Irisin immunohistochemistry in gastrointestinal system cancers

Cancer is the leading cause of morbidity and mortality worldwide. Some studies have shown that high heat kills cancer cells. Irisin is a protein involved in heat production by converting white into brown adipose tissue, but there is no information about how its expression changes in cancerous tissues. We used irisin antibody immunohistochemistry to investigate changes in irisin expression in gastrointestinal cancers compared to normal tissues. Irisin was found in human brain neuroglial cells, esophageal epithelial cells, esophageal epidermoid carcinoma, esophageal adenocarcinoma and neuroendocrine esophageal carcinoma, gastric glands, gastric adenosquamous carcinoma, gastric neuroendocrine carcinoma, gastric signet ring cell carcinoma, neutrophils in vascular tissues, intestinal glands of colon, colon adenocarcinoma, mucinous colon adenocarcinoma, hepatocytes, hepatocellular carcinoma, islets of Langerhans, exocrine pancreas, acinar cells and interlobular and interlobular ducts of normal pancreas, pancreatic ductal adenocarcinoma, and intra- and interlobular ducts of cancerous pancreatic tissue. Histoscores (area × intensity) indicated that irisin was increased significantly in gastrointestinal cancer tissues, except liver cancers. Our findings suggest that the relation of irisin to cancer warrants further investigation.     

Expression analysis of PMP22/Gas3 in premalignant and malignant pancreatic lesions.

PMP22 is a structural protein of Schwann cells, but it also influences cell proliferation. In the present study, quantitative RT-PCR (QRT-PCR) and immunohistochemistry were used to determine PMP22 mRNA levels and to localize PMP22 in the normal pancreas (n=20), chronic pancreatitis (CP) (n=22), pancreatic ductal adenocarcinoma (PDAC) (n=31), intraductal papillary mucinous neoplasms (IPMN) (n=9), mucinous cystic tumors (MCN) (n=4), and in a panel of PanIN lesions (n=29). PMP22 mRNA levels were significantly higher in CP (3-fold) and PDAC (2.5-fold), compared to normal pancreatic tissues. PMP22 expression was restricted to nerves in the normal pancreas, while in CP and PDAC PMP22 was also expressed in PanIN lesions and in a small percentage of pancreatic cancer cells. PMP22 was weak to absent in the tumor cells of IPMNs and MCNs. PMP22 mRNA was present at different levels in cultured pancreatic cancer cells and up-regulated by transforming growth factor (TGF)-beta1 in 2 of 8 of these cell lines. In conclusion, PMP22 expression is present in both CP and PDAC tissues. Its expression in PanIN lesions and some pancreatic cancer cells in vitro and in vivo suggests a role of PMP22 in the neoplastic transformation process from the normal pancreas to pre-malignant lesions to pancreatic cancer.     

Histone H3 messenger RNA in situ hybridization for identifying proliferating cells in formalin-fixed rat gastric mucosa

To devise a more sensitive method for identifying proliferative cells in routinely formalin-fixed, paraffin-embedded tissues, we applied an in situ hybridization (ISH) technique for the detection of histone H3 mRNA in rat gastric mucosa and amplified the signal by a silver intensification method. ISH was performed using a Fluorescein-labelled, single-stranded DNA probe for the human histone H3 gene. To determine the optimal conditions for detecting H3 mRNA in rat gastric mucosa, we tested the effect of changing conditions, such as fixation time and digestion time, by a proteinase before hybridization. Next, the proliferation indices obtained using H3 ISH were compared with those obtained using bromodeoxyuridine (BrdU) immunohistochemistry. In normal rat gastric mucosa, H3 ISH- and BrdU-positive cells were confined to the neck region of both fundic and pyloric mucosa. The two labelling indices were almost the same. In all the serial sections studied, H3 ISH-positive cells were almost always BrdU-positive too. Taken together, these results indicate that the H3 ISH technique is useful for the evaluation of proliferative activity in gastric epithelial cells by virtue of its detection of S-phase cells This revised version was published online in November 2006 with corrections to the Cover Date.     

