Animals ; Carcinoma, Pancreatic Ductal ; genetics ; pathology ; Genes, ras ; genetics ; Humans ; Metaplasia ; MicroRNAs ; genetics ; Mutation ; Pancreatic Ducts ; pathology ; Pancreatic Neoplasms ; genetics ; pathology ; Pancreatitis ; genetics ; Signal Transduction

Pancreatic cancer is currently the major leading cause of cancer-related deaths in the Western countries with an overall 5-year survival rate of less than 3. The key aim of investigation is to identify the cellular population in which some of the earliest molecular events occur, presumably the ultimate target for carcinogenic insult. Advances in pathological classification and genetics have improved our descriptive understanding of this disease. However, important aspects of pancreatic cancer biology remain poorly understood. Factors associated with the increased risk of pancreatic cancer include smoking, chronic pancreatitis, diabetes, prior gastric surgery, and exposure to radiation or chemicals. A number of syndromes have been identified with the increased incidence of pancreatic cancer, including familial atypical multiple-mole melanoma syndrome, hereditary nonpolyposis colorectal cancer, and hereditary pancreatitis, etc. Recently, there have been growing evidences that stem cell biology could provide new insights into the understanding of cancer biology. Three postulates regarding the relationship between stem and tumor cells have been proposed. First, the similarities in the mechanims that regulate self-renewal of normal stem cells and cancer cells. Second, the possibility that tumor cells might arise from normal stem cells and third, the notion that tumors might contain 'cancer stem cells' - rare cells with indefinite proliferative potential which drive the formation and growth of tumors. New insights for the cancer stem cells and their possible markers in pancreatic cancer have been suggested recently. Further observations of molecular and cellular events in the early stage of pancreatic carcinogenesis may have important implications regarding the cellular lineage responsible for pancreatic ductal metaplasia and neoplasia, and provide further support for the presence of stem cell capabilities within mature pancreatic epithelium.
Carcinoma, Pancreatic Ductal/*etiology/genetics/pathology ; Disease Progression ; Humans ; Mutation ; Neoplasm Proteins/genetics ; Neoplastic Syndromes, Hereditary/genetics ; Oncogenes ; Pancreatic Neoplasms/diagnosis/*etiology/genetics ; Risk Factors ; Tumor Markers, Biological

OBJECTIVETo study the clinicopathological significance of the expression of carbonic anhydrase (CA)II protein and mRNA in primary invasive ductal cancer (IDC) of human pancreas.

METHODSThe expression of CAII protein in 33 paired paraffin embedded IDC specimens of the pancreas and paired adjacent non-cancerous pancreatic tissues was detected by immunohistochemistry. Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to examine the expression of CAII protein and mRNA level in 12 paired fresh IDC specimens of the pancreas and adjuvant non-cancerous pancreatic tissues. The relationship between the protein expression and clinicopathological features was analyzed.

RESULTSOverexpression of CAII protein was shown in 11 cases of pancreatic IDC tissues (33.3%, 11/33), which was much lower than that in paired non-cancerous pancreatic tissues (72.7%, t = 6.275, P = 0.000). The expression of CAII protein had no correlation with tumor position (χ² = 0.992, P = 0.319), differentiation (χ² = 0.866, P = 0.352), TNM stage (χ² = 1.210, P = 0.271) and Lymph node metastasis (χ² = 0.798, P = 0.372), but had bordering statistic sig with the prognosis of the patients (χ² = 3.233, P = 0.072). The median survival time in the patients with high expression of CAII protein was 540 days, while that in the patients with low expression was 320 days. The expression of CAII protein and mRNA was lower in IDC than that in paired non-cancerous pancreatic tissues detected by Western blot and RT-PCR respectively (t = 3.399, P = 0.006; t = 2.281, P = 0.043).

CONCLUSIONCAII is down regulated in pancreatic IDC and might be relative with the prognosis.

