How does the structure of the pancreatic acinar cell relates to its function?

So the pancreatic acinar cell synthesizes, stores and secretes digestive enzyme precursors called zymogens e.g. pepsinogen.

The structure of the acinar cell shows that there is an apical and basal side. The basal half of the cell is almost entirely filled with rough endoplasmic reticulum which can be shown with pyronin stain showing up pink due to the rRNA of ribosomes. The nucleus is also on the basal side which explains why rER is there too, since the nuclear envelop is connected with the ER membrane. Zymogen granules are on the apical region. Any thoughts as to why there is this polarity in cell?

The secretion pushes the cell organelles to the basal part.

(although the fat cells have no polarity, their organelles have been pushed to one side of the cell:

Comparing to adipose cells, the acinar cells secrete their specific proteins on one specific end of the cell, this is why in contrast with fat cells they have well defined polarity.

How does the structure of the pancreatic acinar cell relates to its function? - Biology

Pancreatic islets, also called the islets of Langerhans, are regions of the pancreas that contain its hormone-producing endocrine cells.

Learning Objectives

Differentiate among the types of pancreatic islet cells

Key Takeaways

Key Points

  • The pancreatic islets are small islands of cells that produce hormones that regulate blood glucose levels. Hormones produced in the pancreatic islets are secreted directly into the bloodstream by five different types of cells.
  • The alpha cells produce glucagon, and make up 15–20% of total islet cells. The beta cells produce insulin and amylin, and make up 65–80% of the total islet cells. The delta cells produce somatostatin, and make up 3–10% of the total islet cells.
  • The gamma cells produce pancreatic polypeptide, and make up 3–5% of the total islet cells. The epsilon cells produce ghrelin, and make up less than 1% of the total islet cells.
  • The feedback system of the pancreatic islets is paracrine, and is based on the activation and inhibition of the islet cells by the endocrine hormones produced in the islets.

Key Terms

  • endocrine: Produces internal secretions that are transported around the body by the bloodstream.
  • paracrine: Describes a hormone or other secretion released from endocrine cells into the surrounding tissue rather than into the bloodstream.
  • exocrine: Produces external secretions that are released through a duct.

The pancreas serves two functions, endocrine and exocrine. The exocrine function of the pancreas is involved in digestion, and these associated structures are known as the pancreatic acini.

The pancreatic acini are clusters of cells that produce digestive enzymes and secretions and make up the bulk of the pancreas. The endocrine function of the pancreas helps maintain blood glucose levels, and the structures involved are known as the pancreatic islets, or the islets of Langerhans.

Pancreatic islets or islets of Langerhans: The islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells.

The pancreatic islets are small islands of cells that produce hormones that regulate blood glucose levels. Hormones produced in the pancreatic islets are secreted directly into the blood flow by five different types of cells.

Pancreatic tissue: The small cells in the middle are beta cells, and the surrounding larger cells are alpha, delta, gamma, and epsilon cells.

The endocrine cell subsets are:

  • Alpha cells that produce glucagon and make up 15–20% of total islet cells. Glucagon is a hormone that raises blood glucose levels by stimulating the liver to convert its glycogen into glucose.
  • Beta cells that produce insulin and amylin and make up 65–80% of the total islet cells. Insulin lowers blood glucose levels by stimulating cells to take up glucose out of the blood stream. Amylin slows gastric emptying, preventing spikes in blood glucose levels.
  • Delta cells that produce somatostatin and make up 3–10% of the total islet cells. Somatostatin is a hormone that suppresses the release of the other hormones made in the pancreas.
  • Gamma cells that produce pancreatic polypeptide and make up 3–5% of the total islet cells. Pancreatic polypeptide regulates both the endocrine and exocrine pancreatic secretions.
  • Epsilon cells that produce ghrelin and make up less than 1% of the total islet cells. Ghrelin is a protein that stimulates hunger.

The feedback system of the pancreatic islets is paracrine—it is based on the activation and inhibition of the islet cells by the endocrine hormones produced in the islets. Insulin activates beta cells and inhibits alpha cells, while glucagon activates alpha cells, which activates beta cells and delta cells. Somatostatin inhibits the activity of alpha cells and beta cells.

Associated Data

MIST1 is a transcription factor expressed in pancreatic acinar cells and other serous exocrine cells. Mice harboring a targeted deletion of the Mist1 gene (Mist1 −/− ) exhibit alterations in acinar regulated exocytosis and aberrant Ca 2+ signaling that are normally controlled by acinar cell Ca 2+ -ATPases. Previous studies indicated that total sarcoendoplasmic reticulum Ca 2+ -ATPases (SERCA) and plasma membrane Ca 2+ -ATPases (PMCA) remained unaffected in Mist1 −/− acinar cultures. Therefore, we have assessed the expression of Atp2c2, the gene that encodes the secretory pathway Ca 2+ -ATPase 2 (SPCA2). We revealed a dramatic decrease in pancreatic expression of Atp2a2 mRNA and SPCA2 protein in Mist1 −/− mice. Surprisingly, this analysis indicated that the acinar-specific Atp2c2 mRNA is a novel transcript, consisting of only the 3′ end of the gene and the protein and localizes to the endoplasmic reticulum. Expression of SPCA2 was also lost in Mist1 −/− secretory cells of the salivary glands and seminal vesicles, suggesting that Atp2c2 transcription is regulated by MIST1. Indeed, inducible MIST1 expression in Mist1 −/− pancreatic acinar cells restored normal Atp2c2 expression, supporting a role for MIST1 in regulating the Atp2c2 gene. Based on these results, we have identified a new Atp2c2 transcript, the loss of which may be linked to the Mist1 −/− phenotype.


Generation of mice with tamoxifen-inducible, pancreatic acinar cell–specific Sec23b deletion

Mice with tamoxifen-inducible, acinar cell–specific deletion of Sec23b were generated by crossing Sec23b +/ − CreErT + mice to Sec23b +/fl mice. This cross yielded the expected number of Sec23b − /fl CreErT + mice at weaning (Table 1). One week after tamoxifen administration, pancreas tissues were harvested from the latter mice to determine the degree of excision of Sec23b. Sec23b − /fl CreErT + pancreata exhibited ∼90% lower expression of wild-type (WT) Sec23b mRNA by quantitative RT-PCR (qRT-PCR) than WT pancreata (Figure 1B), with similar decreases in steady-state SEC23B protein by Western blot analysis (Figure 1, C and D). Because CreErT is expressed only in acinar cells (Ji et al., 2008), some or all of the residual SEC23B expression could be derived from islet and other nonacinar cells. Thus these data are consistent with high-level excision of Sec23b in pancreatic acinar cells after tamoxifen administration. Sec23a mRNA and protein levels were not increased in pancreata of mice with acinar cell deletion of Sec23b (Figure 1, E–G).

TABLE 1: Results of Sec23b +/ − CreErT(+) x Sec23b +/fl matings to generate mice with tamoxifen-inducible, acinar cell–specific deletion of Sec23b.

a p calculated for Sec23b − /fl CreErT(+) mice versus all other genotypes.

FIGURE 1: Sec23b inactivation in pancreatic acinar cells. (A) Sec23b alleles (not drawn to scale Khoriaty et al., 2014). Each square indicates an exon, and horizontal lines between exons indicate introns. F4 and R4 are primers used for assessing efficiency of Cre-mediated excision. (B) Sec23b excision determined by qPCR (n = 3 for each genotype) and (C) Western blot on pancreas tissues 7 d after administration of tamoxifen. (D) Quantification of the SEC23B band intensities in C relative to average of GAPDH and RalA performed using ImageJ. (E–G) Quantitation of Sec23a expression by (E) qPCR (three controls and four Sec23b − /fl CreErT + mice), (F) chemiluminescence Western blot detection, and (G) quantitative Western blot (infrared fluorescence detection) in pancreas tissues 7 d after administration of tamoxifen (three mice per genotype).

