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PubMed2001

Pancreatic acinar cell carcinoma.

Acinar cell carcinomas (ACCs) are rare neoplasms that represent less than 2% of all exocrine tumors of the pancreas. Although they occur more often in adults between the 5th and 7th decades of life, a few cases have been reported in children. Histologically, ACCs can resemble islet cell tumors, but they differ in their ultrastructural and immunohistochemical features. Although ACCs present a bland histology, they are highly malignant and the survival of patients with these tumors, even though better than that of those with ductal cell carcinomas, is generally poor.

Biomarkers, Tumor↗
PubMed2005

Improved retention of zymogen granules in cultured murine pancreatic acinar cells and induction of acinar-ductal transdifferentiation in vitro.

OBJECTIVES: To establish a primary culture model for murine pancreatic acinar cells and to investigate the effects of different culture conditions on the phenotype and plasticity of these cells in extended culture. METHODS: Acinar cells, cultured in Chee (CME) or Waymouth/Ham F-12 (WHME) media, exhibited 2 markedly dissimilar phenotypes. We employed 5'-bromo-2'-deoxyuridine (BrdU) incorporation, immunocytochemistry, and electron microscopy to investigate differences in cell cycle status and phenotype. RESULTS: CME-cultured cells grew as discrete epithelial islands and retained zymogen granules and endoplasmic reticulum stacks, yet expressed cytokeratin 7, suggesting that they comprise an intermediate between the acinar and ductal cell types. Observed by time-lapse videomicroscopy, cells transferred to WHME formed a confluent monolayer, flattened and dedifferentiated to a duct-like phenotype typified by loss of secretory apparatus, variable beta-catenin expression, an elongated teardrop shape, increased cell size, and nuclear pleomorphism. Transition between phenotypes did not involve apoptosis as assessed by morphologic criteria in Feulgen-stained cultures. The flattened cells exhibited increased BrdU incorporation and mitotic index, suggesting that dedifferentiation precedes the capacity for increased cell cycle entry, while the appearance of meganuclei is consistent with amplified DNA content. We also demonstrate greatly improved gene delivery to cultured acinar cells by adenovirus-mediated transduction compared with lipid-mediated transfection. CONCLUSIONS: This in vitro model confirms the plasticity of acinar cells and may serve to delineate the changes underlying acinar cell dedifferentiation and acquisition of a duct-like pluripotent phenotype.

Adenoviridae↗
PubMed2005

Ca2+ dynamics in salivary acinar cells: distinct morphology of the acinar lumen underlies near-synchronous global Ca2+ responses.

In salivary acinar cells, the pattern of the Ca2+ signals that regulates fluid and enzyme secretion has yet to be resolved, as there are conflicting reports in the literature. We have used a two-photon technique to directly visualize the acinar cell lumen in living fragments of exocrine tissue and simultaneously recorded agonist-induced changes in intracellular Ca2+. We show near-synchronous global Ca2+ responses in submandibular acinar cells, distinct from the typical apical to basal Ca2+ wave usually seen in rodent pancreatic acinar cells. In an effort to explain the basis of these near-synchronous global Ca2+ responses we used immunocytochemical experiments to localize luminal proteins and inositol trisphosphate receptors (InsP3Rs) in tissue fragments. Zona occludens 1 (ZO-1), a tight junction protein, shows that individual submandibular acinar cells are often nearly completely encircled by a narrow luminal structure. By contrast, in pancreatic fragments, ZO-1 staining shows short luminal branches terminating abruptly at the apical pole of single acinar cells. Co-immunostaining of InsP3Rs type 2 and type 3 showed them in the same region as ZO-1 in both exocrine tissues. Functional experiments showed that the near-synchronous global Ca2+ responses were still observed in the absence of extracellular Ca2+ and also in the presence of ryanodine. We conclude that the elaborate luminal region of submandibular cells leads to a hitherto unrecognized extensive distribution of InsP3Rs in a band around the cell and that this underlies the near-synchronous global Ca2+ response to agonists. We suggest that this may be a structural adaptation in submandibular cells to support the copious amounts of fluid secreted.

Animals↗
PubMed1977

Exocrine pancreas under experimental conditions. III. Membrane and cell junctions in isolated acinar cells.