Immunohistochemical detection of the beta4 integrin subunit in pancreatic adenocarcinoma.

The expression of the beta4 integrin subunit protein in pancreatic cancer was investigated using routine immunohistochemical methods on paraffin-embedded archival material. Forty-eight cases of pancreatic ductal adenocarcinoma were immunostained with a monoclonal antibody to the beta4 integrin subunit, and the extent of staining was compared with that seen in non-cancerous pancreatic tissues, including 15 separate cases of chronic pancreatitis and 6 sections from normal pancreas. We found that the beta4 integrin subunit protein was overexpressed in the majority of pancreatic carcinoma cases tested, whereas chronic pancreatitis and normal pancreas did not display substantial levels of expression.     

Claudin-18 Is an Early-Stage Marker of Pancreatic Carcinogenesis

Pancreatic ductal neoplasms exhibit gastric epithelium–like characteristics. In this study, we evaluated the expression of claudin-18 (CLDN18), a gastric epithelium–associated claudin, in pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and pancreatic ductal adenocarcinomas (PDACs) using immunohistochemistry. We observed a high level of expression of CLDN18 in PanINs (31/32, 97%), IPMNs (61/65, 95%), and MCNs (4/5, 80%) using ordinary tissue section analysis. Furthermore, we observed a high level of CLDN18 expression in PDACs (109/156, 70%) using tissue microarray analysis. However, the normal pancreatic duct or the ductal metaplasia of the acinar cells was not immunoreactive. Comparative analysis of CLDN18 and phenotypic markers in IPMNs revealed that simultaneous expression of CLDN18 and intestinal markers frequently occurred, even in intestinal-type IPMNs. CLDN18 variant 2 mRNA was expressed and was similarly upregulated by phorbol 12–myristate 13–acetate (PMA) treatment in pancreatic cancer cell lines and in a gastric cancer cell line. An inhibitor of pan-PKC (GF109203X) completely suppressed this upregulation in pancreatic cancer cells. These results indicate that CLDN18, a marker for the early carcinogenetic process, is commonly expressed in precursor lesions of PDAC. Activation of the PKC pathway might be involved in CLDN18 expression associated with pancreatic carcinogenesis.     

Endoscopic ultrasound-guided fine needle aspiration cytology of intraductal papillary mucinous tumor of the pancreas. A case report

BACKGROUND: Intraductal papillary mucinous tumor (IPMT) of the pancreas is a recently proposed pancreatic tumor entity with a peculiar clinical and pathologic profile. It presents with symptoms that are mostly attributed to the mass effect of the tumor. However, a long history of diabetes mellitus and/or chronic pancreatitis is usually noted. It is thought that IPMT has better prognosis than the usual pancreatic ductal adenocarcinoma and its early identification is important. On imaging studies these neoplasms appear usually as multiloculated, cystic tumors that cannot be easily differentiated from other cystic pancreatic neoplasms. CASE: A 73-year-old, white woman with recent symptoms related to bile duct obstruction and diabetes mellitus and a long history of "chronic pancreatitis" was found to have a pancreatic mass on computed tomography. Endoscopic ultrasound-guided fine needle aspiration of the pancreatic mass and dilated pancreatic duct was performed. Cytopathologic examination of the aspirated material revealed large cells with abundant, eosinophilic cytoplasm arranged singly or occasionally in large sheets with complex papillary fragments. Occasional goblet cells or cells with cytoplasmic mucin-containing vacuoles were also noted within the tumor tissue fragments. The nuclei were large, with nuclear size variability and prominent nucleoli. Copious amounts of mucin and numerous muciphages were noted in the background. A diagnosis of "cystic mucinous tumor, cannot rule out invasion," was entertained. The patient underwent partial pancreatectomy. The histologic features of the resected specimen were consistent with IPMT, with focal areas suggestive of early stromal invasion. CONCLUSION: The cytologic features encountered in the aspirate of this tumor are highly suggestive of IPMT and can help differentiate it from other pancreatic tumors with mucin production, such as the classic mucinous cystic neoplasm and the more common ductal carcinoma.     