Depletion of Sec23b in acinar cells of adult mice results in lower pancreatic weight

One week after tamoxifen administration, mice were killed and pancreata were dissected and weighed. Mice with acinar cell deletion of Sec23b (Sec23b − /fl CreErT + or Sec23b fl/fl CreErT + mice) exhibited ∼40% decrease in pancreatic weight compared with WT control mice (Sec23b fl/fl CreErT , Sec23b +/fl CreErT , Sec23b +/+ CreErT + , and Sec23b +/+ CreErT mice p < 0.0001), whereas pancreatic weights of mice with heterozygous acinar cell deletion of Sec23b (Sec23b +/ − CreErT + , Sec23b +/ − CreErT , and Sec23b +/fl CreErT + mice) were not significantly different than those of WT mice (p = 0.09 Figure 2A).

FIGURE 2: Sec23b deletion in acinar cells results in decreased pancreatic weight from cell loss. (A) Ratios of pancreas to total body weight 7 d after administration of tamoxifen indicate substantial loss of pancreas weight resulting from inactivation of Sec23b in pancreas acinar cells. Mouse weights (B) before and (C) 1 wk after tamoxifen administration indicates no loss of total body weight with acinar deletion of Sec23b. (D) Ratios of pancreas to total body weight 7 d after administration of corn oil demonstrate that only a small portion of the pancreatic weight loss is explained by basal CreErT activity in the absence of tamoxifen induction. (E) A cohort of mice were evaluated 14 d after tamoxifen administration, demonstrating no continued drop in pancreatic weight compared with evaluation performed 7 d after tamoxifen in A. The loss of pancreatic weight is associated with a comparable degree of decrease in pancreas (F) DNA, (G) RNA, and (H) total protein, consistent with cell loss. Each data point represents one mouse.

The mouse weights before and after tamoxifen administration were indistinguishable between mice with acinar depletion of SEC23B and WT control mice (Figure 2, B and C), suggesting no effect of acinar Sec23b deletion on food intake or duodenal pathology.

To determine the baseline CreErT activity in the absence of tamoxifen induction, we gavaged a cohort of mice (Sec23b -/fl CreErT + , Sec23b fl/fl CreErT + , and WT controls) with corn oil not containing tamoxifen. Sec23b − /fl CreErT + and Sec23b fl/fl CreErT + mice exhibited ∼13% lower pancreatic weights than WT mice (p = 0.03 Figure 2D), explaining only a portion of the decrease in pancreatic weight observed in Sec23b − /fl CreErT + and Sec23b fl/fl CreErT + mice after tamoxifen administration.

To determine whether the pancreatic weight after Sec23b acinar cell deletion would drop further with time, we followed a cohort of mice for 2 wk after administration of tamoxifen. The latter mice exhibited a ∼40% decrease in pancreas weight compared with WT control mice (Figure 2 E), which is indistinguishable from the drop observed 1 wk after tamoxifen administration.

The lower pancreatic weight in mice with acinar deletion of Sec23b is due to cell loss

We calculated total pancreatic DNA, RNA, and protein contents 1 wk after tamoxifen administration. Mice with acinar cell deletion of Sec23b exhibited ∼43% decrease in pancreatic DNA content (p = 0.01 Figure 2F), ∼53% decrease in RNA content (p < 0.0001 Figure 2G), and ∼46% decrease in protein content (p < 0.0001 Figure 2H) compared with WT mice. The total DNA, RNA, and protein contents of pancreas tissues decreased proportionately to the decrease in pancreas weights resulting from Sec23b deletion in acinar cells, indicating that the decreased pancreas weight can be fully explained by a reduction in cell number, not cell size.

Acinar Sec23b deletion results in degeneration of exocrine cells, decreased zymogen granules, and ER alterations

One week after acinar cell–specific deletion of Sec23b, histologic evaluation of pancreas tissues demonstrated smaller-than-normal pancreata with mild to moderate disruption of normal lobular architecture due to multifocal degeneration of exocrine epithelial cells within pancreatic lobules, with shrinkage of lobules and prominence of supporting stroma and periductular fibrosis. Degenerate acinar cells were shrunken, with loss of zymogen granules, condensed nuclei, and cytoplasmic enhancement of the eosin stain (Figure 3A). Histologic evaluation of pancreas tissues performed 2 wk after tamoxifen administration revealed comparable findings (Supplemental Figure S1A).

FIGURE 3: Histologic evaluation of pancreas tissues 7 d after deletion of acinar Sec23b. The evaluation was performed by an investigator blinded to the genotypes of the mice from which the tissues were derived (four mice of each genotype were evaluated). (A) At 7 d after acinar Sec23b deletion, evaluation of pancreas tissues by hematoxylin and eosin stains demonstrated overall loss of parenchymal size and lobular atrophy due to degeneration of acinar epithelial cells, characterized by cellular shrinkage, cytoplasmic loss with loss of zymogen granules, enhancement of the eosin stain, and nuclear pyknosis (middle) compared with WT controls (left). Right, positive control for pancreatitis 1 d after cerulean treatment. Immunohistochemistry for (B) CD45 and (C) F4/80 demonstrates a small number of white blood cells (mostly macrophages) infiltrating pancreas tissues of mice with acinar Sec23b deletion compared with mice with cerulean-induced pancreatitis (positive control).

Alteration in acinar morphology after Sec23b excision was also assessed by electron microscopy (Figure 4). Seven days after tamoxifen treatment, acinar cell structure in pancreata of WT mice exhibited the expected concentration of zymogen granules surrounding the acinar lumen in the apical pole of the cell and abundant RER in basolateral regions (Figure 4A). In contrast, the majority of acinar cells in Sec23b − /fl CreErT + mice exhibited striking abnormalities, including decreased zymogen granules (Figure 4) and alterations in ER morphology ranging from vesicular ER to markedly expanded cisternae with accumulation of moderate-density content or intracisternal granules (Figure 4, B–F). Cells containing vesicular ER often showed ribosomes associated with only portions of the vesicular membrane (Figure 4, F and inset). Many acinar cells showed alteration in their general polarity, with granules accumulating in basal regions of the cell, whereas other cells had greatly reduced granule densities. The acinar cell morphology was also assessed 14 d after administration of tamoxifen, with findings similar to those at the earlier time point (Supplemental Figure S2).

FIGURE 4: Electron microscopy of pancreas tissues 7 d after deletion of acinar Sec23b. Evaluation of pancreas tissues by electron microscopy demonstrates normal acinar morphology in WT control mice, with numerous granules adjacent to the lumen (arrowhead) and basal RER cisternae (A). Pancreas tissues with acinar deletion of Sec23b exhibited variably decreased zymogen granules (B arrowhead denotes ER lumen), as well as multiple alterations, including vesicular or expanded RER (C, cells 2 and 3 in contrast to normal cell morphology, C, cell 1), expanded RER cisternae with amorphous content (C, D), small intracisternal granules (E, arrow and higher-magnification inset), crenulated nucleus and vesicular RER (F), with amorphous content and partial studding with ribosomes (F and inset). Scale bars as indicated 250 nm (insets). Three mice of each genotype were evaluated.

Sec23b deletion in acinar cells fails to produce clear manifestations of acute pancreatitis

We measured random blood glucose and plasma amylase levels 1 wk after tamoxifen administration. Mice with acinar cell deletion of Sec23b exhibited indistinguishable blood glucose (Figure 5A) and plasma amylase levels (Figure 5B) compared with mice heterozygous for Sec23b in their acinar cells and WT controls. In addition, a small number of white blood cells (mostly resident macrophages and lymphocytes) were observed by immunohistochemistry, but much fewer than in the pancreatitis positive control samples, which contained a significant number of neutrophils in addition to large numbers of other inflammatory cells (Figure 3, B and C, and Supplemental Figure S1, B and C). Carboxypeptidase A1 cleavage, which is seen in pancreatitis (Leach et al., 1991), was not observed in pancreas tissues of mice with acinar Sec23b deletion (Figure 5C). Other pancreas digestive enzymes were variably affected relative to total protein. Amylase was decreased in total pancreatic cell lysates prepared from mice with acinar deletion of Sec23b compared with WT mice (Figure 5D), with a less clear effect on chymotrypsin and trypsin (Figure 5E).