The ultrastructure of the cell membrane and intercellular junctions was studied after isolation of exocrine pancreatic cells by tryptic digestion and mechanical treatment. The number and distribution of membrane associated particles does not change significantly when acinar cells in situ are compared to those after the isolation procedure. However, intercellular junctions undergo distinct alterations. Gap junctions in normal pancreatic cells are macular in shape and localized at the lateral parts of the cell membrane. In isolated acinar cells gap junctions are irregularly shaped, more extended, and frequently associated with tight junctions. Tight junctions form belt-like structures which are found to persist after isolation but subsequently become elongated and interrupted. Thus extensive macular areas of tight junctions develop. Further, the strands on the P-face and the grooves on the E-face of freeze-fracture replicas change in array, dissociate, and become loosely packed on large membrane areas. The present investigation shows that the intramembranous proteins of tight and gap junctions are mobile structures within the fluid membrane. The shape of their array is dependent on the form of the intercellular contact zone.

Animals↗
PubMed2002

Analysis and optimization of nutritional set-up for murine pancreatic acinar cells.

CONTEXT: Pancreatic acinar cell cultivation poses a serious problem due to limitations in the in vitro survival time despite variations of dissociation protocols, culture media and nutrient supplements. OBJECTIVE: To establish a long term culture of murine pancreatic acinar cells which retain their viability, monolayer formation and responsiveness to secretagogues. In order to investigate the mechanism of the short-life of acinar cells studied in vitro, we studied their survival under the influence of different supplements on nutrient media. INTERVENTIONS: Dissociated pancreatic acini were prepared from BALB/c mice pancreata by collagenase digestion supplemented with bovine serum albumin fraction V and soybean trypsin inhibitor. A nutrient set-up was designed for their long term survival in vitro. RESULTS: It was observed that mouse pancreatic acinar cells dissociated in presence of bovine serum albumin fraction V and soybean trypsin inhibitor result in 95% viability. Further cultivation of these acinar cells in Waymouth's MB 752/1 medium supplemented with 10% fetal calf serum (v/v), soybean trypsin inhibitor, bovine serum albumin, dexamethasone, and epidermal growth factor results in their survival for more than 6 days in culture with 85% viability, retention of the secretagogue responsiveness and formation of a monolayer without any extracellular matrix coating. CONCLUSIONS: Our study clearly demonstrates that the addition of soybean trypsin inhibitor to culture medium reduces zymogen granule fragility and acinar cell death, thus increasing their viability for sufficiently long periods. The present study offers an excellent, in vitro model for the investigation of exocrine dysfunction in response to acinar cell injury.

Amylases↗
PubMed1991

Secretagogue induction of cell differentiation in pancreatic acinar cells in vitro.

The effect of two different types of secretagogues on rat pancreatic acinar cells cultured onto a reconstituted basement membrane was studied. Cells cultured without any secretagogue were able to reaggregate but did not form monolayer patches. Most of them lost their differentiated ultrastructural characteristics but regained their polarity. In contrast, when CCK, caerulein, or carbamylcholine was added to the culture medium cells developed both acini-like structures and cell monolayer patches. The cells retained the differentiated ultrastructural appearance and polarity resembling their in situ morphology. Furthermore, secretagogue-conditioned cells presented higher amylase contents. The use of secretagogue antagonists such as L-364,718 and L-365,260 for caerulein, or atropine and mecamylamine for carbamylcholine, did not profoundly modify the cultures and the morphological effects triggered by the secretagogues alone. However, both CCK antagonists and cholinergic antagonists inhibited to a certain degree the secretory stimulation. Our data support the theory that a major role is played by secretagogues in conjunction with the basement membrane for the maintenance of differentiation in pancreatic acinar cells in vitro which appears to be independent from their secretory effect.

Amylases↗
PubMed2004

cAMP potentiates ATP-evoked calcium signaling in human parotid acinar cells.