MALDI imaging mass spectrometry for in situ proteomic analysis of preneoplastic lesions in pancreatic cancer

The identification of new biomarkers for preneoplastic pancreatic lesions (PanINs, IPMNs) and early pancreatic ductal adenocarcinoma (PDAC) is crucial due to the diseases high mortality rate upon late detection. To address this task we used the novel technique of matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) on genetically engineered mouse models (GEM) of pancreatic cancer. Various GEM were analyzed with MALDI IMS to investigate the peptide/protein-expression pattern of precursor lesions in comparison to normal pancreas and PDAC with cellular resolution. Statistical analysis revealed several discriminative m/z-species between normal and diseased tissue. Intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) could be distinguished from normal pancreatic tissue and PDAC by 26 significant m/z-species. Among these m/z-species, we identified Albumin and Thymosin-beta 4 by liquid chromatography and tandem mass spectrometry (LC-MS/MS), which were further validated by immunohistochemistry, western blot, quantitative RT-PCR and ELISA in both murine and human tissue. Thymosin-beta 4 was found significantly increased in sera of mice with PanIN lesions. Upregulated PanIN expression of Albumin was accompanied by increased expression of liver-restricted genes suggesting a hepatic transdifferentiation program of preneoplastic cells. In conclusion we show that GEM of endogenous PDAC are a suitable model system for MALDI-IMS and subsequent LC-MS/MS analysis, allowing in situ analysis of small precursor lesions and identification of differentially expressed peptides and proteins.     

Caveolin-1 overexpression correlates with tumour progression markers in pancreatic ductal adenocarcinoma

The assessment of caveolin-1 (Cav-1) as a marker of tumor aggressiveness in pancreatic ductal adenocarcinoma (PDAC). In this study, we examined the expression of Cav-1 in 34 human PDAC tissue samples and the associated peritumoral tissues by immunohistochemistry and western blot. Additionally, we correlated Cav-1 expression with other tissue (Ki-67, p53) and serum (CA 19-9) tumor markers. In the tumor-derived tissue, both tumor cells and blood vessels expressed Cav-1. In contrast, in peritumoral tissue, Cav-1 expression was confined mainly to blood vessels and was only occasionally expressed in ductal or parenchymal cells. Western blot analysis confirmed the overexpression of Cav-1 in pancreatic tumors compared with peritumoral tissue. Cav-1 expression in tumor tissues was correlated with both the Ki-67 LI (r = 0.95, P < 0.0001) and p53 expression (χ2 = 9.91, P < 0.005). Overexpression of Cav-1 was associated with tumor size, grade and stage and Cav-1 expression in tumors was correlated with an increased serum level of CA 19-9 (r = 0.795, P < 0.001). Based on the results of this study, the inclusion of Cav-1 in a putative panel of biomarkers predicting pancreatic cancer aggressiveness is warranted.     

Lack of involvement of metallothionein expression in pancreatic carcinogenesis by N-nitrosobis (2-oxopropyl) amine in Syrian hamsters.

The possible involvement of metallothionein (MT) in pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl) amine (BOP) in hamsters was investigated. Hamsters received subcutaneous (s.c.) injections with dissolved BOP to 70 mg/kg body weight (BW) followed 7 days later by 20 mg/kg BW BOP and they were sacrificed at 4, 11, 16 and 27 weeks after the beginning of the experiment. MT expression was studied by immunohistochemistry and MT contents were assayed biochemically. Pancreatic ductal hyperplasias were developed from 11 weeks on and carcinomas from 16 weeks on, the incidence of the latter reaching 73% at the end of experiment. However, while normal appearing proliferating duct cells were sometimes positive, MT expression was not evident in hyperplasia (H), atypical hyperplasia (AH) or carcinoma (C), and MT contents did not significantly differ in pancreas of hamsters receiving saline or BOP at any time point. The results suggest that MT is not involved in pancreatic duct carcinogenesis. However, the presence of MT in proliferating ducts not related to carcinogenesis may suggest some unknown role for MT in cellular homeostasis.     