FIGURE 5: Deletion of Sec23b in mouse acinar cells does not affect plasma glucose or amylase but results in decreased pancreatic amylase in total pancreas cell lysates. (A) Sec23b deletion in acinar cells does not result in increased plasma glucose or (B) increased plasma amylase (each data point represents one mouse). (C) Carboxypeptidase cleavage observed in pancreas tissues of mice given cerulein to induce pancreatitis was not observed in pancreas tissues of mice with acinar Sec23b inactivation. (D) Sec23b deletion in pancreas acinar cells results in decreased pancreatic amylase in total pancreas cell lysates, (E) with a less clear effect on chymotrypsin and trypsin.

Acinar Sec23b deletion results in ER stress and increased apoptosis

To determine whether the ER dilatation observed after acinar Sec23b deletion is associated with induction of ER stress and the unfolded protein response (UPR), we determined the expression level of a panel of associated genes by qRT-PCR. Expression for many of these genes was increased after acinar Sec23b deletion, with the increase in Eif2a and Grp94 reaching statistical significance (p < 0.05 Figure 6A).

FIGURE 6: Expression of UPR genes and TUNEL assay in pancreas tissues after acinar Sec23b deletion. (A) Real time RT-PCR expression of select UPR genes was performed on pancreas tissues harvested 1 wk following administration of tamoxifen, with levels normalized to β-actin. Data are represented by mean ± SEM. Asterisks indicate statistically significant difference between WT and Sec23b − /fl CreErT(+) samples. Six mice from each genotype were evaluated. (B) TUNEL assays overlaid on DAPI were performed 3 d (a, b) and 7 d (c, d) after administration of tamoxifen. Sec23b − /fl CreErT + mice exhibit increased apoptosis at both time points. Immunostaining for active caspase-3 demonstrates increased expression in mice with acinar deletion of Sec23b (f) compared with WT mice (e) on Nomarski image. (C) Average percentage of TUNEL-positive cells (three or four mice were evaluated per condition and ∼2000–2500 cells counted per sample). The evaluation was performed by an investigator blinded to the genotypes of the mice from which the tissues were derived.

After tamoxifen administration, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were also performed on pancreatic tissues harvested from Sec23b -/fl CreErT + mice and WT controls (Figure 6B, a–d). Three days after tamoxifen administration, the percentage of TUNEL-positive cells in Sec23b − /fl CreErT + mice (6.08%) was higher than that in WT control mice (0.04% Figure 6C). The same pattern was observed 7 d after tamoxifen administration (1.62 and 0.11%, respectively Figure 6C). Consistent with these results, the expression of activated caspase 3 was increased in pancreata of Sec23b − /fl CreErT + mice compared with WT control mice (Figure 6B, e and f).

The signs and symptoms of Acinar Cell Cystadenocarcinoma of Pancreas depend upon the size and location of the tumor. During the initial stages, small tumors may not cause any signs and symptoms that are readily recognized. Hence, these tumors are only detected incidentally, when being worked-up for other conditions (i.e., diagnostic tests and exams undertaken for other health conditions).

The following signs and symptoms may be noted, which include:

  • Abdominal pain, back pain
  • Loss of appetite
  • Weight loss
  • Indigestion
  • Yellowing of skin (jaundice)
  • Nausea and vomiting
  • Dark-colored urine
  • Fatigue (getting tired easily)

General features of Acinar Cell Cystadenocarcinoma of Pancreas include:

  • This tumor is present in the form of malignant cysts that infiltrate local areas
  • The tumors are single and well-defined
  • These tumors can become very large and grow up to 20 cm in size

Pancreatic and Salivary Secretion

The pancreas is the source of the majority of enzymes required for digestion of a mixed meal (i.e., carbohydrate, protein, and fat). Pancreatic enzymes are produced in great excess, underscoring their importance in the digestive process. However, unlike the digestive enzymes produced by the stomach and in the saliva, some level of pancreatic function is necessary for adequate digestion and absorption. In general, nutrition is impaired if production of pancreatic enzymes falls below 10% of normal levels, or if outflow of the pancreatic juice into the intestine is physically obstructed.

We should distinguish between the exocrine pancreas, responsible for producing secretions that flow out of the body, and the endocrine pancreas, the site of synthesis of various important hormones that regulate whole-body homeostasis, the most notable of which is insulin (Figure 4–1). These dual secretory functions of the pancreas are segregated to distinct anatomic locations. The functions and regulation of the exocrine pancreas are the province of gastrointestinal physiology, whereas the endocrine functions are a topic for discussion in a general endocrinology course. Thus, the latter will not be discussed further here.

Figure 4–1.

Schematic structure of the exocrine pancreas. [Redrawn from the AGA Undergraduate Teaching Project slide set “The Integrated Response to a Meal” (Unit 29, copyright 1995) by S. Pandol and H.E. Raybould, with permission.]

Pancreatic Secretory Products

The exocrine pancreas is the site of synthesis and secretion predominantly of enzymes. These fall into four main groups—proteases, amylolytic enzymes, lipases, and nucleases—as shown in Table 4–1. In addition, other proteins are produced that modulate the function of pancreatic secretory products, such as colipase and trypsin inhibitors. Finally, the pancreas secretes a peptide known as monitor peptide, which represents an important feedback mechanism linking pancreatic secretory capacity with the requirements of the intestine for digestion at any given moment after the ingestion of a meal more on that topic later. The quantities of each of the secretory products differ greatly. Almost 80% by weight of the proteins secreted by the exocrine pancreas are proteases, with much lower quantities of the enzymes responsible for breaking down other classes of nutrients. Of the proteases, trypsinogen, the inactive precursor of trypsin, is by far the most abundant, accounting for approximately 40% by weight of pancreatic secretory products. This likely reflects a central role for trypsin in initiating the digestion of proteins, which will be discussed further in Chapter 15.

Table 4–1. Pancreatic Acinar Cell Secretory Products

Proteases Amylolytic enzyme Lipases Nucleases Others
Trypsinogen * Amylase Lipase Deoxyribonuclease Procolipase *
Chymotrypsinogen * Nonspecific esterase Ribonuclease Trypsin inhibitors
Proelastase * Prophospholipase A 2 * Monitor peptide
Procarboxypeptidase A *
Procarboxypeptidase B *

As we learned for pepsinogen in the stomach, the proteases synthesized by the pancreas are packaged and stored as inactive precursors. This is also true for at least one lipolytic enzyme, prophospholipase A 2 . The need to store these enzymes in their inactive forms relates to the toxicity of the active products toward the pancreas itself. Under normal circumstances, therefore, the pancreas does not digest itself. Only in the setting of disease, particularly if the secretions are retained in the pancreas for a prolonged period, do the enzymes become inappropriately activated resulting in the very painful condition of pancreatitis .

Anatomic Considerations in Pancreas

As alluded to above, the pancreas has both exocrine and endocrine functions. The latter are restricted to endocrine cells located in the islets of Langerhans, which are scattered throughout the bulk of the pancreatic parenchyma. The exocrine functions, on the other hand, are conducted by a series of blind-ended ducts that terminate in structures known as acini. Many such acini, arranged like clusters of grapes, disgorge their products into a branching ductular system that empties into larger and larger collecting ducts, eventually reaching the main pancreatic duct or Wirsung’s duct. This duct merges with the common bile duct, coming from the liver, and the mixed bile plus pancreatic juice enters the duodenum a short distance distal to the pylorus, under the control of a sphincter called the sphincter of Oddi. A minor part of the pancreas is drained by an accessory collecting duct, known as the duct of Santorini, which has a separate opening to the duodenum. Both the acinar and ductular cells contribute distinct products to the pancreatic juice and both are regulated during the course of responding to a meal.