In salivary acinar cells, intracellular calcium ([Ca(2+)](i)) signaling plays an important role in eliciting fluid secretion through the activation of Ca(2+)-activated ionic conductances. Ca(2+) and cAMP have synergistic effects on fluid secretion such that peak secretion is elicited following activation of both parasympathetic and sympathetic pathways. We have recently demonstrated that cAMP exerts effects on Ca(2+) release, through protein kinase A (PKA)-mediated phosphorylation of inositol 1,4,5-trisphosphate receptors (InsP(3)R) in mouse parotid acinar cells. To extend these findings, in the present study cross-talk between Ca(2+) signaling and cAMP pathways in human parotid acinar cells was investigated. In human parotid acinar cells, carbachol stimulation evoked increases in the [Ca(2+)](i) and the initial peak amplitude was enhanced following PKA activation, consistent with reports from mouse parotid. Stimulation with ATP also evoked an increase in [Ca(2+)](i). The ATP-evoked Ca(2+) elevation was largely dependent on extracellular Ca(2+), suggesting the involvement of the P2X family of purinergic receptors. Pharmacological elevation of cAMP resulted in a approximately 5-fold increase in the peak [Ca(2+)](i) change evoked by ATP stimulation. This enhanced [Ca(2+)](i) increase was not dependent on intracellular release from InsP(3)R or ryanodine receptors, suggesting a direct effect on P2XR. Reverse transcription-polymerase chain reaction and Western blot analysis confirmed the presence of P2X(4)R and P2X(7)R mRNA and protein in human parotid acinar cells. ATP-activated cation currents were studied using whole cell patch clamp techniques in HEK-293 cells, a null background for P2XR. Raising cAMP resulted in a approximately 4.5-fold enhancement of ATP-activated current in HEK-293 cells transfected with P2X(4)R DNA but had no effects on currents in cells expressing P2X(7)R. These data indicate that in human parotid acinar cells, in addition to modulation of Ca(2+) release, Ca(2+) influx through P2X(4)R may constitute a further locus for the synergistic effects of Ca(2+) and PKA activation.

Adenosine Triphosphate↗
PubMed2002

Evidence that zymogen granules do not function as an intracellular Ca2+ store for the generation of the Ca2+ signal in rat parotid acinar cells.

Rat parotid acinar cells lacking zymogen granules were obtained by inducing granule discharge with the beta-adrenoceptor agonist isoproterenol. To assess whether zymogen granules are involved in the regulation of Ca(2+) signalling as intracellular Ca(2+) stores, changes in cytosolic free Ca(2+) ion concentration ([Ca(2+)](i)) were studied with imaging microscopy in fura-2-loaded parotid acinar cells lacking zymogen granules. The increase in [Ca(2+)](i) induced by muscarinic receptor stimulation was initiated at the apical pole of the acinar cells, and rapidly spread as a Ca(2+) wave towards the basolateral region. The magnitude of the [Ca(2+)](i) response and the speed of the Ca(2+) wave were essentially similar to those in control acinar cells containing zymogen granules. Western blot analysis of the inositol 1,4,5-trisphosphate receptor (IP(3)R) was performed on zymogen granule membranes and microsomes using anti-IP(3)R antibodies. The immunoreactivity of all three IP(3)Rs was clearly observed in the microsomal preparations. Although a weak band of IP(3)R type-2 was detected in the zymogen granule membranes, this band probably resulted from contamination by the endoplasmic reticulum (ER), because calnexin, a marker protein of the ER, was also detected in the same preparation. Furthermore, Western blotting and reverse transcriptase-PCR analysis failed to provide evidence for the expression of ryanodine receptors in rat parotid acinar cells, whereas expression was clearly detectable in rat skeletal muscle, heart and brain. These results suggest that zymogen granules do not have a critical role in Ca(2+) signalling in rat parotid acinar cells.

Animals↗
PubMed2025

GZMK+CD8+ T cells target a specific acinar cell type in Sjögren's disease.

