bromochloroacetic-acid and Carcinoma--Pancreatic-Ductal

Development of a pragmatic pathologic classifier of pancreatic ductal adenocarcinoma (PDAC) that reflects biological behavior is needed.. The tumor epithelial and stromal features of PDAC and molecular subtype-related markers were evaluated in three independent cohorts.. In the non-neoadjuvant therapy cohort (n = 108), regarding tumor-epithelial feature, non-gland-forming type showed worse prognosis compared to gland-forming type (P < .001). For tumor-stromal feature, in gland-forming type, the prognosis was good in order of inactivated stroma-rich, stroma-poor, and activated stroma-rich (P = .027). Whereas, non-gland-forming type revealed no difference of prognosis according to tumor stroma. Of molecular subtype-related markers, keratin 81 expression was correlated with non-gland-forming type and poor prognosis (P = .005 and P = .021, respectively). Other markers (HNF1A, c-MET, and p53) showed no significant differences in prognosis. In the neoadjuvant therapy cohort (n = 68), non-gland-forming type was correlated with high residual tumor volume (≥20%) (P < .001) and gland-forming/stroma-poor type was not present. In the next-generation sequencing cohort (n = 55), non-gland-forming type was correlated with a higher number of the KRAS, TP53, CDKN2A, and SMAD4 mutations (P = .038).. Combined tumor epithelial and stromal histopathology with keratin 81 expression is suggested to be useful for predicting prognosis of PDAC.

Topics: Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Humans; Keratins; Neoadjuvant Therapy; Pancreatic Neoplasms; Prognosis

Pancreatic ductal adenocarcinoma (PDAC) has dismal 5-year survival (<9%). We hypothesize that exposure of tumors to conventional therapies may preferentially modulate immune biomarkers in the tumor microenvironment in PDAC. PDAC patients who underwent upfront surgical resection or who received neoadjuvant FOLFIRINOX with or without neoadjuvant radiotherapy followed by surgical resection were selected for study. Total expression of immunologically relevant transcripts and spatially resolved expression of immunologically relevant proteins was quantitated using multiplexed methods (NanoString nCounter and GeoMX platforms). This analysis identified numerous differentially expressed transcripts associated with the type of neoadjuvant therapy received. Moreover, we identified significant alterations in the expression and/or spatial distribution of immunologically relevant proteins in different regions (tumor cell rich, immune cell rich, stromal cell rich) of the tumor microenvironment. These data provide insight into the immunological effects of clinically relevant neoadjuvant therapy for resectable/borderline-resectable PDAC by describing significant differences in the expression of key immunologic biomarkers within the PDAC microenvironment that were associated with the type of treatment patients received prior to surgical resection. This represents a comprehensive analysis of numerous biomarkers conducted on the PDAC microenvironment. This work may guide strategic new combination therapies for pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Female; Fluorouracil; Gene Expression; Humans; Irinotecan; Keratins; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Radiotherapy; Transcriptome; Tumor Microenvironment

Circulating epithelial cells (CECs) are identified in the blood of patients with intraductal papillary mucinous neoplasms (IPMNs) despite the absence of malignancy. We assessed the blood of patients undergoing resection for IPMN or other benign pancreatic lesions for CECs.. Peripheral blood was collected from 26 patients prior to pancreatic resection and filtered by the ISET (Isolation by Size of Epithelial Tumor Cells) method. Circulating epithelial cells were identified with antibodies to cytokeratin and Pdx1 (pancreas and duodenal homeobox protein 1), a pancreas marker.. Nineteen patients underwent resection of an IPMN without associated malignancy. Eleven patients (58%) had cytokeratin-positive CECs. Circulating epithelial cells were significantly more likely to be found in patients with IPMNs with high-grade dysplasia (P = 0.04). In addition, 10 of the 11 patients with cytokeratin-positive CECs also had separate populations of cytokeratin-positive, Pdx1-positive CECs, suggesting a pancreatic source. Dual-staining CECs were more frequently found in patients with high-grade dysplasia (P = 0.04). Patients with IPMNs were significantly more likely to have pan-cytokeratin CECs in the blood compared with those without IPMNs (P = 0.01).. Circulating epithelial cells staining with potential pancreas-specific markers have been found in patients with IPMNs, even without malignancy. Circulating epithelial cells may help to differentiate patients with high-grade IPMN from lower grades of dysplasia and other pancreatic cysts.

Topics: Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adult; Aged; Aged, 80 and over; Carcinoma, Pancreatic Ductal; Epithelial Cells; Female; Homeodomain Proteins; Humans; Keratins; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Trans-Activators

Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Carcinoma, Pancreatic Ductal; Cell Differentiation; Cell Line, Tumor; Cell Lineage; Deoxycytidine; Drug Resistance, Neoplasm; Female; Gemcitabine; Heterografts; Humans; Keratins; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Transplantation; Neuroendocrine Cells; Pancreatic Neoplasms; Prognosis; Proto-Oncogene Proteins c-myc; Synaptophysin

Topics: AC133 Antigen; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Aldehyde Dehydrogenase; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Keratins; Male; Middle Aged; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Prognosis