Acinar Cells

Pancreatic acinar cells are specialized exocrine secretory cells that are the source of the majority of the proteinaceous components of the pancreatic juice. They are somewhat triangular in shape when viewed in cross-section, with a basolaterally-displaced nucleus. The basolateral membrane faces the bloodstream and contains receptors for a variety of neurohumoral agents responsible for regulating pancreatic secretion. The apical pole of the cell, on the other hand, is packed at rest with large numbers of zymogen granules that contain the digestive enzymes and other regulatory factors. These granules are closely apposed to the apical membrane and thus to the lumen of the acinus. When the cell is stimulated by secretagogues, the granules undergo a process of compound exocytosis and fuse with each other and the apical membrane, thereby discharging their contents into the lumen.

Ductular Cells

The cells lining the intercalated ducts of the pancreas also play an important role in modifying the composition of the pancreatic juice. They are classical columnar epithelial cells, comparable to those lining the intestine itself, whose passive permeability is restricted by well-developed intercellular tight junctions. When stimulated, these cells transport bicarbonate ions into the pancreatic juice as it passes along the duct, with water following paracellularly in response to the resulting transepithelial osmotic gradient. Thus, the effect of the duct cells is to dilute the pancreatic juice and to render it alkaline. Quantitatively, the pancreas plays the major role in supplying the bicarbonate necessary to neutralize gastric acid so that appropriate digestion can take place in the small intestine.

The relative roles of acinar and ductular cells in contributing to the pancreatic juice can be demonstrated in animals fed a diet that is deficient in copper while also receiving the drug penicillamine. Among other effects, this treatment leads to atrophy of the pancreatic acini but has no effect on the ducts. Following a meal, such animals are unable to secrete pancreatic enzymes, but remain capable of increasing the volume of pancreatic juice due to the residual duct activity. In fact, the activity of the ductular cells is likely critical to “wash” the pancreatic enzymes out into the small intestine. Later in this chapter, we will consider the effects of cystic fibrosis, a disease state where ductular function is abnormal, on pancreatic secretory function.

Regulation of Pancreatic Secretion

Phases of Secretion

As we saw for gastric secretion, pancreatic secretory activity related to meal ingestion occurs in phases. In humans, the majority of the secretory response (approximately 60–70%) occurs during the intestinal phase, but there are also significant contributions from the cephalic (20–25%) and gastric (10%) phases. Pancreatic secretion is activated by a combination of neural and hormonal effectors. During the cephalic and gastric phases, secretions are low in volume with high concentrations of digestive enzymes, reflecting stimulation primarily of acinar cells. This stimulation arises from cholinergic vagal input during the cephalic phase, and vago-vagal reflexes activated by gastric distension during the gastric phase. During the intestinal phase, on the other hand, ductular secretion is strongly activated, resulting in the production of high volumes of pancreatic juice with decreased concentrations of protein, although the total quantity of enzymes secreted during this phase is actually also markedly increased. Ductular secretion during this phase is driven primarily by the endocrine action of secretin on receptors localized to the basolateral pole of duct epithelial cells. The inputs to the acinar cells during the intestinal phase include CCK and 5-HT from the intestine as well as neurotransmitters including acetylcholine (ACh) and GRP. The large magnitude of the intestinal phase is also attributable to amplification by so-called enteropancreatic reflexes transmitted via the enteric nervous system. The mechanisms regulating CCK and secretin release during the intestinal phase will be addressed in the following sections.

Role of CCK

CCK can be considered a master regulator of the duodenal cluster unit, of which the pancreas is an important component (Figure 4–2). CCK is a potent stimulus of acinar secretion, acting predominantly via CCK 1 receptor-dependent stimulation of vagal afferents close to its site of release in the duodenum, thereby evoking vago-vagal reflexes that stimulate acinar cell secretion via cholinergic and noncholinergic neurotransmitters (the latter including both GRP and VIP). There are also CCK 1 receptors on the basolateral pole of acinar cells, but it now seems likely that these are only activated if circulating concentrations of CCK rise to supraphysiologic levels. In addition to its effects on the pancreas, CCK coordinates the activity of other GI segments and draining organs, including by contracting the gallbladder (the physiologic function for which this hormone was named), relaxing the sphincter of Oddi, and slowing gastric motility to retard gastric emptying and thereby control the rate of delivery of partially digested nutrients to more distal segments of the gut. The latter activity serves to match luminal nutrient availability to the digestive and absorptive capacity of the small intestine. Finally, CCK can modulate the activity of other neurohumoral regulators in a synergistic fashion. Notably, while CCK is a weak agonist of pancreatic ductular secretion of bicarbonate by itself, it markedly potentiates the effect of secretin on this transport mechanism. During the integrated response to a meal, therefore, it is likely that the ability of secretin to evoke pancreatic bicarbonate secretion is amplified by occurring against the background of a CCK “tone.”

Figure 4–2.

Multiple effects of cholecystokinin (CCK) in the duodenal cluster unit. CCK serves to coordinate nutrient delivery to match intestinal capacity.

Nevertheless, CCK predominantly affects acinar cell secretion. Thus, during the initial response to a meal (i.e., the cephalic and gastric phases), pancreatic secretions are low in volume with a high concentration of enzymes and enzyme precursors. This situation should be contrasted with secretory flows occurring in the intestinal phase, where 5-HT and secretin also play a role. The effects of secretin are mediated predominantly at the level of the ducts. However, 5-HT, released from intestinal enterochromaffin cells in response to nutrients, activates a vago-vagal reflex that mirrors and augments that of CCK itself. It has been calculated that CCK and 5-HT are each responsible for about 50% of pancreatic enzyme secretion during the intestinal phase.

Factors Causing CCK Release

CCK is synthesized and stored by endocrine cells located predominantly in the duodenum, labeled in some sources as “I” cells (Figure 4–3). Control of CCK release from these cells is carefully regulated to match the body’s needs for CCK bioactivity. In part, this is accomplished by the activity of two luminally active CCK releasing factors, which are small peptides. One of these peptides is derived from cells in the duodenum, and called CCK-releasing peptide (CCK-RP). It is likely released into the lumen in response to specific nutrients, including fatty acids and hydrophobic amino acids. The other luminal peptide that controls CCK secretion is monitor peptide, which is a product of pancreatic acinar cells. Release of monitor peptide can be neurally mediated, including by the release of ACh and GRP in the vicinity of pancreatic acinar cells during the cephalic phase, and mediated by subsequent vago-vagal reflexes during the gastric and intestinal phases of the response to a meal. Likewise, once CCK release has been stimulated by CCK-RP, it too can cause monitor peptide release via the mechanisms outlined for acinar cell stimulation discussed earlier.

Figure 4–3.

Mechanisms responsible for controlling cholecystokinin (CCK) release from duodenal I cells. CCK-RP, CCK releasing peptide ACh, acetylcholine GRP, gastrin-releasing peptide. Solid arrows represent stimulatory effects while dashed arrows indicate inhibition.

The significance of having peptide factors that regulate CCK release lies in their ability to match pancreatic secretion of proteolytic enzymes to the need for these enzymes in the small intestinal lumen. When meal proteins and oligopeptides are present in the lumen in large quantities, they compete for the action of trypsin and other proteolytic enzymes, meaning that CCK-RP and monitor peptide are degraded only slowly. Thus, CCK release is sustained, causing further secretion of proteases and other components of the pancreatic juice. On the other hand, once the meal has been fully digested and absorbed, CCK-RP and monitor peptide will be degraded by the pancreatic proteases. This then leads to the termination of CCK release, and thus a marked reduction in the secretion of pancreatic enzymes. This feedback mechanism for the control of CCK release, and in turn, pancreatic secretion, can be demonstrated in animals in which pancreatic juices have been diverted away from the intestinal lumen. In such experiments, CCK release in response to fatty acids or amino acids is potentiated and prolonged, presumably reflecting the persistence of CCK-RP.