OBJECTIVES: Sjögren's disease (SjD) is a systemic autoimmune disorder characterized by dysfunction of exocrine glands, particularly the salivary and lacrimal glands, with no clear etiology or effective therapy. This study explores the complex interplay of varied cell types in the salivary glands and their role in the pathology of Sjögren's disease. METHODS: Utilizing single-cell and spatial transcriptomics alongside spatial immunophenotyping to analyze human minor salivary glands, we developed a comprehensive understanding of the cellular landscape of non-SjD salivary glands and how that landscape changes in SjD patients. In vitro cellular assays and novel patient-derived primary epithelial cells were co-cultured with autologous T cells to confirm effector states and the delivery and effect of disease-associated granzymes. RESULTS: We identified previously unrecognized heterogeneity among acinar cells, including a PRR4⁺CST3⁺WFDC2⁻ seromucous acinar population that is selectively lost in Sjögren's disease. Expression and organizational changes were linked to clinical features: (i) T cells in the glands of SSA⁺, high-focus score patients showed increased transcriptional signatures of activation, antigen presentation, and apoptosis resistance compared with patients with mild or moderate disease, and (ii) patients with low immune infiltration exhibited distinct epithelial organization. Notably, GZMK⁺CD8⁺ T cells, which accumulate with disease severity, displayed a cytotoxic transcriptional program, degranulated upon stimulation ex vivo, and localized spatially with immune-engaged epithelial cells. Functional assays demonstrated that GZMK activates interferon signaling in vitro, and autologous co-cultures of patient-derived T cells and epithelial cells validated these findings. CONCLUSIONS: Using single-cell and spatial transcriptomics and proteomics, this study identifies a selective loss of PRR4⁺CST3⁺WFDC2⁻ seromucous acinar cells and a rise in GZMK⁺CD8⁺ T cells in Sjögren's disease, revealing distinct immune-mediated epithelial remodeling and interferon-driven dysfunction across diverse clinical presentations. These findings uncover a novel sub-cytolytic effector mechanism by which GZMK⁺CD8⁺ T cells impair mitochondrial integrity and activate innate immune signaling, linking epithelial injury to type I interferon responses and offering new therapeutic targets.

Humans↗
PubMed1983

Uptake, storage and secretion of 5-hydroxytryptamine and its amino acid precursor by dispersed rat pancreas acinar cells.

Rat pancreas acinar cells contain 5-hydroxytryptamine (5-HT; 10.86 +/- 2.52 ng/i.u. amylase), all of which can be accounted for by the 5-HT recovered from the zymogen granule fraction of these cells (10.70 +/- 3.06 ng/i.u. amylase). When incubated with [14C]5-HT dispersed acinar cells take up the amine and concentrate it in zymogen granules. These cells will also take up [14C]5-HTP (5-hydroxytryptophan), decarboxylate it and store the [14C]5-HT so produced in zymogen granules. 5-HTP itself is not taken up by the granules. 5-HT is incorporated into zymogen granules early in their formation; no amine is accumulated by mature zymogen granules and the amine within the mature granule is not exchangeable with extragranular amine. When dispersed acinar cells pre-labelled with [14C]5-HT and [3H]leucine are stimulated with caerulein, there is a synchronous increase in amylase activity and secretion of [14C]5-HT and [3H]protein; the ratios of [3H]protein/[14C]5-HT in zymogen granules and in the secretory products are identical. Pancreas acinar cells take up L-DOPA, decarboxylate it and store the dopamine produced in zymogen granules but the dopamine is not retained by the granules (t1/2 approximately equal to 90 min) and dopamine secretion from cells exposed to caerulein could not be demonstrated. It is concluded that 5-HT is a normal component of rat pancreas acinar cell zymogen granule. The granular amine has a turnover rate similar to that of granular protein and is released when the cells are stimulated to secrete protein. All the 5-HT released from the cell originates in zymogen granules.

5-Hydroxytryptophan↗
PubMed1999

Quantitative description of the spatial arrangement of organelles in a polarised secretory epithelial cell: the salivary gland acinar cell.

Previous quantitative descriptions of cellular ultrastructure have focused on spatial content (volume, surface area and number of organelles and membrane domains). It is possible to complement such descriptions by also quantifying spatial arrangements. Hitherto, applications of stereological methods for achieving this (notably, estimation of covariance and pair correlation functions) have been confined to organ and tissue levels. This study explores 3-dimensional subcellular arrangements of key organelles within acinar cells of rabbit parotid salivary glands, highly polarised epithelial cells specialised for exocrine secretion of alpha-amylase. It focuses on spatial arrangements of secretion product stores (zymogen granules), rough endoplasmic reticulum (RER) and mitochondria. Systematic random samples of electron microscopical fields of view from 3 rabbits were analysed using test grids bearing linear dipole probes of different sizes. Unbiased estimates of organelle volume densities were obtained by point counting and estimates of covariance and pair correlation functions by dipole counting. Plots of pair correlation functions against dipole length identified spatial arrangement differences between organelle types. Volumes within RER and mitochondrial compartments were positively correlated with themselves at distances below 4 microm and 2 microm respectively but were essentially randomly arranged at longer distances. In sharp contrast, zymogen granules were not randomly arranged. They were clustered at distances below 6-7 microm and more widely scattered at greater distances. These findings provide quantitative confirmation of the polarised arrangement of zymogen granules within acinar cells and further support for the relative invariance of biological organisation between subjects.