To improve the identification for CTCs with weak or negative CK and diploid CTCs in pancreatic cancer, we combined immune-staining of CK, CD45, DAPI and fluorescence in situ hybridization with the centromere of chromosome 8 (CEP8) probe method. CTCs in 3.75 mL of blood were depleted for CD45 positive cells with anti-CD45 antibodies and identified by combining CK, CD45, DAPI and CEP8 in 61 cases including 22 pancreatic cancers, 3 borderline pancreatic solid pseudopapillary tumors, 6 pancreatic benign tumors, and 30 healthy individuals. We found that enriched cells could be classified into 5 patterns: CK+CD45-DAPI+CEP8=2 (2 hybridization signals), CK+CD45-DAPI+CEP8>2 (>2 hybridization signals), CK-CD45-DAPI+CEP8>2, CK-CD45-DAPI+CEP8=2, and CK+/-CD45+DAPI+CEP8=2 or >2. Among 22 pancreatic cancers, CK+CD45-DAPI+CEP8=2 and CK+CD45-DAPI+CEP8>2 patterns were identified in two cases, and CK-CD45- DAPI+CEP8>2 pattern was identified in 16 cases. CK-CD45-DAPI+CEP8=2 and CK+/-CD45+DAPI+CEP8=2 or >2 patterns were detected in pancreatic cancers, other pancreatic diseases and healthy individuals. Among the five patterns, CK+CD45-DAPI+CEP8=2, CK+CD45-DAPI+CEP8>2 and CK-CD45-DAPI+CEP8>2 were considered as CTCs, while CK-CD45-DAPI+CEP8=2 and CK+/-CD45+DAPI+CEP8=2 or >2 were considered as indeterminate cells. When the cutoff value was set as 2 cells/3.75 mL based on ROC curve, the sensitivity and specificity in the diagnosis of pancreatic cancer was 68.18 and 94.87%, respectively. Dynamically monitoring CTCs changes prior to and after surgery in pancreatic patients revealed that CTCs count decreased in 3 days after surgery, but increased in 10 days after surgery in most patients. During our one and a half year follow-up, CTCs positive patients showed metastasis and worse survival rate.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Case-Control Studies; Centromere; Chromosomes, Human, Pair 8; Female; Follow-Up Studies; Humans; In Situ Hybridization, Fluorescence; Keratins; Leukocyte Common Antigens; Lymphatic Metastasis; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplastic Cells, Circulating; Pancreatic Neoplasms; Prognosis; Survival Rate

Pancreatic ductal adenocarcinoma (PDA) is comprised of a prominent desmoplastic stromal compartment and only 10-40% of the tumour consists of PDA cells. However, how stromal components should be assessed and how the characteristics of the stromal compartment determine clinical outcomes in PDA patients remain unknown.. A cohort of 66 consecutive patients who underwent pancreaticoduodenectomy and were primarily followed at Johns Hopkins Hospital between 1998 and 2004, and treated with adjuvant therapy, were included in a retrospective analysis. Resected PDA blocks with good tissue preservation were available for all patients. A new, computer-aided, quantitative method was developed to assess the density and activity of stroma in PDAs and the associations of these characteristics with clinical outcomes.. High stromal density in resected PDA was found to be significantly associated with longer disease-free [adjusted hazard ratio (aHR) 0.39; P = 0.001] and overall (aHR 0.44; P = 0.004) survival after adjusting for the use of pancreatic cancer vaccine therapy, as well as gender and resection margin positivity. Stromal activity, representing activated pancreatic stellate cells in PDAs, was not significantly associated with the prognosis of resected PDAs.. These results illustrate the complexity of the role of stroma in PDAs. Further exploration of the prognostic ability of the characteristics of stroma is warranted.

Topics: Actins; Adult; Aged; Aged, 80 and over; Baltimore; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Chemoradiotherapy, Adjuvant; Collagen; Disease-Free Survival; Female; Humans; Image Interpretation, Computer-Assisted; Immunohistochemistry; Kaplan-Meier Estimate; Keratins; Male; Middle Aged; Neoplasm, Residual; Pancreatic Neoplasms; Pancreaticoduodenectomy; Predictive Value of Tests; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stromal Cells; Time Factors; Treatment Outcome

Immature squamous metaplasia of the pancreatic duct (ISMPD) can be difficult to differentiate from an intraductal carcinoma of the pancreas (ICP), and little is known about the pathological nature of ISMPD. The aim of this study was to analyse 20 ISMPD and 10 ICP tissue samples.. ISMPD shares some characteristics with ICP. Seven of 20 ISMPD samples were covered by a layer of pancreatic duct epithelium, whereas this was not seen in the ICP samples. Immunohistochemistry of ISMPD revealed positivity for p63 (100%), cytokeratin 5/6 (95%), cytokeratin 7 (95%), cytokeratin 20 (10%), and MUC-1 (95%), and the samples were negative for p53, carcinoembryonic antigen (CEA), and bcl-2. In contrast, ICP was positive for p63 (40%), p53 (10%), cytokeratin 7 (90%), cytokeratin 20 (20%), CEA (30%), and MUC-1 (80%), and negative for cytokeratin 5/6. However, in 84% (16) of the ISMPD samples, cytokeratin 7 was expressed only by an epithelial layer at the apical surface; this expression pattern was not found in any of the 10 ICP samples. The mean Ki67 labelling index was 1.0% in ISMPD and 18.5% in ICP.. Our study suggests that immunohistochemical staining for cytokeratin 5/6 and Ki67 constitutes the best combination for differentiating ISMPD from ICP.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Metaplasia; Middle Aged; Mucin-1; Pancreatic Ducts; Pancreatic Neoplasms; Transcription Factors; Tumor Suppressor Proteins

Standard cancer cell lines do not model the intratumoural heterogeneity situation sufficiently. Clonal selection leads to a homogeneous population of cells by genetic drift. Heterogeneity of tumour cells, however, is particularly critical for therapeutically relevant studies, since it is a prerequisite for acquiring drug resistance and reoccurrence of tumours. Here, we report the isolation of a highly tumourigenic primary pancreatic cancer cell line, called JoPaca-1 and its detailed characterization at multiple levels. Implantation of as few as 100 JoPaca-1 cells into immunodeficient mice gave rise to tumours that were histologically very similar to the primary tumour. The high heterogeneity of JoPaca-1 was reflected by diverse cell morphology and a substantial number of chromosomal aberrations. Comparative whole-genome sequencing of JoPaca-1 and BxPC-3 revealed mutations in genes frequently altered in pancreatic cancer. Exceptionally high expression of cancer stem cell markers and a high clonogenic potential in vitro and in vivo was observed. All of these attributes make this cell line an extremely valuable model to study the biology of and pharmaceutical effects on pancreatic cancer.