Role of Secretin

The other major regulator of pancreatic secretion is secretin, which is released from S cells in the duodenal mucosa. When the meal enters the small intestine from the stomach, the volume of pancreatic secretions increases rapidly, shifting from a low-volume, protein-rich fluid to a high volume secretion in which enzymes are present at lower concentrations (although in greater absolute amounts, reflecting the effect of CCK and neural effectors on acinar cell secretion). As the secretory rate rises, the pH and bicarbonate concentration in the pancreatic juice rises, with a reciprocal fall in the concentration of chloride ions (Figure 4–4). These latter effects on the composition of the pancreatic juice are mediated predominantly by the endocrine mediator, secretin. The postprandial bicarbonate secretory response can largely be reproduced by intravenous administration of secretin, particularly if given with a low dose of CCK that potentiates ductular secretion, as discussed earlier.

Figure 4–4.

Ionic composition of the pancreatic juice as a function of its flow rate. Note that the pancreatic juice becomes alkaline at high rates of secretion.


alpha cell: pancreatic islet cell type that produces the hormone glucagon

beta cell: pancreatic islet cell type that produces the hormone insulin

delta cell: minor cell type in the pancreas that secretes the hormone somatostatin

diabetes mellitus: condition caused by destruction or dysfunction of the beta cells of the pancreas or cellular resistance to insulin that results in abnormally high blood glucose levels

glucagon: pancreatic hormone that stimulates the catabolism of glycogen to glucose, thereby increasing blood glucose levels

hyperglycemia: abnormally high blood glucose levels

insulin: pancreatic hormone that enhances the cellular uptake and utilization of glucose, thereby decreasing blood glucose levels

pancreas: organ with both exocrine and endocrine functions located posterior to the stomach that is important for digestion and the regulation of blood glucose

pancreatic islets: specialized clusters of pancreatic cells that have endocrine functions also called islets of Langerhans

PP cell: minor cell type in the pancreas that secretes the hormone pancreatic polypeptide

Anatomy of the Pancreas

The pancreas lies in the epigastrium or upper central region of the abdomen and can vary in shape.

Learning Objectives

Outline the anatomy of the pancreas

Key Takeaways

Key Points

  • The pancreas lies in the epigastrium or upper central region of the abdomen.
  • The pancreas is composed of a head, uncinate process, neck, body, and tail.
  • A number of blood vessels connect the pancreas to the duodenum, spleen, and liver.

Key Terms

  • epigastrium: The upper middle region of the abdomen, between the umbilical and hypochondriac regions.


Pancreatic tissue is present in all vertebrate species, but its precise form and arrangement varies widely. There may be up to three separate pancreases, two of which arise from ventral buds, and the other dorsally. In most species (including humans), these fuse in the adult, but there are several exceptions.

Even when a single pancreas is present, two or three pancreatic ducts may persist, each draining separately into the duodenum (or an equivalent part of the foregut). Birds, for example, typically have three such ducts.

In teleosts, and a few other species (such as rabbits), there is no discrete pancreas at all, with pancreatic tissue being distributed diffusely across the mesentery and even within other nearby organs, such as the liver or spleen.

Anatomy of the Pancreas

The pancreas lies in the epigastrium or upper central region of the abdomen. It is composed of several parts.

  • The head lies within the concavity of the duodenum.
  • The uncinate process emerges from the lower part of head, and lies deep to superior mesenteric vessels.
  • The neck is the constricted part between the head and the body.
  • The body lies behind the stomach.
  • The tail is the left end of the pancreas. It lies in contact with the spleen.

The superior pancreaticoduodenal artery from the gastroduodenal artery and the inferior pancreaticoduodenal artery from the superior mesenteric artery run in the groove between the pancreas and the duodenum and supply the head of pancreas.

The pancreatic branches of the splenic artery also supply the neck, body, and tail of the pancreas. The body and neck of the pancreas drain into the splenic vein the head drains into the superior mesenteric and portal veins. Lymph is drained via the splenic, celiac, and superior mesenteric lymph nodes.

Parts of a pancreas: 1: Head of pancreas 2: Uncinate process of pancreas 3: Pancreatic notch 4: Body of the pancreas 5: Anterior surface of the pancreas 6: Inferior surface of the pancreas 7: Superior margin of the pancreas 8: Anterior margin of the pancreas 9: Inferior margin of the pancreas 10: Omental tuber 11: Tail of the pancreas 12: Duodenum.