Animals↗
PubMed1978

Effects of calcium and chelating agents on the ability of various agonists to increase cyclic GMP in pancreatic acinar cells.

In dispersed acinar cells from guinea pig pancreas we found that chelating extracellular calcium with EDTA did not alter cellular cyclic GMP but caused a 50% reduction in the increase in cyclic GMP caused by the synthetic C-terminal octapeptide of porcine cholecystokinin (cholecystokinin octapeptide). This effect was maximal within 2 min and preincubating the cells with EDTA for as long as 30 min caused no further reduction in the action of cholecystokinin octapeptide. In acinar cells preincubated without calcium, adding calcium caused a time dependent increase in the action of cholecystokinin octapeptide and this increase was maximal after 10 min of incubation. An effect of extracellular calcium on the action of cholecystokinin octapeptide could be detected with 0.5 mM calcium and was maximal with 2.0 mM calcium. Magnesium alone or with calcium did not alter the action of cholecystokinin octapeptide. Extracellular calcium did not alter the time course or the configuration of the dose vs. response curve for the action of cholecystokinin octapeptide on cellular cyclic GMP. Low concentrations of EGTA (0.1 mM) decreased the effect of cholecystokinin octapeptide on cellular cyclic GMP to the same extent as did EDTA or preincubating acinar cells without calcium. Increasing EGTA above 0.1 mM caused progressive augmentation of the action of cholecystokinin octapeptide on cellular cyclic GMP and this augmentation did not require extracellular calcium or magnesium. Results similar to those obtained with cholecystokinin octapeptide were also obtained with bombesin, carbamylcholine, litorin and eledoisin. In contrast, the action of sodium nitroprusside on cyclic GMP in pancreatic acinar cells was not altered by adding EDTA or EGTA. These results indicate that the ability of extracellular calcium to influence the action of cholecystokinin octapeptide and other agents on cyclic GMP results from changes in cellular calcium and not from effects of extracellular calcium per se. The action of low concentrations of EGTA on the increase in cyclic GMP caused by various agents reflects the ability of EGTA to chelate extracellular calcium. The actions of high concentrations of EGTA were independent of extracellular calcium or magnesium and appear to reflect a direct action of EGTA on pancreatic acinar cells.

Animals↗
PubMed1993

Derivation of ductlike cell lines from a transplantable acinar cell carcinoma of the rat pancreas.

Two cell lines were derived from a transplantable acinar cell carcinoma that had been established from a primary carcinoma of the pancreas in an azaserine-treated Lewis rat. The cultured tumor cells initially produced amylase, but production of exocrine enzymes ceased after 1-2 weeks in culture. The cultured cells were tumorigenic in Lewis rats, and one line produced solid tumors composed of ductlike structures surrounded by dense fibrous tissue. The second cell line produced partially solid and partially cystic tumors with a mixed phenotype of squamous, mucinous, and glandular areas when it grew in vivo following regrafting. Both cell lines lost structural and immunohistochemical acinar cell markers while acquiring duct cell markers during culture and regrafting. These studies provide strong support for the hypothesis that ductlike carcinomas can arise from neoplastic pancreatic acinar cells in rats.

Animals↗
PubMed1994

Triggered exocytosis may not incorporate functional Cl(-)-channels into the luminal membrane in pancreatic acinar cells.

Pancreatic acinar cells secrete Cl- rich fluid and release digestive enzymes into the lumen. Ca(2+)-dependent Cl(-)-channels in the luminal membrane participate such unidirectional Cl- secretion after stimulation of basolateral surface receptors. Simultaneous recordings of increases in membrane capacitance (an estimate of granular fusion or of increase in membrane surface area) and conductance (reflecting activities of Cl- and Na/K nonselective cation channels) demonstrate that an increase in membrane capacitance (delta C) lags behind that of membrane conductance (delta G) after an increase in [Ca2+]i by muscarinic receptor stimulation and/or using A23187. The take-off of delta C never accompanies any notches or humps in the paired delta G-trace. The results suggest that granular fusion does not incorporate functional channels into the luminal membrane during the stimulation of secretagogues.