Immunohistochemical demonstration of the carbonic anhydrase isoenzymes I and II in pancreatic tumours

Summary The location of carbonic anhydrase (CA) isoenzymes I, II and VI in normal and neoplastic pancreatic tissue was studied using polyclonal antisera and the immunoperoxidase technique. Samples were obtained from patients with well-differentiated (n = 4), moderately differentiated (n = 1) and poorly differentiated (n = 4) ductal adenocarcinomas, cystadenocarcinoma (n = 2), adenosquamous carcinoma (n = 1), acinar adenocarcinoma (n = 1), gastrinoma (n = 3), insulinoma (n = 3) and glucagonoma (n = 1). The control specimens were from a patient with traumatic laceration of the pancreas. The normal and malignant endocrine tissue showed intense positive staining for CA I localized in the cells expressing glucagon. In the exocrine pancreatic tissue, CA II was detected in the normal and neoplastic ductal epithelium. No specific staining was detected with anti-CA VI serum in either normal or malignant tissue.     

Evaluation of cell proliferation in rat tissues with BrdU, PCNA, Ki-67(MIB-5) immunohistochemistry and in situ hybridization for histone mRNA.

The standard method for assessment of cell proliferation in paraffin-embedded tissue sections is 5-bromodeoxyuridine (BrdU) immunohistochemistry (IHC). BrdU can be administered to laboratory animals via IP injections, is readily incorporated into nuclei during the DNA synthetic phase of the cell cycle, and is detected with an anti-BrdU antibody. This method has several disadvantages, and an accurate method for evaluation of proliferative activity that can substitute for BrdU IHC, when necessary, is of great interest to investigators. Alternative methods for detection of proliferating cells in tissue sections are proliferating cell nuclear antigen (PCNA) IHC, Ki-67 IHC, and in situ hybridization (ISH) for histone mRNA. To determine the optimal choice, we analyzed the correlation of anti-PCNA, anti-Ki-67(MIB-5), and histone mRNA labeling indices (LIs) with anti-BrdU LI in rat highly replicative (renewing) tissues. The correlation between anti-BrdU and histone mRNA LIs, as well as the correlation between anti-BrdU and anti-Ki-67 LIs, was statistically significant. There was no significant correlation between anti-BrdU and anti-PCNA LIs. These results suggest that both ISH for histone mRNA and IHC with MIB-5 are preferable techniques for assessment of cell proliferation in rat paraffin-embedded renewing tissues compared to PCNA IHC. They can substitute for BrdU IHC when necessary.     