Original Research Reports ▼

  • Seymour AB, Hruban RH, Redston MS, Caldas C, Powell SM, Kinzler KW, Yeo CH, Kern SE. Allelotype of pancreatic adenocarcinoma. Cancer Res 1994 54:2761-2764.
  • Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CH, Kern, SE. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 1994 54:3025-3033.
  • Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern, SE. Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 1994 54:3568-3573.
  • Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nature Genetics 1994 8:27-32.
  • Schutte M, da Costa LT, Hahn SA, Moskaluk C, Hoque ATMS, Rozenblum E, Weinstein CL, Bittner M, Meltzer PS, Trent JM, Yeo CJ, Hruban RH, Kern SE. A homozygous deletion identified by representational difference analysis in pancreatic carcinoma overlaps the BRCA2 region. Proc Natl Acad Sci USA 1995 92:5950-5954.
  • DiGiuseppe, Redston MS, Yeo CJ, Kern SE, Hruban RH. p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma. Amer J Pathol 1995 147:884-888.
  • Day JD, DiGiuseppe JA, Yeo CJ, Lai-Goldman M, Anderson SM, Kern SE, Hruban RH. Immunohistochemical evaluation of Her-2/neu oncogene expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Human Pathology 1996 27:119-124.
  • Hahn SA, Seymour AB, Hoque ATMS, Schutte M, da Costa LT, Redston MS, Caldas C, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. Allelotype of pancreatic adenocarcinoma using a xenograft model. Cancer Res 1995 55: 4670-4675.
  • Schutte M, Rozenblum E, Moskaluk CA, Guan X, Hoque ATMS, Hahn SA, da Costa LT, de Jong PJ, Kern, SE. An integrated high-resolution physical map of the DPC/BRCA2 region at chromosome 13q12-13. Cancer Res 1995 55:4570-4574.
  • Rozenblum E, Schutte M, Kern SE. INK4 genes in pancreatic carcinoma. Oncology Reports 1996 3:743-745.
  • Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor-suppressor gene at human chromosome 18q21.1. Science 1996 271:350-353. [8 th most cited research paper of 1996, Science Watch 1997 8:2]
  • Hoque ATMS, Hahn SA, Schutte M, Kern SE. DPC4 gene mutation in colitis-associated neoplasia. Gut 1997 40:120-122.
  • Hahn SA, Hoque ATMS, Moskaluk CA, da Costa LT, Schutte M, Rozenblum E, Seymour AB, Weinstein CL, Yeo CJ, Hruban RH, Kern SE. Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res 1996 56:490-494.
  • Brat DJ, Hahn SA, Griffin CA, Yeo CJ, Kern SE, Hruban RH. The structural basis of molecular genetic deletions: An integration of classical cytogenetic and molecular analyses in pancreatic adenocarcinoma. Am J Pathol 1997 150:383-391.
  • Moskaluk CA, Hruban RH, Lietman A, Smyrk T, Fusaro L, Fusaro R, Lynch J, Yeo CJ, Jackson CE, Lynch HT, Kern SE. Novel p16 INK4A mutation in familial pancreatic carcinoma. Human Mut 1998 (in press).
  • Schutte M, Hruban RH, Hedrick L, Molnar’Nadasdy G, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero R, Meltzer PS, Hahn SA, Kern SE. DPC4 in various tumor types. Cancer Res 1996, 56:2527-2530.
  • Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, Willson JKV, Markowitz S, Hamilton SR, Kern SE, Kinzler K, Vogelstein B. Evaluation of candidate tumor-suppressor genes on chromosome 18q in colorectal cancers. Nature Genet 1996 13:343-346.
  • Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JKV, Markowitz SD, Kinzler KW, Vogelstein B. MAD-related genes in the human. Nature Genetics 1996 13:347-349.
  • Derynck R, Gelbart WM, Harland RM, Heldin C-H, Kern SE, Massagué J, Melton DA, Mlodzik M, Padgett RW, Roberts AB, Smith J, Thomsen GH, Vogelstein B, Wang X-F. Nomenclature: vertebrate mediators of TGFb family signals. Cell 1996 87:173.
  • Moskaluk C, Hruban RH, Schutte M, Lietman AS, Smyrk T, Fusaro L, Rusar R, Lynch J, Yeo CJ, Jackson CE, Lynch HT, Kern SE. Genomic sequencing of DPC4 in the analysis of familial pancreatic cancer. Diag Mol Pathol 1997 6:85-90.
  • Barrett MT, Schutte M, Kern SE, Reid BJ. Allelic loss and mutational analysis of the DPC4 gene in esophageal adenocarcinoma. Cancer Res 1996 56:4351-4353.
  • Goggins M, Schutte M, Lu J, Moskaluk, CA, Weinstein C, Petersen G, Yeo CJ, Jackson, CE, Lynch HT, Hruban RH, Kern SE. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996, 56:5360-5364.
  • Rozenblum E, Schutte M, Goggins M, Hahn SA, Lu J, Panzer S, Zahurak M, Goodman SN, Hruban RH, Yeo CJ, Kern SE. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997 57:1731-1734.
  • Moskaluk C, Kern SE. Microdissection and PCR amplification of genomic DNA from histologic tissue sections. Am J Pathol 1997 150:1547-1552.
  • Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997 57:2140-2143.
  • Zhang L, Zhou W, Velculescu VE, Kern SE, Hruban RH, Hamilton SR, Vogelstein B, Kinzler KW. Gene expression profiles in normal and cancer cells. Science 1997 276:1268-1272.
  • Zhou W, Sokoll LJ, Bruzek DJ, Zhang L, Velculescu VE, Goldin SB, Hruban RH, Kern SE, Hamilton SR, Chan DW, Vogelstein B, Kinzler KW. Identifying markers for pancreatic cancer by gene expression analysis. Cancer Epid Bio Prev 1998 7:109-112.
  • Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE, Herman JG. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997 57:3126-3130.
  • Goggins M, Offerhaus GJA, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn T, Yeo CJ, Kern SE, Hruban RH. Adenocarcinomas of the pancreas with DNA replication errors (RER + ) are associated with wild-type K-ras and characteristic histopathology: poor differentiation, a syncytial growth pattern, and pushing borders suggest RER + . Am J Pathol 1998 152:1501-1507.
  • Sirard C, de la Pompa JL, Elia AJ, Itie A, Mirtsos C, cheung A, Hahn S, Wakeham A, Schwartz L, Kern SE, Rossant J, Mak TW. The tumor suppressor gene Dpc4/Smad4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 1998 12:107-119.
  • Okami K, Wu L, Riggins G, Cairns P, Goggins M, Evron E, Halachmi N, Ahrendt SA, Reed AL, Hilgers W, Kern SE, Sidransky D, Jen J. Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res 1998 58:509-511.
  • Zhou S, Buckhaults P, Zawel L, Bunz F, Riggins G, Dai JL, Kern SE, Kinzler KW, Vogelstein B. Targeted deletion of Smad4 shows it is required for transforming growth factor-b and activin signaling in colorectal cancer cells. Proc Natl Acad Sci USA 1998 95:2412-2416.
  • Zawel L, Dai J, Buckhaults P, Zhou S, Kinzler, KW, Vogelstein B, Kern SE. Human Smad3 and Smad4 are sequence-specific transcription activators. Molec Cell 1998 1:611-617.
  • Goggins M, Lietman A, Miller RE, Yeo CJ, Jaffee E, Coleman J, O’Reilly S, Cullen B, Kern SE, Hruban RH. The pancreatic cancer web site at Johns Hopkins: patterns of use and benefits of an institutional disease-based web site. JAMA 1998 280:1309-1310.
  • Su GH, Hilgers W, Shekher M, Tang D, Yeo CJ, Hruban RH, Kern SE. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor-suppressor gene. Cancer Res 1998 58:2339-2342.
  • Wilentz RE, Geradts J, Offerhaus GHA, Kang M, Goggins M, Yeo, CJ, Kern SE, Hruban RH. Inactivation of the p16 (INK4A) tumor-suppressor gene early in pancreatic neoplasia: loss of intranuclear expression. Cancer Res 1998 58:4740-4744.
  • Dai JL, Turnacioglu K, Schutte M, Sugar AY, Kern SE. DPC4 transcriptional activation and dysfunction in cancer cells. Cancer Res 1998 58:4592-4597.
  • Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE. Genetic alterations of the TGFb receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 1998 58:5329-5332.
  • Hilgers W, Tang DJ, Sugar AY, Shekher MC, Hruban RH, Kern SE. High-resolution deletion mapping of chromosome 1p in pancreatic cancer identifies a major consensus at 1p35. Genes Chromosom Can 1999 24:351-355.
  • DaDai JL, Bansal RK, Kern SE. G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4 – phenotypes reversed by a tumorigenic mutation. Proc Natl Acad Sci USA 1999 96:1427-1432i J, Schutte M, Sugar A, Kern SE. TGFb responsiveness in DPC4-null cancer cells. Molec Carcinog 1999 26:37-43.
  • Su GH, Hruban RH, Bova GS, Goggins M, Bansal RK, Tang DT, Shekher MC, Entius MM, Yeo CJ, Kern SE. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999 154:1835-1840.
  • Hilgers W, Su GH, Groot Koerkamp B, Tang DJ, Shekher MC, Sugar AY, Yeo CJ, Hruban RH, Kern SE. Novel homozygous deletions of chromosome 18q22 in pancreatic adenocarcinoma identified by STS marker scanning. Genes Chrom Can 1999 25:370-375.
  • Hilgers W, Koerkamp BG, Geradts J, Tang DJ, Yeo CJ, Hruban RH, Kern SE. Genomic FHIT alterations in RER + and RER - adenocarcinomas of the pancreas. Genes Chrom Cancer 2000, 27:239-243.
  • Hilgers W, Song JJ, Hayes M, Hruban RR, Kern SE, Fearon ER. Homozygous deletions inactivate DCC, but not MADH4/DPC4/SMAD4, in a subset of pancreatic and biliary cancers. Genes Chrom Cancer 2000 27:353-357.
  • Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, Sohn TA, Yeo CJ, Kern SE, Hruban RH. Immunohistochemical labeling for Dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am J Pathol 2000 156:37-43.
  • Wilentz RE, Goggins M, Redston M, Marcus VA, Sohn TA, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJA, Hruban RH, Kern SE. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol 2000 156:1641-1651.
  • Goggins M, Hruban RH, Kern SE. The late temporal pattern of BRCA2 inactivation in pancreatic intraductal neoplasia: Evidence and implications. Am J Pathol 2000 156:1767-1771.
  • Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: Evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000 60:2001-2005.
  • Jones J, Kern SE. Functional mapping of the MH1 DNA-binding domain of DPC4/SMAD4. Nucl Acids Res 2000 28:2363-2368.
  • Iacobuzio-Donahue CA, Klimstra DS, Volkan Adsay N, Wilentz RE, Argani P, Sohn TA, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Dpc4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal carcinomas. Am J Pathol 2000 157:755-761.
  • Su GH, Sohn TA, Ryu B, Kern SE. A novel histone deacetylase inhibitor identified by high-throughput transcriptional screening of a compound library. Cancer Res 2000 60:3137-3142
  • Iacobuzio-Donahue CA, Wilentz RE, Argani P, Yeo CJ, Kern SE, Hruban RH. Dpc4 protein in mucinous cystic neoplasms of the pancreas: Frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 2000, 157:755-761.
  • Lynch HT, Brand RE, Lynch JF, Fusaro RM, Smyrk, TC, Goggins M, Kern SE. Genetic counseling and testing for germ-line p16 mutations in two pancreatic cancer-prone families: Case Report. Gastroenterol 2000 119:1756-60.
  • Argani P, Shaukat A, Kaushal M, Wilentz RE, Su GH, Sohn TA, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Differing rates of loss of DPC4 expression and of p53 overexpression among carcinomas of the proximal and distal bile ducts: evidence for a biologic distinction. Cancer 2001 91:1332-1341
  • Montgomery E, Goggins M, Zhou S, Argani P, Wilentz RE, Kaushal M, Booker S, Romans K, Bhargava P, Hruban RH, Kern SE. Nuclear localization of Dpc4 (Madh4, Smad4) in colorectal carcinomas and relation to mismatch repair/transforming growth factor-b receptor defects. Am J Pathol 2001 158:537-542.
  • Jones J, Hempen PM, Song J, Hruban RH, Kern SE. Detection of mutations in the mitochondrial genome in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear mutations. Cancer Res 2001 61:1299-1304.
  • Ryu B, Song J, Hruban RH, Kern SE. Frequent germline deletion polymorphism of chromosomal region 8p12-p21 detected as a recurrent homozygous deletion in human tumors. Genomics 2001 72:108-112.
  • Tersmette AC, Petersen GM, Offerhaus GJA, Falatko FC, Goggins M, Rozenblum E, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clinical Cancer Res 2001 7:738-744.
  • Ryu B, Jones J, Hollingsworth MA, Hruban RH, Kern SE. Invasion-specific genes in malignancy: SAGE comparisons of primary and passaged cancers. Cancer Res 2001 61:1833-1838.
  • Su GH, Bansal R, Montgomery E, Yeo CJ, Hruban RH, Kern SE. ACVR1B (ALK4) gene mutations in pancreatic carcinoma. Proc Natl Acad Sci USA 2001 98:3254-3257.
  • McCarthy DM. Brat DJ, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Pancreatic intraepithelial neoplasia and infiltrating adenocarcinoma: analysis of progression and recurrence by DPC4 immunohistochemical labeling. Hum Pathol 2001 32:638-642.
  • Argani P, Rosty C, Reiter RE, Wilentz RE, Murugesan S, Leach SB, Ryu B, Goggins M, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Discovery of new markers of cancer through serial analysis of gene expression (SAGE): prostate stem cell antigen (PSCA) is overexpressed in pancreatic adenocarcinoma. Cancer Res 2001 61:4320-24
  • Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra D, Klöppel G, Longnecker D, Lüttges J, Offerhaus GJA. Pancreatic intraepithelial neoplasia: A new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001 25:579-586.
  • Sohn TA, Su GH, Ryu B, Yeo CJ, Kern SE. High-throughput drug screening of the DPC4 tumor-suppressor pathway in human pancreatic cancer cells. Ann Surg 2001 233:696-703.
  • Feldser DM, Kern SE. Oncogenic functionality of the dinucleotide KRAS2 mutations: G12F and GG12-13VC. Human Mutation 2001 18:357.