Carbonic Anhydrase II ; genetics ; metabolism ; Carcinoma, Pancreatic Ductal ; metabolism ; pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Pancreas ; metabolism ; Pancreatic Neoplasms ; metabolism ; pathology ; RNA, Messenger ; genetics

Pancreatic cancer is the only major cancer with very low survival rates (1%). It is the fourth leading cause of cancer-related death. Hyperactivated growth hormone receptor (GHR) levels have been shown to increase the risk of cancer in general and this pathway is a master regulator of key cellular functions like proliferation, apoptosis, differentiation, metastasis, etc. However, to date there is no available data on how GHR promotes pancreatic cancer pathogenesis. Here, we used an RNA interference approach targeted to GHR to determine whether targeting GHR is an effective method for controlling pancreatic cancer growth and metastasis. For this, we used an in vitro model system consisting of HPAC and PANC-1 pancreatic cancer cells lines. GHR is upregulated in both of these cell lines and silencing GHR significantly reduced cell proliferation and viability. Inhibition of GHR also reduced the metastatic potential of pancreatic cancer cells, which was aided through decreased colony-forming ability and reduced invasiveness. Flow cytometric and western blot analyses revealed the induction of apoptosis in GHR silenced cells. GHR silencing affected phosphatidylinositol 3 kinase/AKT, mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase, Janus kinase/signal transducers and activators of transcription and mammalian target of rapamycin signaling, as well as, epithelial to mesenchymal transition. Interestingly, silencing GHR also suppressed the expression of insulin receptor-beta and cyclo-oxygenease-2. Altogether, GHR silencing controls the growth and metastasis of pancreatic cancer and reveals its importance in pancreatic cancer pathogenesis.
Carcinoma, Pancreatic Ductal/*genetics/*pathology ; Cell Line, Tumor ; Cell Movement ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Metastasis/genetics/pathology ; Pancreatic Ducts/metabolism/*pathology ; Pancreatic Neoplasms/*genetics/*pathology ; *RNA Interference ; RNA, Small Interfering/administration & dosage/genetics ; Receptors, Somatotropin/*genetics ; Transfection

Objective To investigate the effects of miR-125a-5p on cell proliferation,apoptosis and cell cycle of pancreatic cancer cells.Methods The expression level of miR-125a-5p in pancreatic cancer was determined using quantitative real-time polymerase chain reaction analysis in 4 pairs of pancreatic cancer tissues and matched adjacent normal tissues samples. The expression of miR-125a-5p was downregulated in pancreatic cancer cell lines by transfection with miR-125a-5p inhibitor. Cell counting kit-8 assays was conducted to detect the growth ability of pancreatic cancer cell lines. Flow cytometry was applied to detect the cell cycle and apopotosis. Soft agar colony formation test was employed to assess the role of miR-125a-5p in process of malignant transformation.Results MiR-125a-5p was significantly highly expressed in pancreatic ductal adenocarcinoma tissues than adjacent normal tissues(P<0.05). After the expression level of miR-125a-5p in Panc-1 and MIA PaCa-2 was downregulated,the growth ability was suppressed(P<0.05),early apopotosis rate was promoted by 13.6% and 11.0% respectively(P<0.05),the amount of colony formation was reduced by 27.3% and 27.8%,respectively(P<0.05),and the percentage of S stage of Panc-1 was reduced by 11.8% (P<0.05).Conclusions The expression of miR-125a-5p is high in pancreatic ductal adenocarcinoma tissues. After the expression level of miR-125a-5p is downregulated,the growth ability,colony formation,and cell cycle of Panc-1 and MIA PaCa-2 are suppressed,and the early apopotosis rate will be promoted. Therefore,miR-125a-5p may play an oncogenic role in pancreatic ductal adenocarcinoma.
Apoptosis ; Carcinoma, Pancreatic Ductal ; pathology ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; MicroRNAs ; genetics ; metabolism ; Pancreatic Neoplasms ; pathology

OBJECTIVETo investigate the association of nerve growth factor (NGF) expression with perineural invasion and pain in pancreatic cancer.

