native PanINs, including prominent stromal responses, can be replicated histologically as lesions formed by mutant clones. This occurs after pancreatic transplantation. Through gene expression profilling, molecular similarities of these mutant clones with native PanINs have been highlighted and pinpoints potential PanIN biomarker candidates. Future experiments on pancreas cancer development, progression and early-stage detection can be provided by prospective reconstitution of human PanIN development from primary cells. [89]

Pancreatic ductal cells as a source of Beta cells

One of the main characteristics of Type I diabetes is the autoimmune destruction of pancreatic cells. An acceptable and obvious treatment for organ failure is organ transplantation – however it comes with complications such as lack of apropiate donors and the need for immunosuppression. A recent study conducted in May 2017 by Javad et al, presented an in vivo recellularization of acellular pancreas by implanting between the host pancreas and the adjacent omental flap. They achieved this by harvesting and cannulating the pancreases via the common bile duct, then acellularizing the scaffolds by a detergent-based protocol. This was then stretched over the host pancreas and the omentum was wrapped around it. The results obtained showed marked recellularization of acellularized pancreas with visible neovascularization and neoβ-cells with minimal inflammatory response. They observed that in vivo transplantation of acellularized pancreas can promote recellularization, proliferation, and differentiation by blood circulation, leading to the conclusion that in vivo studies can contribute to quicker solutions for treating diabetes. Ultimately, this study provides a new approach to producing a normal pancreas by allograft transplantation for pancreas tissue engineering. [90]

The effect of high glucose on cell proliferation and on the secretion and mRNA expression of Osteopontin in human pancreatic duct epithelial cells

In Japan, the incidence rate of pancreatic cancer increases every year. Furthermore, diabetes is one of the most common diseases that complicate pancreatic cancer. Recent studies have shown that people who are either diabetic or obese exhibit an increased expression of osteopontin (OPN). Hence, this study aims to determine the effect of high glucose on cell proliferation and high insulin culture conditions on a human pancreatic duct epithelial cell line (HPDE-6). It specifically focused on OPN expression. HPDE-6 was cultured under different conditions, applying several combinations of glucose: normal, 6mM high, 30 mM and 60 mM, and insulin: 0.1 nM, 1 nM concentration. The results obtained from the study showed that HPDE-6 cell proliferation was significantly accelerated under high glucose culture conditions in comparison to samples in 6 mM glucose, and was more prominent under high insulin conditions. Simultaneously, there was an increason in the secretion and mRNA expression of osteopontin in human pancreatic duct epithelial cells. Therefore upon completion of the experiment, it was concluded that HPDE-6 cells show accelerated proliferation and increased OPN expression when cultured under high glucose and high insulin conditions. In addition, the presence of high glucose brought about oxidative stress in the cells. [91]


Take the Quiz

1

True or False? At the foregut junction, the septum transversum generates a dorsal bud and at least one ventral bud, which then fuses to form the pancreas.

True
False

2

Which of the following is correct regarding the exocrine and endocrine functions of the pancreas?

As an exocrine gland, the pancreas contains islet cells which secretes hormones into other organs. As an endocrine gland, digestive enzymes are produced and released into the jejunum.
As an exocrine gland, the pancreas produces enzymes important to digestion. As an endocrine gland, it consists of Islets of Langerhans that secretes insulin and glucagon directly into the bloodstream.
As an exocrine gland, the pancreas maintains blood sugar levels by controlling insulin and glucagon. As an endocrine gland, pancreatic juices are produced and taken to the gallbladder.

3

Intralobular ducts:

lead directly from the acinus to interlobular duct, are lined with simple cuboidal epithelial cells and receive secretions from intercalated ducts
leads directly from the acinus to a striated duct, have flattened cuboidal epithelium and receive secretions from acini
joins the pancreas to the common bile duct prior to entering the intestine, supplies pancreatic juice and receives secretion from interlobular ducts

4

Which pancreatic ductal cell abnormality is caused by genetic disease formed by mutations in the Cystic Transmembrane Conductance Regulator protein (CFTR)?