Topics: AC133 Antigen; Aldehyde Dehydrogenase 1 Family; Alleles; Animals; Antigens, CD; Antimetabolites, Antineoplastic; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Deoxycytidine; Disease Models, Animal; Drug Resistance, Neoplasm; Gemcitabine; Genomic Instability; Glycoproteins; GPI-Linked Proteins; Humans; Isoenzymes; Keratins; Male; Mesothelin; Mice; Middle Aged; Mutation; Neoplasm Metastasis; Neoplastic Stem Cells; Pancreatic Neoplasms; Peptides; Polyploidy; Retinal Dehydrogenase; Transplantation, Heterologous; Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n = 115) were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and-by implication-to tumor progression is possible.

Topics: Adult; Aged; Aged, 80 and over; beta Catenin; Biopsy; Cadherins; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Cell Adhesion; Cell Line, Tumor; Cell Nucleus; Epithelial-Mesenchymal Transition; Female; Homeodomain Proteins; Humans; Keratins; Leukocyte Elastase; Liver Neoplasms; Male; Middle Aged; Neutrophils; Nuclear Proteins; Organic Cation Transport Proteins; Pancreatic Neoplasms; Transcription Factors; Twist-Related Protein 1; Zinc Finger E-box-Binding Homeobox 1

Intraductal papillary mucinous neoplasm of the pancreas is a rare but well-established entity in contrast to intraductal papillary mucinous neoplasm of the biliary tract. The aim of this study was to compare the clinicopathologic features of intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas. Twenty patients who underwent resection for intraductal papillary mucinous neoplasm of the biliary tract were compared with 29 cases resected for intraductal papillary mucinous neoplasm of the pancreas. Clinicopathologic characteristics and resection specimens of all patients were reassessed and immunohistochemically screened for expression of a distinct set of tumor markers. Median ages of patients with intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas were 66 and 62 years, respectively (P < .05). Twelve patients with intraductal papillary mucinous neoplasm of the biliary tract (60%) had neoplasms with infiltrating carcinoma, compared with 6 patients with intraductal papillary mucinous neoplasm of the pancreas (21%, P < .05). Cytokeratin 7 and 20 expressions were equal in biliary and pancreatic intraductal papillary mucinous neoplasms. Cytokeratin 20 expression was mainly found in intestinal-type tumors. Gastric, pancreaticobiliary, and oncocytic subtypes were all observed in the intraductal papillary mucinous neoplasm of the biliary tract group. The distribution was significantly different from the intraductal papillary mucinous neoplasm of the pancreas group. The 3-year overall survival rate of malignant biliary and pancreatic intraductal papillary mucinous neoplasm was 63% and 65%, respectively (P = .798). Positive lymph nodes and a high expression of membranous mucin were associated with a significantly shorter overall survival in patients with malignant intraductal papillary mucinous neoplasm. Finally, p53 and Ki67 proliferation index were both associated with the carcinogenesis of intraductal papillary mucinous neoplasm, whereas DPC4 and CDX2 were not. Clinicopathologic features of intraductal papillary mucinous neoplasm of the biliary tract largely resemble those of intraductal papillary mucinous neoplasm of the pancreas, although intraductal papillary mucinous neoplasm of the biliary tract was associated with a higher malignancy rate at the time of surgical treatment. The level of membranous mucin expression and positive lymph nodes are significant prognosticators in patients with malignant intra

Topics: Adult; Aged; Aged, 80 and over; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Carcinoma, Papillary; Female; Humans; Keratins; Ki-67 Antigen; Male; Middle Aged; Netherlands; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

Malignant ascites may be the first presentation of an unsuspected cancer. Pancreas and ovary are among the organs that are usually evaluated as a source of primary. The purpose of this study is to investigate a panel of immunohistochemical stains to help differentiate pancreatic from ovarian carcinoma. We evaluated the immunohistochemical staining of eight commercially available antibodies MUC1, MUC2, MUC5ac, Wilm's tumor susceptibility gene 1 (WT1), cytokeratin 7 (CK7), CK20, CA125, and CA19.9 in 25 effusion specimens with evidence of metastatic carcinoma including 14 ovarian serous carcinomas, 9 pancreatic adenocarcinomas, and 2 unknown primaries. Primary ovarian serous carcinomas were positive for WT-1 (100%), CK7 (93%), CK20 (43%), CA125 (100%), CA19.9 (50%), MUC1 (100%), MUC2 (0%), and MUC5ac (0%). Primary pancreatic carcinomas were positive for MUC5ac (100%), MUC1 (100%), CA19.9 (100%), CK7 (78%), CK20 (22%), CA125 (89%), WT-1 (0%), and MUC 2 (0%). The combination of MUC5ac positivity/WT-1 negativity was seen in 100% of pancreatic carcinoma, whereas MUC5ac negativity/WT-1 positivity in 100% of ovarian serous carcinoma. It appears that the combination of MUC5ac and WT-1 stains is useful in distinguishing pancreatic ductal from ovarian serous carcinoma in body fluid cytology.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; CA-125 Antigen; Carcinoma, Pancreatic Ductal; Cystadenocarcinoma, Serous; Cytological Techniques; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Male; Membrane Proteins; Middle Aged; Mucin 5AC; Mucin-1; Mucin-2; Neoplasms, Unknown Primary; Ovarian Neoplasms; Pancreatic Neoplasms; WT1 Proteins