METHODSNGF expression was detected by Northern blotting and immunohistochemistry in 28 pancreatic cancer and 20 normal pancreatic tissue samples. Correlation analysis of the results with the extent of perineural invasion, pain and histopathologic characteristics of the tumor was performed.

RESULTSNorthern blot analysis revealed that NGF levels in pancreatic cancer tissues increased by 3.1 folds in comparison with normal pancreas tissue (P<0.05), and immunohistochemistry detected the presence of obvious NGF expression in the cytoplasm of pancreatic cancer cells. Tumors with high NGF expression were associated with more frequent perineural invasion (P<0.01), and increased NGF expression was related to more intense pain (P<0.01).

CONCLUSIONIncreased NGF expression may contribute to perineural invasion and pain in pancreatic cancer.

Adult ; Aged ; Blotting, Northern ; Carcinoma, Pancreatic Ductal ; genetics ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Neoplasm Invasiveness ; Nerve Growth Factor ; biosynthesis ; genetics ; Neuralgia ; genetics ; metabolism ; pathology ; Pancreatic Neoplasms ; genetics ; metabolism ; pathology ; Peripheral Nerves ; metabolism ; pathology ; RNA, Messenger ; biosynthesis ; genetics

OBJECTIVETo study the pathologic features, diagnosis, differential diagnosis and molecular characteristics of colloid carcinoma of the pancreas.

METHODSThe clinical findings, morphologic features, immunophenotype and K-ras gene alterations were investigated in 4 cases of pancreatic colloid carcinoma.

RESULTSIn the 4 cases of colloid carcinoma of the pancreas, three tumors were located in the head of the pancreas, one was located in the body and tail. The average age was 56.5 years old. The presenting symptom was abdominal pain in 2 cases, increased level of U-GLU in 1 patient, and an accidental finding presented in 1 patient. Grossly, 3 cases were cystic and solid, with mucin in the cyst; 1 case was solid. Microscopically, the colloid carcinoma was characterized by large pools of extracellular mucin, containing neoplastic cells, which were in the pattern of cuboidal, cribriform or irregular clusters, or formed an incomplete lining separating mucin pools from the stroma. Three cases developed from pre-existing pancreatic ductal adenocarcinoma (IPMN), intestinal-type, and 1 from IPMN, pancreatobiliary-type. Immunohistochemical studies showed that MUC2 was positive in 3 cases, and MUC1 in 1 case. K-ras gene mutation was identified in 2 cases, showing a single-amino-acid substitution in codon 12, as Gly12Asp (GGT > GAT) and Gly12Arg (GGT > CGT).

CONCLUSIONSPancreatic colloid carcinoma is a rare variant of pancreatic ductal adenocarcinoma, which is associated with IPMN and mucinous cystic neoplasms. Positive MUC2 staining and absent MUC1 expression are commonly found, and K-ras gene mutation is occasionally identified in these tumors.

Adenocarcinoma, Mucinous ; genetics ; metabolism ; pathology ; surgery ; Adult ; Aged ; Carcinoma, Pancreatic Ductal ; pathology ; Diagnosis, Differential ; Exons ; Female ; Genes, ras ; Humans ; Male ; Middle Aged ; Mucin-1 ; metabolism ; Mucin-2 ; metabolism ; Mutation ; Pancreatic Neoplasms ; genetics ; metabolism ; pathology ; surgery

OBJECTIVETo investigate the association of artemin and GFRalpha3 expressions with perineural invasion and metastasis of pancreatic carcinoma.

METHODSSemi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to detect the expression of artemin and GFRalpha3 in pancreatic carcinoma tissues, adjacent tissues and normal pancreas tissues, and the relevance of artemin and GFRalpha3 expressions to the perineural invasion and metastasis of pancreatic carcinoma were analyzed.