Acute and Chronic Pancreatitis
Pancreatic Ductal Adenocarcinoma
Cystic Fibrosis

5

The protein ZO-1:

synthesizes long chains or polymers of nucleic acids in the panceas
is found around the cells facing the lumen of the ducts and is partly responsible for the polarization of the peripheral cells in the pancreatic buds.
is a small protein that helps regulate the processes of other proteins in the pancreas.


Glossary

  • Allele - each of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome
  • Ascites - the accumulation of fluid in the peritoneal cavity, causing abdominal swelling
  • Cirrhosis - a chronic degenerative disease in which normal liver cells are damaged and are then replaced by scar tissue
  • Cyst - a membranous sac or cavity of abnormal character in the body, containing fluid
  • Fisula - an abnormal or surgically made passage between a hollow or tubular organ and the body surface, or between two hollow or tubular organs
  • Homeobox - any of a class of closely similar sequences which occur in various genes and are involved in regulating embryonic development in a wide range of species
  • Hypertension - abnormally high blood pressure
  • Hypothermia - abnormally low body temperature
  • Morphogenesis - the biological process that causes an organism to develop its shape
  • Neoplasia - the presence or formation of new, abnormal growth of tissue
  • Pancreatectomy - surgical removal of the pancreas
  • Paracellular - passing or situated beside or between cells
  • Progenitor - a biologically related ancestor
  • Transcription factor - any of various proteins that bind to DNA and play a role in the regulation of gene expression by promoting transcription.
  • Trypsinogen - an inactive substance secreted by the pancreas, from which the digestive enzyme trypsin is formed in the duodenum.