Pancreatic cancer still remains a challenge for its biological complexity and lack of effective therapeutic strategies. Establishing new pancreatic cancer cell lines is therefore of paramount importance to clarify its biology.. We established and characterized 4 new pancreatic cancer cell lines (PP78, PP109, PP117, and PP161) according to their genetic (K-Ras, TP53, CDKN2A, and MADH4; DNA fingerprinting; karyotype), cytostructural (cytokeratins 7, 8, 18, and 19 vimentin, and ezrin), and functional profiles (doubling time; migration assay).. K-Ras, TP53, and CDKN2A gene alterations were detected in all 4 of them. Each cell line had a unique DNA profile revealed by DNA fingerprinting. A complex karyotype with numerous structural and numeric chromosomal abnormalities was present in each cell line. All 4 cell lines showed positivity for cytokeratins 7, 8, and 18. All but PP78 expressed cytokeratin 19, whereas vimentin was expressed only in PP117 and PP78 cells. A different ezrin cellular distribution was noticed in PP78 and PP117, being mostly located at membrane ruffles. This peculiar distribution was associated with the strongest migratory capability.. Our results seem to confirm the pancreatic ductal adenocarcinoma heterogeneity; in fact, the same genetic abnormalities (K-Ras, TP53, and CDKN2A) may have different effects on tumor biology depending on cellular differentiation.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; DNA Fingerprinting; Female; Genes, p16; Genes, p53; Genes, ras; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Karyotyping; Keratins; Male; Middle Aged; Pancreatic Neoplasms; Phenotype; Smad4 Protein; Vimentin

A 65-year-old man presented with obstructive jaundice from a 3-cm mass in the head of the pancreas. A Whipple resection was performed. Histologic examination of the tumor showed scanty tumor cells arranged in a single-file manner set within a desmoplastic sclerotic stroma. In other areas, the tumor was arranged around preexisting ducts in a targetoid fashion. Very focal ductal and signet-ring cell differentiation was noted. This unusual variant of pancreatic cancer was characterized by paucicellularity and a pattern of invasion resembling lobular carcinoma of breast.

Topics: Actins; Aged; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Humans; Keratins; Male; Mucin-1; Neoplasm Invasiveness; Pancreatic Neoplasms

It is extremely rare to encounter tumors arising exclusively in the minor duodenal papilla. We report a 60-year-old male patient with a polypoid type of adenocarcinoma of the minor papilla. Preoperative examinations, including computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP), suggested pancreas divisum and showed a series of stones in the dorsal pancreatic duct. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy (SSpPD). On histology, an adenocarcinoma was located in the minor papilla, which was limited to the mucosa, without invasion of the duodenum, sphincter muscles of the minor papilla, or the underlying pancreas. The carcinoma cells, together with dysplastic and hyperplastic epithelium of the pancreatic duct, extended peripherally within the pancreatic duct. No cystic dilatation of the pancreatic duct was observed. The ventral pancreatic duct was short and narrow; there was evidence of chronic pancreatitis in the dorsal pancreas, whereas the ventral pancreas was almost normal, suggesting the existence of pancreas divisum. Although it is well known that adenocarcinoma of the duodenal papilla is sometimes accompanied by intraepithelial spread in the pancreatic duct, an adenocarcinoma arising in the minor papilla in this case with pancreas divisum was more extended than our thoughts.

Topics: Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Humans; Keratins; Magnetic Resonance Imaging; Male; Middle Aged; Mucin 5AC; Mucins; Pancreas; Pancreatic Diseases; Pancreatic Ducts; Pancreatic Neoplasms; Pancreaticoduodenectomy; Tomography, X-Ray Computed; Treatment Outcome

Up-regulation of S100P, a member of the S100 calcium-binding protein family, is an early molecular event in the development of pancreatic cancer and it is expressed at high levels in both precursor lesions and invasive cancer. To gain more insight into the molecular mechanisms underlying the functional roles of this protein, we stably overexpressed S100P in the Panc1 pancreatic cancer cell line and identified the consequent changes in global protein expression by two-dimensional difference in-gel electrophoresis. The observed changes in target proteins were confirmed by Western blot analysis and immunofluorescence, whereas their functional effect was investigated using motility and invasion assays. In this study, we have shown that overexpression of S100P led to changes in the expression levels of several cytoskeletal proteins, including cytokeratins 8, 18, and 19. We have also shown disorganization of the actin cytoskeleton network and changes in the phosphorylation status of the actin regulatory protein cofilin. Additionally, we have shown that overexpression of S100P leads to increased expression of another early pancreatic cancer marker, S100A6, as well as the aspartic protease cathepsin D, both of which are involved in cellular invasion. Functional studies showed that the increased invasive potential of S100P-overexpressing cells was at least partially due to the increase in cathepsin D expression. In summary, our data suggest that these changes could contribute to the metastatic spread of pancreatic cancer and may explain the devastating prognosis of this disease.

Topics: Calcium-Binding Proteins; Carcinoma, Pancreatic Ductal; Cathepsin D; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cytoskeleton; Electrophoresis, Gel, Two-Dimensional; Humans; Keratins; Neoplasm Invasiveness; Neoplasm Proteins; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; S100 Calcium Binding Protein A6; S100 Proteins