RESULTSThe positivity rates of artemin and GFRalpha3 expressions were 72.09% and 67.44% in pancreatic carcinoma, respectively, significantly higher than those in the adjacent tissue (18.19% and 22.73%). The positivity rates of artemin and GFRalpha3 expressions were significantly higher in patients with perineural invasion than in those without perineural invasion (chi(2)=11.11 and 11.78, respectively, P<0.01). Significantly higher expression of artemin mRNA was noted in pancreatic carcinoma (0.741-/+0.014) than in the normal pancreas tissue (0.101-/+0.031, P<0.05), and patients with perineural invasion showed significantly higher positivity rates of artemin mRNA expression (0.843-/+0.012) than those without perineural invasion (0.512-/+0.017, P<0.05).

CONCLUSIONArtemin and GFRalpha3 expressions may play an important role in perineural invasion of pancreatic carcinoma and can be used a useful indicators for evaluating the biological behavior of pancreatic carcinomas.

Adult ; Aged ; Carcinoma, Pancreatic Ductal ; metabolism ; pathology ; Female ; Glial Cell Line-Derived Neurotrophic Factor Receptors ; genetics ; metabolism ; Humans ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Nerve Tissue Proteins ; genetics ; metabolism ; physiology ; Neurons ; pathology ; Pancreatic Neoplasms ; metabolism ; pathology

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK^6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK^6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK^6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK^6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK^6/7 in cells. These results suggested that FAK^6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.
Female ; Humans ; Alternative Splicing ; Breast Neoplasms/metabolism* ; Carcinoma, Pancreatic Ductal/pathology* ; Focal Adhesion Protein-Tyrosine Kinases/therapeutic use* ; Nerve Tissue Proteins/genetics* ; Neuroendocrine Tumors/genetics* ; Oncogenes ; Pancreatic Neoplasms/metabolism*

OBJECTIVETo study the pathologic features, diagnosis, differential diagnosis and molecular characteristics of intraductal tubulopapillary neoplasm of the pancreas (ITPN).

METHODSThe clinical findings, morphologic features, immunophenotype (by EnVision method) and KRAS gene alterations (by reverse transcriptase-polymerase chain reaction) of 6 cases of ITPN encountered during the period from January, 2001 to June, 2010 were analyzed.

RESULTSThere were altogether 2 males and 4 females. The mean age of the patients was 64 years. Gross examination showed that the tumors were located in large pancreatic ducts and appeared as polypoid nodules with ductal obstruction. Solid tumor nodules associated with adjoining dilated ducts were identified in one case. Histologically, the tumors were characterized by tubulopapillary growth pattern without luminal mucin. The tumor cells showed high-grade nuclear atypia with scanty intracytoplasmic mucin. Intraductal necrotic foci were frequently observed. Immunohistochemical study showed that the tumor cells expressed CK7 and CK19. Focal positivity for MUC5AC was demonstrated. Two cases expressed MUC1. The staining for MUC2 was negative. KRAS gene mutations were identified in 2 cases, with a single-amino-acid substitution in codon 12 (35G > A and 35G > T/34G > A).

CONCLUSIONSITPN is a newly described pancreatic intraductal neoplasm and different from intraductal papillary mucinous neoplasm. ITPN is characterized by intraductal tubulopapillary growth pattern, severe cytologic atypia and scanty mucin secretion.

Aged ; Amino Acid Substitution ; Carcinoma, Pancreatic Ductal ; genetics ; metabolism ; pathology ; surgery ; Carcinoma, Papillary ; genetics ; metabolism ; pathology ; surgery ; Female ; Follow-Up Studies ; Humans ; Keratin-19 ; metabolism ; Keratin-7 ; metabolism ; Ki-67 Antigen ; metabolism ; Male ; Middle Aged ; Mucin 5AC ; metabolism ; Mucin-1 ; metabolism ; Pancreatectomy ; Pancreatic Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Treatment Outcome