Biliary papillary neoplasm of the liver

Biliary papillary neoplasia of the liver characterized by intraductal papillary growth of neoplastic biliary epithelia with a fine fibrovascular stalk has been sporadically reported, and includes intraductal growing cholangiocarcinoma and biliary papillomatosis. In addition, biliary papillary dysplasia and in situ and microinvasive carcinoma with papillary configuration reported in hepatolithiasis and in other chronic biliary diseases, could be included in this category. Usually, they arise in the intrahepatic large bile ducts, and the neoplastic and non-neoplastic parts of the intrahepatic biliary tree show saccular and segmental dilatation with mucin hypersecretion. This neoplasia frequently shows intraductal spreading and peribiliary glandular involvement. Acute repeated episodes of cholangitis or obstructive jaundice are a frequent clinical manifestation. Gastroenteric metaplasia with aberrant expression of cytokeratin 20, MUC2, MUC5AC, and/or MUC6, is frequent in the neoplastic parts, and biliary epithelial dysplasia with such metaplasia may give rise to in situ and then invasive carcinoma in hepatolithiasis. Interestingly, this type tends to contain foci of mucinous carcinoma elements, and this element may be predominant (mucinous carcinoma). Some may progress to "mucinous biliary cystadenocarcinoma" without ovarian mesenchymal stroma and with intraluminal continuous growth into the neighboring bile duct lumens. Interestingly, the biliary papillary neoplasm resembles histologically, phenotypically and clinically intraductal papillary mucinous neoplasm of the pancreas which is now being established as an infrequent, slow-growing pancreatic neoplasm. Recognition of such biliary papillary neoplasm with respect to the pancreatic equivalent may lead to a better understanding and further studies of the intrahepatic biliary neoplasm.     

Expression of gastric gland mucous cell-type mucin in normal and neoplastic human tissues.

Gastric gland mucous cells produce class III mucin, which is also found in Brunner's glands and mucous glands along the pancreaticobiliary tract, and in metaplasia and adenocarcinomas differentiating towards gastric mucosa. Recently, we showed that class III mucin possesses GlcNAcalpha1-->4Galbeta-->R, formed by alpha1,4-N-acetylglucosaminyltransferase (alpha4GnT). Examining the tissue-specific expression of mucin epitopes is useful to clarify cell-lineage differentiation and to identify the site of origin of metastatic carcinomas in histological specimens. Formalin-fixed, paraffin-embedded tissue sections from esophagus, stomach, colon, liver, pancreas, lung, kidney, prostate, breast, and salivary gland resected for carcinoma, as well as salivary gland adenoma, colon adenoma, and metastatic adenocarcinoma of lymph nodes from stomach, pancreas, colon, and breast, were immunostained for MUC6, alpha4GnT, and GlcNAcalpha1-->4Galbeta-->R. These were all expressed in normal, metaplastic, and adenocarcinoma tissues of stomach, pancreas, and bile duct, and in pulmonary mucinous bronchioloalveolar carcinomas. Cells expressing alpha4GnT uniformly expressed GlcNAcalpha1-->4Galbeta-->R. Only MUC6 was expressed in normal salivary glands, pancreas, seminal vesicles, renal tubules, and colon adenomas, and in normal tissue and adenocarcinomas of prostate and breast. No tissues showed immunoreactivity for alpha4GnT alone. Immunohistochemistry (IHC) profiles were similar for metastatic carcinomas and primary carcinoma tissues. The IHC profiles for MUC6, alpha4GnT, and GlcNAcalpha1-->4Galbeta-->R may be diagnostically relevant.     

The distribution and localization of the monoclonal antibody-defined antigen 19-9 (CA19-9) in chronic pancreatitis and pancreatic carcinoma. An immunohistochemical study