Pancreatic endocrine tumours (PET) containing ductules are an uncommon histological variant. Considerable conjecture surrounds the origin and histogenesis of the ductules. Opinions range from the ductules being an inherent part of the tumour, to others who feel they are merely entrapped. A study of 21 cases of this variant was undertaken with particular attention paid to the distribution and morphology of the ductules, the presence of entrapped acinar tissue and the surrounding uninvolved pancreatic tissue.. Twenty-one cases were detailed occurring in either gender equally and with a wide age range (19-85 years). All cases, except one, were sporadic, the vast majority were located in the tail and were of small size (less than 2.0 cm). All cases were typified by stromal fibrosis, either diffuse (15) or in the form of septae (6). Embedded within the fibrous tissue were ductular structures, some of which were dilated and ectatic. The ductules were centrally located (5), at the periphery of the tumour (9) or diffusely scattered throughout the lesion (7). All cases showed ductulo-insular complexes. Insulin was demonstrated in 15 immunohistochemically.. It is likely that in some cases the ductules are entrapped as the tumour grows into surrounding normal pancreatic tissue and the ductular proliferation is a secondary phenomenon. In a proportion of cases, the ductules are likely to be a part of the tumour arising as part of focal chronic inflammation or as a result of the growth factor effects of insulin, in cases associated with insulin production. There is nothing to suggest that the ductules confer any special biological characteristics to the PET and are merely a histological nuance. However, some cases may have a dominant tubular component, which could present problems at frozen section where the association with fibrosis may invoke a mistaken diagnosis of pancreatic ductal adenocarcinoma or chronic pancreatitis.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma, Islet Cell; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Female; Fibrosis; Humans; Immunohistochemistry; Insulin; Islets of Langerhans; Keratins; Male; Middle Aged; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatitis, Chronic

To examine cytokeratin, epithelial glycoprotein (mucin) and glycoprotein CD10 expression in benign mucinous cystdenomas (MCAs) in comparison with intraductal papillary mucinous adenomas (IPMAs).. Thirty MCAs of the pancreas were analysed for immunohistochemical expression of cytokeratin (CK) 7, CK20, MUC1, MUC2, MUC5AC and CD10 and were compared with 16 IPMAs. CK7 was expressed in all neoplasms. CK20 was significantly more frequent in MCAs compared with IPMAs (56.66% versus 18.75%, P = 0.027). MUC1 was more frequent in MCAs (40% versus 12.5%, P = 0.0915), whereas MUC5AC was significantly less frequent in MCAs (33.33% versus 100%). MUC2 was expressed in goblet cells of seven MCAs. In MCAs, CD10 was observed both in epithelial cells and in the ovarian-type stromal cells (24/30). Epithelial expression of CD10 was significantly lower in IPMAs (66.66% versus 6.25%, p = 0.0001).. MCA is characterized by a significantly greater frequency of expression of CK20 and CD10 when compared with IPMA, which preferentially expresses MUC5AC.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cystadenoma, Mucinous; Cystadenoma, Papillary; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratin-20; Keratins; Male; Middle Aged; Mucin 5AC; Mucins; Neprilysin; Pancreatic Neoplasms

Basic research aimed at a better understanding of pancreatic carcinogenesis and improving the treatment of this disease is crucial because the majority of pancreatic cancers are highly aggressive and therapeutically nonaccessible. Cyclooxygenase (COX)-2, which is a key enzyme of prostaglandin (PG) biosynthesis, is overexpressed in around 75% of human carcinomas including those of the pancreas.. The pathologic changes of transgenic mouse pancreas with keratin 5-promoter-driven expression and activity of COX-2 were characterized.. Aberrant expression of COX-2 in a few ductal cells and COX-2-mediated PG synthesis in the transgenic mice resulted in keratin 19- and mucin-positive intraductal papillary mucinous neoplasm- and pancreatic intraepithelial neoplasia-like structures, characterized by an increased proliferation index and serous cystadenomas. Moreover, Ras activation was enhanced and the HER-2/Neu receptor was overexpressed. Loss of acini, fibrosis, and inflammation were pronounced. Feeding a COX-2-selective inhibitor to the transgenic mice suppressed the accumulation of PG and the phenotype. The changes resemble the human disease in which COX-2 was overexpressed consistently.. We present strong evidence for a causal relationship between aberrant COX-2 overexpression and COX-2-mediated PG synthesis and the development of serous cystadenoma, intraductal papillary mucinous, and pancreatic intraepithelial neoplasms. This model offers the unique possibility of identifying molecular pathways leading to the formation and malignant progression of the various types of preinvasive lesions of pancreatic adenocarcinomas that show different dismal outcomes.

Topics: Animals; Biopsy, Needle; Carcinoma, Pancreatic Ductal; Cyclooxygenase 2; Dinoprost; Dinoprostone; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genes, ras; Immunoblotting; Immunohistochemistry; Keratins; Male; Mice; Mice, Transgenic; Pancreatic Neoplasms; Probability; Promoter Regions, Genetic

Solid pseudopapillary tumor, pancreatoblastoma, undifferentiated carcinoma with osteoclastic-like giant cells, and acinar cell carcinomas are rare pancreatic nonductal neoplasms. Compared to the significant advances in our understanding of the pathogenesis of pancreatic ductal adenocarcinomas in the last decades, the molecular mechanisms underlying pancreatic nonductal neoplasms are poorly understood. In order to elucidate their molecular pathogenesis, we constructed tissue microarrays to study the expression of some novel pancreatic ductal adenocarcinoma-associated tumor markers in these nonductal pancreatic neoplasms. We analyzed nine markers including tumor suppressor gene (14-3-3 sigma), proliferation marker (topoisomerase II alpha), epithelial markers (prostate stem cell antigen, mesothelin and cytokeratin 19), stromal markers (fascin, hsp47 and fibronectin), and gamma-synuclein whose function is not delineated. In addition, we included tumor suppressor gene DPC4 and oncogene Beta-catenin to further confirm their expression in pancreatic nonductal tumors. Our results showed that in contrast to pancreatic ductal adenocarcinomas that show loss of Dpc4 protein in 55% of cases, loss of Dpc4 expression is absent in pancreatic nonductal neoplasms. Expression of 14-3-3 sigma is frequently seen in both pancreatic nonductal neoplasms (25-100%) and ductal adenocarcinomas (89%). Aberrant nuclear expression of beta-catenin is common in pancreatic nonductal neoplasms, specifically in solid pseudopapillary tumors (88%) and pancreatoblastomas (100%) but is rarely seen in pancreatic ductal adenocarcinomas (<5%). Expression of topoisomerase II alpha is not seen in solid pseudopapillary tumors and undifferentiated carcinomas with osteoclastic-like giant cells but is focally seen in pancreatoblastomas (50%) and acinar cell carcinomas (85%). Expression of PSCA and mesothelin was observed in pancreatic nonductal neoplasms but their expression was seen less frequently (0-50%) and weaker than that in pancreatic ductal adenocarcinomas (60-100%). CK19, a marker of pancreatic ductal adenocarcinomas, is not expressed in pancreatic nonductal neoplasms. Expression of gamma-synuclein as well as stromal markers (fascin, hsp47 and fibronectin) is frequently seen in both. Our findings indicate pancreatic nonductal neoplasms have distinctive patterns of protein expression relative to pancreatic ductal adenocarcinomas and suggest that pancreatic nonductal neoplasms have different gene