Reviews, Editorials, and Chapters ▼

  • Kern SE. Clonality: More than just a tumor-progression model. (Editorial) J Natl Can Inst 1993 85:1020-1021.
  • Kern SE. p53: Tumor suppression through control of the cell cycle. (Editorial) Gastroenterology 1994 106:1708-1711.
  • Kern SE. Oncogenes/proto-oncogenes and tumor suppressor genes in human neoplasia. In Cellular and Molecular Pathogenesis. Sirica AE, ed. Raven Press 1996. pp 321-340
  • Yeo CJ, Hruban RH, Kern SE, Abrams RA, Grochow LB, Griffin CA, Cameron JL. Adenocarcinoma of the pancreas: Factors influencing outcome following pancreaticoduodenectomy - The Johns Hopkins Experience. (Review) The Cancer Bulletin 1994 46:504-510.
  • Caldas C, Kern SE. K-Ras mutation and pancreatic adenocarcinoma. (Review) Int J Pancreatol 1995 16:192.
  • Hahn SA, Kern SE. Molecular genetics of exocrine pancreatic neoplasms. (Review) Surg Clin N Amer 1995 55:857-869.
  • Hahn SA, Kern SE, Schmiegel W-H. Molekularbiologische Veränderungen bei gastrointestinalen Tumoren, Diagnostische und therapeutische Perspektiven. Deutsches Ärzteblatt 1995 92:137-143.
  • Schutte M, Kern SE. The molecular genetics of pancreatic adenocarcinoma. (Chapter) In Pancreatic Cancer: Molecular and Clinical Advances. Neoptolemos and N. Lemoine, eds., Blackwell Scientific, Oxford, 1996. pp 115-132.
  • Lynch HT, Smyrk T, Kern SE, Hruban RH, Lightdale CJ, Lemon SJ, Lynch JF, Fusaro LR, Fusaro RM, Ghadirian P. Familial pancreatic cancer: A review. Seminars in Oncology 1996 23:251-275.
  • Yeo CJ, Kern SE, Hruban RH, Camerson JL. Pancreatic cancer: New aspects of genetics and surgical management: The Johns Hopkins experience. Asian J Surg 1997 20:221-228.
  • Moskaluk CA, Kern SE. Molecular genetics of pancreatic cancer. (Chapter) In Advances in Pancreatic Cancer, H Reber, ed., The Human Press, 1998. pp 3-20.
  • Moskaluk CA, Kern SE. Mad About Cancer: DPC4 and Other TGF-b Pathway Genes in Human Cancer (Review) BBA (Reviews on Cancer) Online 1996 1288: M31-M33.
  • Goggins M, Hruban RH, Kern SE. Hereditary Pancreatic Cancer - Part I: Genetic profile of the disease. Oncology News International 1997 6 (6):24. Hereditary pancreatic Cancer - Part II: The candidate genes. Oncology New International 1997 6 (7):8. Hereditary Pancreatic Cancer - Part III: Clinical recognition of hereditary predisposition. Oncology News International 1997 6 (8):15.
  • Hruban RH, Yeo SJ, Kern SE. Screening for pancreatic cancer. In Cancer Screening: Theory and Practice, B. Kramer, P. Provok, and J. Gohagan, eds., Dekker Publ, 1999, pp 441-459
  • Kern SE. Advances from genetic clues in pancreatic cancer. Curr Opin Onc 1998 10:74-80.
  • Hruban RH, Petersen GM, Ha P, Kern SE. Genetics of pancreatic cancer: From genes to families. Surg. Onc. Clin N Amer 1998 7:1-23.
  • Slebos RJC, Ceha HM, Kern SE, Hruban RH. Molecular genetics of pancreas cancer. Dugan M and Sarkar F, eds. BioTechniques Books 1998, pp 65-82.
  • Hahn SA, Kern SE, Schmiegel W-H. Neue molekularbiologische Erkenntnisse aus des Pankreaskarzinom-Forschung, Diagnostische und therapeutische Perspektiven. Deutsches Ärzteblatt 1997 94:3-10.
  • Hruban R, Offerhaus GJA, Kern SE, Goggins M, Wilentz RE, Yeo CJ. Tumor-suppressor genes in pancreatic carcinoma. (Review) J Hep Bil Pancr Surg 1998 5:383-391.
  • Hilgers W, Kern SE. The molecular genetic basis of pancreatic cancer. (review) Genes Chrom Cancer 1999 26:1-12.
  • Goggins M, Kern SE, Offerhaus GJA, Hruban RH. Progress in cancer genetics: Lessons from pancreatic cancer. Annals of Oncology 1999 10 Suppl 4: S4-S8.
  • Hruban RH, Wilentz RE, Goggins M, Offerhaus GJA, Kern SE. Pathology of incipient pancreatic cancer. Annals of Oncology 1999 10 Suppl 4: S9-S11.
  • Hruban RH, Petersen GM, Goggins M, Termette AC, Offerhaus GJA, Falatko F, Yeo CJ, Kern SE. Familial pancreatic cancer. Annals of Oncology 1999 10 Suppl 4: S69-S73.
  • Hruban RH, Goggins M, Kern SE. Molecular genetics and related developments in pancreatic cancer. (Review) Curr Opin Gastro 1999 15:404-409.
  • Klöppel G, Hruban RH, , Longnecker DS, Adler G, Kern SE, Partanen TJ. Ductal adenocarcinoma of the pancreas. World Health Organization. 2000, pp 219-230.
  • Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000 6:2969
  • Kern SE. Molecular genetic alterations in ductal pancreatic adenocarcinomas. (review) Med Clin N Amer 2000 84:691-695.
  • Su GH, Kern SE. The molecular genetics of pancreatic ductal neoplasia. (review) Curr Opin Gastro 2000 16:419-425.
  • Hruban RH, Wilentz R, Kern SE. Genetic progression in the pancreatic ducts. (Commentary) Am J Pathol 2000 156:1821-1825.
  • Hruban RH, Yeo CJ, Kern SE. Pancreatic cancer. (Chapter) In Metabolic and Molecular Basis of Inherited Diseases (MMBID): The Genetic Basis of Human Cancer, B Vogelstein and KW Kinzler, section eds., McGraw-Hill, CD-ROM edition, 1997 and In The Genetic Basis of Human Cancer, , B Vogelstein and KW Kinzler, eds., McGraw-Hill, 7 th edition, 1998, pp 603-614 and 8 th edition, 2001, pp 1077-1090.
  • Hruban RH, Offerhaus GJA, Kern SE. Familial pancreatic cancer. In Atlas of Clinical Oncology: Pancreatic Cancer. John L. Cameron, ed. American Cancer Society, 2001, pp. 25-36.
  • Kern SE, Hruban RH. The molecular genetics of adenocarcinoma of the pancreas. In Atlas of Clinical Oncology: Pancreatic Cancer. John L. Cameron, ed. American Cancer Society, 2001, pp. 13-24.
  • Kern SE, Hruban RH, Hollingsworth MA, Brand R, Adrian TE, Jaffee E, Tempero MA. A "white paper": The product of a pancreas cancer think tank. Cancer Res 2001, 61:4923-32.
  • The Pancreatic Cancer NIH Progress Review Group, Tempero M and Kern SE, co-chairs. Pancreatic Cancer: An Agenda for Action. NCI publication 2001.
  • Hruban RH, Iacobuzio-Donahue C, Wilentz RE, Goggins M, Kern SE. The molecular pathology of pancreatic cancer. Cancer Journal 2001 7:251-258.
  • Sohn TA, Su GH, Ryu B, Yeo CJ, Kern SE. High-throughput drug screening of the DPC4 tumor-suppressor pathway in human pancreatic cancer cells. Ann Surg 2001 233:696.
  • Kern SE. Progressive genetic abnormalities in human cancer. In Molecular Basis of Cancer, 2 nd edition, J. Mendelsohn, M. Israel, L. Liotta, P.M. Howley, eds. W.B. Saunders Co., 2 nd edition, 2001, pp 41-69.