The carbohydrate antigen 19-9 (CA19-9) is considered to be of great importance in the diagnosis, differential diagnosis and follow-up of human pancreatic carcinoma. CA19-9 antigen has been isolated and characterized as the oligosaccharide sialylazed lacto-N-fucopentaose II and a monoclonal antibody against CA19-9 is commercially available. In this immunochemical study we have examined the localisation and distribution of monoclonal anti-CA19-9 in pancreatic tissue obtained from 20 patients with a normal pancreas (lacking pancreatic tumour or evidence of inflammation), from 50 patients with chronic pancreatitis and from 50 patients with pancreatic carcinomas of various types. In the normal pancreas (free from tumour or inflammation) we found anti-CA19-9 to be localized in the branches of the pancreatic ducts with discontinuities predominantly at the apical surfaces of the lining epithelium. In chronic pancreatitis a continuous positive reaction was found in the small, medium and large ramifications of the pancreatic ducts. In ductal epithelium exhibiting mucoid transformation, a mosaic-like, discontinuous positive reaction was found, whereas in epithelium showing pseudopapillary and papillary hyperplasia a uniform positive reaction was obtained. Multilayered epithelium ("squamous metaplasia") was negative. The fluid content of any cysts present and the tubular accumulations found in chronic pancreatitis showed a positive reaction. The reaction in chronic pancreatitis differed from that in normal pancreas in its distribution but not in its intensity. All carcinomas of the exocrine pancreas showed intensely positive reaction in a very varied distribution whereas the anaplastic carcinomas gave a negative reaction. Whilst in chronic pancreatitis the binding of anti-CA19-9 was unimpressive and strictly localized, in exocrine pancreatic carcinomas binding was and strictly localized, in exocrine pancreatic carcinomas binding was very marked and diffuse in distribution. From this we conclude that malignant cells display a greater number of CA19-9 epitopes than cells in chronic pancreatitis. The difference can only be regarded as quantitative, since the immunohistochemical reaction does not allow qualitative discrimination between chronic pancreatitis and pancreatic carcinoma; CA19-9 should not be therefore termed a "tumour marker". The glycoprotein nature of CA19-9 was confirmed by sialidase and chemical desialylation.     

Proliferation index and karyometric features of pancreatic intraductal proliferative lesions.

The increasing frequency and poor prognosis in pancreatic cancer prompt us to search for morphological lesions being a substrate for its development. Studies of autopsy and surgically resected material as well as recent molecular studies have proved that one of the possible pathways of pancreatic neoplasia is the intraepithelial proliferation--dysplasia--cancer sequence. In the present paper we studied the proliferative activity (Ki-67 index) in pancreatic intraepithelial proliferative lesions and its correlation with geometric features of cell nuclei as signs of increasing dysplasia. The studies were carried out in a group of 35 patients operated on for pancreatic cancer, chronic pancreatitis and other conditions not associated with the pancreas. We used immunohistochemical methods and basic morphometric parameters. The results of our studies indicate that the cell proliferative activity depends both on the type of epithelial proliferation and underlying pancreatic disease. The values of Ki-67 index are significantly different in low-grade proliferation (flat and papillary hyperplasia) and high-grade proliferation (atypical papillary hyperplasia and carcinoma in situ). A set of karyometric features correlates with Ki-67 index but there is no single feature which would have a diagnostic value.     

A noninvasive mucinous cystic neoplasm with intermediate-grade dysplasia of the pancreas and extensive squamous metaplasia: a case report with clinicopathological correlation

ABSTRACT: Squamous metaplasia presenting in noninvasive mucinous cystic neoplasm (MCN) of the pancreas is extremely rare. We described a case of 39-year-old Chinese female with a 5-year history of a slow growing mass in the left upper abdomen and an 18-month history of surgical incision exudation. The patient underwent cystojejunostomy, laparotomy and distal pancreatectomy consecutively because of the initial diagnosis of "pancreatic cyst". The histological section showed columnar mucin-producing epithelium formed small papillary projections and extensively visible squamous metaplasia. Therefore the diagnosis of "noninvasive MCN with intermediate-grade dysplasia of the pancreas and extensive squamous metaplasia" was made finally. The squamous component of the pancreas may be derived from pluripotent stem cells, and may be in association with cystojejunostomy. Virtual slides The virtual slide(s) for this article can be found here http://www.diagnosticpathology.diagnomx.eu/vs/1322364365718540.     