Topics: 14-3-3 Proteins; Antigens, Neoplasm; beta Catenin; Biomarkers, Tumor; Carcinoma, Acinar Cell; Carcinoma, Pancreatic Ductal; Carrier Proteins; Cytoskeletal Proteins; DNA-Binding Proteins; Exonucleases; Exoribonucleases; Fibronectins; gamma-Synuclein; GPI-Linked Proteins; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Humans; Immunohistochemistry; Keratins; Membrane Glycoproteins; Mesothelin; Microfilament Proteins; Neoplasm Proteins; Nerve Tissue Proteins; Pancreatic Neoplasms; Serpins; Smad4 Protein; Synucleins; Trans-Activators

Pancreatobiliary and ampulla of Vater adenocarcinomas frequently metastasize to regional lymph nodes, liver, or lung and are difficult to diagnose because they lack specific immunohistochemical markers. We studied the expression of cytokeratin 7 (CK7), cytokeratin 17 (CK17), cytokeratin 20 (CK20), CDX2, mucin 1 (MUC1), mucin 2 (MUC2), and mucin 5AC (MUC5AC) in 46 cases of pancreatic ductal carcinoma, 18 ampulla of Vater adenocarcinomas, and 24 intrahepatic cholangiocarcinomas. The expression of MUC1 and CK17 was restricted to pancreatic ductal carcinoma (41 of 46, 89%; 38 of 46, 83%, respectively), the ampullary carcinoma of pancreatobiliary origin (6 of 6, 100%; 5 of 6, 83%, respectively), and intrahepatic cholangiocarcinoma (20 of 24, 83%; 17 of 24, 71%, respectively). More than 50% of cases of pancreatobiliary adenocarcinomas showed diffuse cytoplasmic CK17 positivity. In contrast, less than 5% cases (8 of 184) of extra-pancreatobiliary nonmucinous adenocarcinomas expressed CK17, and only 3 of them showed diffuse CK17 positivity. The expression of MUC2 and CDX2 was restricted to the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin (9 of 11, 82%; 11 of 11, 100%, respectively). MUC2 was rarely expressed in pancreatic ductal carcinoma (1 of 46, 2%) and was negative in the ampullary carcinoma of pancreatobiliary origin and in intrahepatic cholangiocarcinoma. A heterogeneous CDX2 staining pattern was seen in 1 of 6 cases of the ampullary carcinoma of pancreatobiliary origin (17%), 5 of 24 intrahepatic cholangiocarcinomas (21%), and 10 of 46 (22%) pancreatic ductal carcinomas. In contrast, all 11 cases of the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin showed homogeneous CDX2 nuclear positivity. We concluded that CK17 is a useful marker in separating pancreatobiliary adenocarcinomas from extra-pancreatobiliary nonmucinous adenocarcinomas, including adenocarcinomas from the colon, breast, gynecologic organs, stomach, lung, prostate, thyroid, kidney, and adrenal gland, and malignant mesothelioma. MUC1+/CK17+ can be used as positive markers for pancreatic ductal carcinomas, the ampullary carcinoma of pancreatobiliary origin, and cholangiocarcinomas with positive predictive values of 76%, 83%, and 58%, respectively. MUC2+/CDX2+ can be used as positive markers for the intestinal-type adenocarcinoma of duodenal papillary origin with a positive predictive value of 82%.

Topics: Adenocarcinoma; Ampulla of Vater; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; CDX2 Transcription Factor; Cholangiocarcinoma; Common Bile Duct Neoplasms; Female; Homeodomain Proteins; Humans; Immunohistochemistry; Keratins; Male; Mucins; Neoplasm Proteins; Pancreatic Neoplasms

Osteoclast-like giant cell tumor of the pancreas is a very rare neoplasm, of which the histiogenesis remains controversial. A 63-yr-old woman was hospitalized for evaluation of epigastric pain. An abdominal computerized tomography revealed the presence of a large cystic mass, arising from the tail of pancreas. A distal pancreatectomy with splenectomy was performed. Histologically, the tumor was composed of mononuclear stromal cells intermingled with osteclast-like giant cells. In addition, there was a small area of moderately to well differentiated ductal adenocarcinoma. The final pathologic diagnosis was osteoclast-like giant cell tumor of the pancreas with ductal adenocarcinoma. Here, we describe the histopathological, immunohistochemical, ultrastructural and molecular biological findings of this tumor with review of the literature pertaining to this condition.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Female; Giant Cell Tumors; Humans; Immunohistochemistry; Keratins; Microscopy, Electron; Middle Aged; Mucin-1; Osteoclasts; Pancreatic Neoplasms; Proliferating Cell Nuclear Antigen; Vimentin