Animals↗
PubMed1986

Size and number of nuclei differ in normal and neoplastic acinar cells from rat pancreas.

Acinar cells were isolated by enzymatic digestion from normal pancreas and from azaserine-induced atypical acinar cell nodules and a transplantable acinar cell carcinoma. Normal acinar cells were predominately binuclear, with abundant cytoplasm. They were 10-24 micron in diameter, with a size distribution skewed toward smaller sizes but with a peak at 18 micron. Cells were isolated from 41 enucleated nodules varying in weight from 1.1 to 200 mg. These cells were predominantly mononuclear, with a more uniform size than normal cells and a peak at 9 micron diameter. Cells from all nodules studied were grossly similar, and there was no relation between nodule size and the degree of mononucleation. Cells from the transplantable tumor were small, with little cytoplasm, and were almost exclusively mononuclear. The extent of binucleation in normal and microscopic atypical acinar cell nodules was also studied in sections from the pancreas of rats injected with azaserine 4 months before killing. Nuclear and cell counts in these sections confirmed that binucleation is more frequent in normal than in nodule tissue. These studies emphasize the high degree of binucleation found in normal pancreatic acinar cells. They demonstrate the feasibility of using cell separation techniques to obtain preparations of acinar cells from normal and neoplastic pancreatic tissue for studies of functional and morphological differences in these cells.

Animals↗
PubMed1978

Actions of peptides isolated from amphibian skin on pancreatic acinar cells.

In dispersed acinar cells prepared from guinea pig pancreas, peptides isolated from amphibian skin (caerulein, bombesin, litorin, and physalaemin) as well as eledoisin, a peptide isolated from the posterior salivary gland of a Mediterranean octopod, increased outflux of 45Ca, release of bound 45Ca, accumulation of cyclic GMP, and release of amylase. In addition, bombesin, litorin, physalaemin, and eledoisin each increased the initial uptake of 45Ca by dispersed acinar cells, whereas C-terminal octapeptide of porcine cholecystokinin (CCK-OP) and carbamylcholine did not increase the initial uptake of 45Ca but, rather, abolished the increase caused by the other agents. None of the actions of these amphibian peptides was altered by concentrations of atropine sufficient to abolish the effects of muscarinic cholinergic agents. None of the amphibian peptides altered cellular cyclic AMP or the increase caused by secretin or porcine vasoactive intestinal peptide (VIP). Acinar cells preincubated with 45Ca plus bombesin showed the same rate of release of 45Ca as did control cells and this rate was not altered by adding bombesin but was increased fivefold by adding CCK-OP. In terms of their chemical structures as well as the potency and efficacy with which they alter acinar cell function, the amphibian peptides plus CCK-OP can be grouped into three pairs: caerulein with CCK-OP, bombesin with litorin, and physalaemin with eledoisin.

Amylases↗
PubMed1981

Cell surface properties of normal, differentiating, and neoplastic pancreatic acinar cells.

Acinar, centroacinar, and endocrine cells of the adult rat pancreas each exhibit distinctive cell-surface glycoconjugate patterns as detected by binding of a battery of lectin-ferritin conjugates. Acquisition of these unique glycoconjugate patterns appears to be developmentally regulated, as studies on embryonic rat pancreases at days 15, 17, and 19 of gestation indicate. Further, the three cell types appear to arise from a common stem cell(s) with surface glycoconjugate properties similar to those of the adult centroacinar cell. STudies on the cell-surface properties of a rat acinar cell tumor indicate that the neoplastic acinar cells are likely to be arrested at a developmental stage equivalent to acinar cells of the day 19 embryonic pancreas and are characterized by absence of detectable basal lamina. We hypothesize that pancreatic cancers may arise from the equivalent of the undifferentiated embryonic stem cell(s) and that the morphologic features of the tumor depend on the extent of cell differentiation, including expression of cell-surface glycoproteins and extracellular matrix, prior to neoplastic proliferation.

Animals↗