Un adénocarcinome mucineux non kystique (carcinome colloïde) du pancréas de découverte fortuite à la TEP-TDM au 18F-FDG : à propos d’un cas

Colloid carcinoma (CC) of the pancreas, also known as mucinous noncystic carcinoma, is a rare histological variant of pancreatic cancer which had been included in the past under the category of ordinary ductal carcinoma, a tumor with a dismal prognosis, or was frequently misdiagnosed as mucinous cystadenocarcinoma. As CC has a better prognosis than pancreatic ductal carcinoma, early detection of CC by 18 FDG PET SCAN is of great value for the therapeutic management of patients. We report the case of a 66-year-old patient who underwent 18 FDG PET SCAN as part of a post-therapy evaluation of a moderately differentiated carcinoma of the stomach treated with surgery and chemotherapy, in whom a hypermetabolic focus of the body of the pancreas was discovered incidentally. The anathomopathological diagnosis was in favor of a low-grade mucinous noncystic carcinoma of the pancreas. Thus, 18 FDG PET SCAN allowed the discovery of an infraradiological CC synchronous with a gastric adenocarcinoma and provided information on its metabolic activity as well as locoregional and distant staging, which are important prognostic markers and which could improve the therapeutic management of the patient.     

The use of microwave irradiation as a pretreatment toin situ hybridization for the detection of measles virus and chicken anaemia virus in formalin-fixed paraffin-embedded tissue

Summary Microwave irradiation was investigated as a pretreatment toin situ hybridization on formalin-fixed, paraffin-embedded tissue. Two probe/tissue systems were used: a single-stranded RNA probe for the detection of measles virus nucleocapsid genome in subacute sclerosing panencephalitis brain tissue, and a double stranded DNA probe for chicken anaemia virus in thymus of chicken infected with the virus. Microwaving, when used as sole pretreatment, was not as effective as the more traditional enzyme pretreatments forin situ hybridization. However, when used in combination with existing pretreatments, a significant increase was found in hybridization signal in both brain and thymus tissue. This was emphasized when combination enzyme/microwave pretreatments were used prior to detection of measles virus byin situ hybridization in a series of five archival subacute sclerosing panencephalitis cases. The use of microwave irradiation would be recommended as a means of supplementingin situ hybridization methods, especially when using long-term formalin fixed paraffin-embedded tissue.     

Preferential expression of cystein-rich secretory protein-3 (CRISP-3) in chronic pancreatitis

BACKGROUND: Chronic pancreatitis (CP) is a progressive inflammatory process resulting in exocrine and endocrine pancreatic insufficiency in advanced stages. Cysteine-rich secretory protein (CRISP-3) has been identified as a defense-associated molecule with predominant expression in the salivary gland, pancreas and prostate. AIMS: In this study, we investigated CRISP-3 expression in normal pancreatic tissues, chronic pancreatitis tissues, pancreatic cancer tissues and pancreatic cancer cell lines, as well as in other gastrointestinal organs. MATERIALS AND METHODS: 15 normal pancreatic tissues, 14 chronic pancreatitis tissues and 14 pancreatic cancer tissues as well as three pancreatic cancer cell lines were analyzed. Moreover, hepatocellular carcinoma and esophageal, stomach and colon cancers were also analyzed together with the corresponding normal controls. RESULTS: CRISP-3 was expressed at moderate to high levels in chronic pancreatitis tissues and at moderate levels in pancreatic cancer tissues but at low levels in normal pancreatic tissues, and was absent in three pancreatic cancer cell lines. CRISP-3 expression was below the level of detection in all cancerous gastrointestinal tissues and in all normal tissues except 2 of 16 colon tissue samples. CRISP-3 mRNA signals and immunoreactivity were strongly present in the cytoplasm of degenerating acinar cells and in small proliferating ductal cells in CP tissues and CP-like lesions in pancreatic cancer tissues. In contrast, CRISP-3 expression was weak to absent in the cytoplasm of cancer cells as well as in acinar cells and ductal cells in pancreatic cancer tissues and normal pancreatic tissues. CONCLUSION: These results reveal that the distribution of CRISP-3 in gastrointestinal tissues is predominantly in the pancreas. High levels of CRISP-3 in acinar cells dedifferentiating into small proliferating ductal cells in CP and CP-like lesions in pancreatic cancer suggests a role of this molecule in the pathophysiology of CP.