There are a large number of stable pancreatic ductal carcinoma cell lines that are used by researchers worldwide. Detailed data about their differentiation status and growth features are, however, often lacking. We therefore attempted to classify commonly used pancreatic carcinoma cell lines according to defined cell biological criteria. Twelve pancreatic ductal adenocarcinoma cell lines were cultured as monolayers and spheroids and graded according to their ultrastructural features. The grading system was based on the integrity of membrane structures and on the presence of mucin granules, cell organelles, nuclear and cellular polymorphism, cell polarity, and lumen formation. On the basis of the resulting scores the cell lines were classified as well, moderately, or poorly differentiated. In addition, immunocytochemistry was performed for the markers cytokeratin 7, 8, 18, 19, carcinoembryonic antigen, MUC1 MUC2, MUC5, and MUC6. The population doubling time of monolayer cultures, determined by a tetrazolium salt based proliferation assay was correlated with the ultrastructural grade. The grading of the ultrastructural features of the monolayers, and particularly of the spheroids, revealed that Capan-1 and Capan-2 cells were well differentiated; Colo357, HPAF-2, Aspc-1, A818-4, BxPc3, and Panc89 cells were moderately differentiated and PancTu-I, Panc1, Pt45P1, and MiaPaCa-2 cells poorly differentiated. Membrane-bound MUC1 staining was a characteristic of well differentiated cell lines. The population doubling time of the monolayer cultures was related to the differentiation grade. No relationship was found between the p53, K-ras, DPC4/Smad4, or p16(INK4a) mutation status and the grade of differentiation. We conclude that the proposed ultrastructural grading system combined with the proliferative activity provides a basis for further comparative studies of pancreatic ductal adenocarcinoma cell lines.

Topics: Carcinoembryonic Antigen; Carcinoma, Pancreatic Ductal; Cell Differentiation; Cell Division; Cell Membrane; Cell Nucleus; Cell Polarity; DNA Mutational Analysis; Humans; Immunohistochemistry; Keratins; Microscopy, Electron; Mucin-1; Mucin-2; Mucin-5B; Mucin-6; Mucins; Mutation; Organelles; Pancreatic Neoplasms; Research; Tumor Cells, Cultured

A frequent genetic alteration found in premalignant stages of pancreatic adenocarcinoma is K-ras oncogene point mutation. The mechanistic basis for the inability of K-ras mutation to transform pancreatic ductal cells is unclear, although cooperating events with p16 inactivation, p53 mutation, and SMAD 4 mutation are recognized to be necessary. We have generated a novel mouse model in which the cytokeratin 19 promoter, specifically active in pancreatic ductal cells but not other cell types of the pancreas, is fused to mutant K-ras. This is of direct relevance to human pancreatic cancer because premalignant lesions are found specifically in ductal cells. There is dramatic periductal lymphocytic infiltration in the pancreata of transgenic mice, predominantly CD4+ T lymphocytes, which may act as an adaptive immune response to activated ras-mediated signaling. In addition, gene array analysis reveals an induction of N-cadherin in transgenic mice pancreatic ductal cells, the significance of which relates to promotion of cell adhesion and deterrence of cell migration. Apart from these important biological considerations, there is parallel activity of the cytokeratin 19 promoter in the stem cell region of the gastric epithelium, namely in mucous neck cells. Activated K-ras in this context causes mucous neck cell hyperplasia, a precursor to gastric adenocarcinoma. There is concomitant parietal cell decrease, which is a key step toward gastric adenocarcinoma. Taken together, we have defined how mutant K-ras signaling modulates important molecular events in the initiating events of pancreatic and gastric carcinogenesis.

Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Gastric Mucosa; Genes, ras; Humans; Hyperplasia; Keratins; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Transgenic; Mutation; Pancreatic Neoplasms; Precancerous Conditions; Promoter Regions, Genetic; Stomach Neoplasms; Transfection; Tumor Cells, Cultured

DNA mismatch repair system defects cause microsatellite instability (MSI) and form an alternative pathway in cancer development. Germline mutations of DNA mismatch repair genes account for hereditary nonpolyposis colorectal cancer, which has a different morphology and biology than sporadic cancers. MSI has also been found in sporadic neoplasms and some inflammatory conditions (chronic pancreatitis, ulcerative colitis). The purpose of the present study was to evaluate the expression of hMLH1 and hMLH2 proteins in infiltrating pancreatic cancer and to find out whether there is a relationship between some phenotypic manifestations and expression of MMR genes. We studied 30 cases of infiltrating pancreatic cancer and apart from hMLH1 and hMLH2 expression cytokeratin 7 and chromogranin were measured as markers of ductal and endocrine differentiation, respectively. All ductal pancreatic cancers expressed cytokeratin 7. In most cases the expression was strong, present in 50-100% of cells in moderately differentiated cancers and in 80-100% of cells in poorly differentiated cancers. Chromogranin expression was seen in 5 moderately differentiated cancers and in 6 poorly differentiated cancers (up to 20% of positive cells). In all cases DNA mismatch repair genes expression was present.. Ductal pancreatic carcinomas express hMLH1 and hMLH2 proteins irrespective of their differentiation. The expression of cytokeratin 7 is typical of ductal pancreatic carcinoma and its level is related to cancer differentiation. Some ductal pancreatic carcinomas irrespective of their differentiation show the expression of chromogranin, which is associated with the expression of hMSH2 gene.