References

  1. Manfred Schwab. Pancreas. Encyclopedia of Cancer. 2011, 1 (1); 2762-2763
  2. <pubmed>16702400</pubmed>
  3. <pubmed>15618005</pubmed>
  4. <pubmed>28494747</pubmed>
  5. <pubmed>26030186</pubmed>
  6. <pubmed>26030186</pubmed>
  7. <pubmed>26030186</pubmed>
  8. <pubmed>26030186</pubmed>
  9. <pubmed>15618005</pubmed>
  10. <pubmed>15257112</pubmed>
  11. <pubmed>12801084</pubmed>
  12. <pubmed>7735568</pubmed>
  13. <pubmed>7735568</pubmed>
  14. <pubmed>15618005</pubmed>
  15. <pubmed> 21893120</pubmed>
  16. <pubmed>20978133</pubmed>
  17. <pubmed>23738005</pubmed>
  18. <pubmed>22692904</pubmed>
  19. <pubmed>25332973</pubmed>
  20. <pubmed>1329554</pubmed>
  21. <pubmed>8120821</pubmed>
  22. <pubmed>20398666</pubmed>
  23. 23.0 23.1 23.2 23.3 23.4 23.5 23.6 <pubmed>12120005</pubmed>
  24. Howard JM, Hess W. History of the Pancreas: Mysteries of a Hidden Organ. New York, NY: Kluwer Academic/Plenum Publishers: 2002.
  25. Howard JM, Hess W. History of the Pancreas: Mysteries of a Hidden Organ. New York, NY: Kluwer Academic/Plenum Publishers: 2002.
  26. <pubmed>3512385</pubmed>
  27. Howard JM, Hess W. History of the Pancreas: Mysteries of a Hidden Organ. New York, NY: Kluwer Academic/Plenum Publishers: 2002.
  28. <pubmed>3512385</pubmed>
  29. Hill, M.A. 2017 Embryology Gastrointestinal Tract - Pancreas Development. Retrieved May 24, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Gastrointestinal_Tract_-_Pancreas_Development
  30. <pubmed>17258745</pubmed>
  31. Hill, M.A. 2017 Embryology Gastrointestinal Tract - Pancreas Development. Retrieved May 24, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Gastrointestinal_Tract_-_Pancreas_Development
  32. <pubmed>22133881</pubmed>
  33. <pubmed>17258745</pubmed>
  34. Hill, M.A. 2017 Embryology Gastrointestinal Tract - Pancreas Development. Retrieved May 24, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Gastrointestinal_Tract_-_Pancreas_Development
  35. <pubmed>15618005</pubmed>
  36. <pubmed>19506583</pubmed>
  37. <pubmed>26962810</pubmed>
  38. <pubmed>20814421</pubmed>
  39. <pubmed>24665406</pubmed>
  40. <pubmed>12668723</pubmed>
  41. <pubmed>24665406</pubmed>
  42. <pubmed>26962810</pubmed>
  43. <pubmed>19506583</pubmed>
  44. <pubmed>22692904</pubmed>
  45. <pubmed>21620466M/pubmed>
  46. Ilhan, M. Alis, H. Acute Biliary Pancreatitis. Acute Pancreatitis. 2012.
  47. Ilhan, M. Alis, H. Acute Biliary Pancreatitis. Acute Pancreatitis. 2012.
  48. Andersson, R. Swärd, A. Tingstedt, B. Akerberg, D. Treatment of Acute Pancreatitis. Drugs. 2009. 69: 505.
  49. WedMD. What is Pancreatitis? Accessed 20 May 2017. http://www.webmd.com/digestive-disorders/digestive-diseases-pancreatitis#1
  50. <pubmed>11179244</pubmed>
  51. The National Pancreas Foundation. Chronic pancreatitis pain management and treatment. 2017. Accessed 20 May 2017 https://pancreasfoundation.org/patient-information/chronic-pancreatitis/chronic-pancreatitis-pain-management-and-treatment/
  52. <pubmed>28507102</pubmed>
  53. <pubmed>21620466</pubmed>
  54. Pancreapedia. Pancreatic Ductal Adenocarcinoma. 2017. Accessed 20 May 2017. https://www.pancreapedia.org/reviews/pancreatic-ductal-adenocarcinoma
  55. National Heart, Lung and Blood Institute. What are the signs and symptoms of Cystic Fibrosis? 2013. Accessed 20 May 2017. https://www.nhlbi.nih.gov/health/health-topics/topics/cf/signs
  56. <pubmed>19403164</pubmed>
  57. National Heart, Lung and Blood Institute. How is cystic fibrosis treated? 2013. Accessed 20 May 2017. https://www.nhlbi.nih.gov/health/health-topics/topics/cf/treatment
  58. Nagar, A. Gorelick, F. Epidemiology and Pathophysiology of Acute Pancreatitis. Pancreatitis and its complications. 2004. 1; 3-48
  59. Sommermeyer, L. Acute Pancreatitis. The American Journal of Nursing. 1935. 35 (12); 1157-1161.
  60. <pubmed>21893120</pubmed>
  61. <pubmed>27681504</pubmed>
  62. Nagar, A. Gorelick, F. Epidemiology and Pathophysiology of Acute Pancreatitis. Pancreatitis and its complications. 2004. 1; 3-48
  63. <pubmed>22132114</pubmed>
  64. <pubmed>15686632</pubmed>
  65. <pubmed>156886632</pubmed>
  66. <pubmed>27610015</pubmed>
  67. <pubmed>28507102</pubmed>
  68. <pubmed>24797069</pubmed>
  69. <pubmed>27610015</pubmed>
  70. <pubmed>21620466</pubmed>
  71. <pubmed>26883357</pubmed>
  72. <pubmed>26592447</pubmed>
  73. Matthaei, H. Dal Molin, M. Maitra, A. Identification and Analysis of Precursors to Invasive Pancreatic Cancer. Pancreatic Cancer: Methods and Protocols. 2013. 980; 1-12.
  74. <pubmed>26592447</pubmed>
  75. <pubmed>21620466</pubmed>
  76. <pubmed>26883357</pubmed>
  77. <pubmed>20398666</pubmed>
  78. <pubmed>19403164</pubmed>
  79. <pubmed>10478873</pubmed>
  80. <pubmed>10478873</pubmed>
  81. <pubmed>19403164</pubmed>
  82. <pubmed>25332973</pubmed>
  83. <pubmed>10478873</pubmed>
  84. <pubmed>16840743</pubmed>
  85. <pubmed>28472055</pubmed>
  86. <pubmed>27803085</pubmed>
  87. <pubmed>28521289</pubmed>
  88. <pubmed>24931343</pubmed>
  89. <pubmed>28272465</pubmed>
  90. <pubmed>28500662</pubmed>
  91. <pubmed>28417915</pubmed>