After an outline description of pancreatic structure and function, and a more detailed account of acinar cell morphology, this review traces the pathway of amino acids as they are taken up by the acinar cell, incorporated into digestive hydrolases, transported through the cell and finally discharged from the cell, and considers the mechanisms by which these steps are controlled. At all stages comparisons are made with other secretory cells.

The use of radioautography and cell-fractionation techniques in determining this pathway in the pancreas are described. The route and kinetics of the process in pancreas are compared with those in other cells.

Amino-acid entry is by an active mechanism. However the intracellular pool of accumulated amino acids may not be used directly in protein synthesis. Selection of amino acids for incorporation into proteins may occur whilst they are associated with carrier systems within the plasma membrane. There is no convincing evidence that amino-acid entry can be influenced by the pancreatic secretagogues, cholecystokin-pancreazymin (CCK-PZ) or acetylcholine.

Secretory proteins are synthesized on ribosomes bound to the endoplasmic reticulum (ER) and the nascent proteins vectorially transferred across the ER membrane into the ER cisternae. All messenger RNA molecules which are templates for secretory proteins appear to possess an initial sequence of codons whose translation produces a ‘signal’ sequence of amino acids. This signal sequence somehow triggers attachment of the ribosomes to the ER, thereby automatically determining that the final translation product is destined for the ER cisternae.

The effects of CCK-PZ and acetylcholine on pancreatic protein synthesis are controversial. Whereas stimulation can be observed in vivo, this has not been convincingly demonstrated in vitro. I conclude that while CCK-PZ and acetylcholine may accelerate protein synthesis, the physiological significance of this effect remains to be clarified. Long-term stimulation can modify pancreatic enzyme synthesis and this, together with other factors, may be the means of dietary adaptation by the gland.

Newly synthesized proteins travel from the ER cisternae via the peripheral Golgi components to the Golgi cisternae. Transport from ER to Golgi cisternae may occur by a vesicle shuttle service or by direct tubular connexions. Although sustained stimulation with CCK-PZ analogues can accelerate this intracellular transport step, pancreatic secretagogues have not yet been shown to accelerate transport under physiological conditions.

The Golgi complex has a number of functions including: glycosylation and, where appropriate, sulphation of glycoprotein and mucopolysaccharide components of the zymogen granules (ZG) and granule membranes sequestration of divalent cations which bind to secretory proteins the formation of condensing vacuoles (CV) from the inner Golgi cisternae.

Aggregation of proteins occurs passively within CV so as to form osmotically inert complexes, thereby reducing internal osmotic activity and causing water to diffuse out. This condensation imparts a gel-like consistency to the mature ZG so formed.

Discharge of ZG occurs by a process of exocytosis involving fusion of the ZG membrane with the apical plasma membrane, release of the ZG contents, and retrieval of the ZG membrane from the plasma membrane by endocytotic mechanisms. The mechanisms responsible for migration of ZG towards the cell apex and for exocytosis remain unknown but may involve the participation of microtubules and/or microfilaments. Although there is a small, basal discharge of ZG at all times, stimulation with CCK-PZ or acetylcholine greatly accelerates the process.

The basic tenet of the secretory mechanism summarized above is that, following synthesis, secretory proteins are confined within an intracellular organelle at all times. This ‘segregation’ hypothesis has been challenged by the ‘equilibrium’ hypothesis in which secretory proteins are suggested to move across cellular membranes and are therefore at equilibrium within the various compartments of the cell. While many of the observations on which the equilibrium hypothesis are based are tenuous, some others cannot readily be explained by the segregation model. Proponents of the equilibrium hypothesis therefore suggest that preferential release of individual hydrolases from ZG occurs, followed by their separate transport across the apical cell membrane. The claims of this alternative model are discussed.

In the final section are discussed the intracellular mechanisms by which CCK-PZ and acetylcholine act on the acinar cell to cause discharge. The overall membrane perturbations brought about by CCK-PZ and acetylcholine appear to be the same and include cell depolarization, and perhaps increased phospholipid turnover. Both events may be related to an altered membrane permeability to cations. CCK-PZ, but not acetylcholine, will activate adenylate cyclase, but cyclic AMP does not appear to be involved in regulating enzyme discharge. Instead, Ca 2+ is the major intracellular second messenger. However, rather than increase Ca 2+ uptake into the cell, CCK-PZ and acetylcholine appear to raise the intracellular Ca 2+ concentration by causing release of Ca 2+ from intracellular stores. The mechanism by which they do this, and the role of Ca 2+ in the discharge process remain unknown.

Watch the video: Καρκίνος του παγκρέατος: Τα συμπτώματα και η θεραπεία της δύσκολης νόσου (November 2021).