Topics: Adaptor Proteins, Signal Transducing; Base Pair Mismatch; Carcinoma, Pancreatic Ductal; Carrier Proteins; Chromogranins; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Keratin-7; Keratins; Male; Microsatellite Repeats; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Invasiveness; Neoplasm Proteins; Nuclear Proteins; Pancreatic Neoplasms; Phenotype; Proto-Oncogene Proteins

Apoptosis plays a central role in the development and/or progression of cancer. There are several methods for detection of apoptotic cells in tissue sections including light and electron microscopy, in situ nick end-labeling (ISEL), TdT-mediated dUTP nick-end labeling (TUNEL) and immunohistochemical detection of proteins associated with apoptosis. Apoptosis was assessed by the monoclonal antibody M30 CytoDEATH (M30), which is specific for neo-epitope in cytokeratin 18 that becomes available at an early caspase cleavage during apoptosis. Expression of bcl-2 protein was evaluated, because bcl-2 protein plays an important role in the regulation of apoptosis. Twenty-six invasive ductal adenocarcinomas of the pancreas were studied immunohistochemically with antibodies M30 and bcl-2. The mean apoptotic index (AI, the percentage of apoptotic cells of the total tumor cells number) was 2.75%. High AI (> 10%) was observed in 4 cases of the 26 pancreatic carcinomas (15%). Protein bcl-2 was expressed in 3 cases (11.5%). The AI did not correlate with the expression of protein bcl-2. In conclusion, the detection of neo-epitope in cytokeratin 18 by monoclonal antibody M30 can be used for quantification of apoptotic cells with immunohistochemical techniques in tissue sections. It is a new approach to evaluate apoptosis in pancreatic carcinomas. The low positivity of bcl-2 expression in pancreatic adenocarcinomas suggests that bcl-2 protein does not play a central role in pancreatic tumorigenesis and cancer progression.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Carcinoma, Pancreatic Ductal; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Proto-Oncogene Proteins c-bcl-2

We report a rare case of minute (5 mm x 4 mm) mixed ductal-endocrine carcinoma of the pancreas with predominant intraductal growth. A 34-year-old Japanese man was admitted because of elevated serum pancreatic enzymes. Endoscopic retrograde pancreatography revealed an unidentified material of 18 mm within the main pancreatic duct. Stone or parasite with acute pancreatitis was suspected clinically, and the biopsy revealed malignant cells positive for CA19-9, carcinoembryonic antigen (CEA) and synaptophysin. No apparent tumor was identified in the pancreas by various imaging techniques. Resection of pancreatic body and tail was performed. Grossly, the main pancreatic duct in the pancreatic body was occluded by as much as 20 mm. The pancreas had minute carcinoma of 5 mm x 4 mm just around the occluded main pancreatic duct. The tumor cells invaded the main pancreatic duct and spread within it as long as 20 mm. Histologically, the carcinoma had biphasic pattern; one was ductal carcinoma with tubular formations and another was carcinoma with neuroendocrine features. These two elements were admixed, and the ductal element comprised 30% while the endocrine element comprised 70%. The ductal element was immunoreactive for cytokeratins, CEA and CA19-9, while the endocrine element was immunoreactive for chromogranin A and synaptophysin. No immunoreactivity for pancreatic enzymes was noted. Ultrastructural observations showed dense core granules and no zymogen granules. Our case is unique clinically in that the tumor manifested as an intraductal material and no apparent tumor was found by imaging modalities, and pathologically in that the tumor was rare mixed ductal-endocrine carcinoma and the tumor was very small and mainly grew within the main pancreatic duct.

Topics: Adult; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; Carcinoma, Islet Cell; Carcinoma, Pancreatic Ductal; Chromogranin A; Chromogranins; Humans; Keratins; Male; Pancreatic Neoplasms; Synaptophysin; Treatment Outcome

The serological analysis of recombinant cDNA expression libraries (SEREX) by utilizing a library derived from a human pancreatic adenocarcinoma cell line and IgG antibodies from an allogeneic patient serum led to the identification of 18 genes: 13 of these were known genes, and 5 were unknown genes. In Northern and RT-PCR analyses, we found that the expression of mRNA of 14 genes was elevated in pancreatic cancer cell lines compared with the levels in normal pancreatic tissues. In addition, the expression of mRNA of hsp105 in colon cancer was greater than that in normal colon tissue. Immunohistochemical analysis using anti-hsp105 antibody revealed that an increased expression of hsp105 is a characteristic feature of pancreatic ductal and colon adenocarcinoma. Furthermore, hsp105 immunoreactivity in some cases of gastric, esophageal, and hepatocellular carcinoma was much stronger than that in normal corresponding tissues. These molecules identified may provide good diagnostic markers for cancer cells.

Topics: Actins; Antigens, Neoplasm; Blotting, Northern; Carcinoma, Pancreatic Ductal; Cloning, Molecular; DNA, Complementary; Gene Expression Regulation, Neoplastic; Gene Library; Heat-Shock Proteins; HSP110 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Immunohistochemistry; Keratins; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tissue Distribution; Tumor Cells, Cultured

We describe an insulinoma of the pancreas in a 56-year-old patient, which showed insular-ductular differentiation in its liver metastasis. Although the primary tumor was uniformly endocrine in nature with insulin production, the metastasis contained two distinct cell types in organoid arrangement. One cell type was insulin-positive and was arranged in islet-like structures; the other was insulin-negative but distinctly pan-cytokeratin and cytokeratin 7 positive and arranged in ducts. In the primary tumor and the metastasis, the tumor cells were surrounded by a desmoplastic stroma. As to the histogenesis of the tumor and its metastasis, we discuss the following possibilities: (1) the tumor cells might derive from a common stem cell that matures into two phenotypically different cell lines, resembling the situation in embryogenesis and (2) one tumor cell type originates from the other by transdifferentiation (metaplasia). We conclude that the parallel occurrence of endocrine and ductal differentiation supports the concept that, under certain conditions, islet cells and ductular cells may also originate from islets and that mixed endocrine/exocrine pancreatic tumors do not necessarily arise from totipotent duct cells but might also have a primary endocrine cell origin.

Topics: Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Humans; Insulin; Insulinoma; Keratin-7; Keratins; Liver Neoplasms; Male; Middle Aged; Neoplastic Stem Cells; Pancreas; Pancreatic Neoplasms