Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteomics is the term used for the large-scale analysis of proteins in biological fluids or cells by biochemical methods. Two approaches are used for proteomics analysis: two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and a mass-spectrometry-based approach, such as surface-enhanced laser desorption ionization (SELDI). SELDI can be used for large protein profiling or peptide identification after enzymatic digestion. In pancreatic cancer, proteomics analysis can be performed with the aim to identify all differentially expressed proteins in cancer cells vs normal pancreatic cells. Protein profiling of pancreatic juice or serum may also identify biomarkers for pancreatic cancer that could be used as diagnostic markers or therapeutic targets. This chapter outlines the use of 2D-PAGE and SELDI for profiling the protein content of pancreatic juice samples and for identifying proteins differentially expressed in pancreatic cancer patient samples compared to control patient samples.
Methods Mol Med 2005
PMID:Identification of differentially expressed proteins in pancreatic cancer using a global proteomic approach. 1554 7

Telomerase, which ensures the unlimited proliferation by adding TTAGGG repeat at the end of the chromosome, is strongly activated at a very high incidence in a variety of malignant neoplasms including pancreatic cancer. In addition to the acquisition of the immortality, telomerase plays an important role in the aggressive behavior of pancreatic cancer. Invasiveness of human pancreatic cancer cells correlates well with telomerase activity. Exposure of pancreatic cancer to anticancer drugs up-regulates telomerase activity, and the increase in telomerase activity correlates with resistance to the drug-induced apoptosis. More important, diagnositic values of telomerase activity are highly focused because of the lack of other specific genetic markers for pancreatic cancer. Samples of pancreatic juice are obtained at endoscopic retrograde pancreatography using a balloon catheter after intraveneous injection of secretin. Because the pancreatic juice has strong protease and RNase activity, addition of protease inhibitors and RNase inhibitors in the telomerase extraction buffer is necessary for the detection of telomerase activity in the pancreatic juice. A telomeric ladder was detected in 80% patients with carcinoma, whereas only 4.3% patients with adenoma and none with chronic pancreatitis showed positive telomerase activity.
Methods Mol Med 2005
PMID:Detection of telomerase activity in patients with pancreatic cancer. 1554 8

Multiple experimental approaches have been employed to study exocrine pancreatic cancer, including the use of animals as surrogates for the human disease. Animals have the advantage that they can be manipulated to address specific hypotheses regarding mechanisms underlying this disease. Implicit in this opportunity is the necessity to match the question being asked with an appropriate animal model. Several approaches to modeling pancreatic cancer have been established that involve animals. First, xenogeneic cell transplantation, generally into immunocompromised rodent subcutis or pancreas, allows examination of (1) the effect of host environment on human or rodent pancreatic cancer cells, (2) whether specific genetic changes in donor cells correlate with certain cancer cell behaviors, and (3) novel approaches to cancer therapy or imaging of tumor growth. Second, carcinogen administration, typically to hamster or rat, allows examination of whether specific genetic, biochemical, cellular, and tissue phenotypic changes, including progression to neoplasia, accompany exposure to a particular chemical. Third, genetically engineered animals, usually transgenic or gene targeted mice, allow examination of (1) whether genetic changes, including oncogene overexpression/mutation or tumor suppressor gene loss, can increase the risk for neoplastic progression, (2) whether specific genetic changes can cooperate during pancreatic carcinogenesis, and (3) how the genetic signature of a neoplasm correlates with particular biological aspects of tumor initiation and progression. Collectively, these experimental approaches permit detailed exploration of pancreatic cancer genetics and biology in the whole animal context, thereby mimicking the environment in which human disease occurs.
Methods Mol Med 2005
PMID:Modeling pancreatic cancer in animals to address specific hypotheses. 1554 10

The developmental plasticity of adult pancreas is evidenced by the ability to undergo conversion between different epithelial cell types. Specific examples of such conversions include acinar to ductal metaplasia, ductal to islet metaplasia, and generation of ductal structures within islets. Although 90% of human pancreatic cancers are classified as ductal adenocarcinoma, markers of all pancreatic epithelial cell types (acini, ductal, and endocrine) as well as markers of gastric and intestinal lineages can be detected in these tumors. In recent years considerable knowledge has been gained regarding regulation of cellular differentiation and various signaling pathways involved in normal and neoplastic pancreas through studies of pancreatic cancer and immortalized ductal cell lines. However, these studies provide little insight into the context of normal developmental cues, the disruption of which leads to organ pathology. Here we have described a detailed method for preparation, maintenance, and manipulation of adult and embryonic mouse pancreas. These methods may be utilized in studies involving normal epithelial differentiation, contributing to improved understanding of pancreatic development and disease.
Methods Mol Med 2005
PMID:Primary explant cultures of adult and embryonic pancreas. 1554 12

Elucidation of basic mechanisms that regulate pancreatic organogenesis may help define molecular pathways involved in the development of exocrine pancreas cancer. The zebrafish has emerged as a powerful model for genetic dissection of the mechanisms underlying vertebrate organogenesis including formation of the pancreas. Unique properties of zebrafish enable genetic and embryological analyses not feasible using other vertebrate model organisms. The optical clarity of the zebrafish embryos allows visual detection of markers for pancreatic morphogenesis and cytodifferentiation by whole mount immunohistochemistry and RNA in situ hybridization. This feature, coupled with the accessibility of the externally fertilized zebrafish embryo and the small size and fecundity of adult zebrafish, facilitates large-scale forward genetic screens using chemical or insertional mutagenesis techniques. Furthermore, these properties allow high throughput studies that target functions of known genes via antisense or enforced expression studies. Together, such studies are predicted to identify novel genes, or known genes essential for pancreas development. Work in zebrafish is predicted to complement research performed using other vertebrate model organisms, and may help identify markers that define early stages of pancreatic tumorigenesis as well as potential targets for therapy.
Methods Mol Med 2005
PMID:Zebrafish as a model for pancreatic cancer research. 1554 13

The management of patients with pancreatic cancer is a multidisciplinary approach that presents enormous challenges to the clinician. Overall 5-yr survival for all patients remains < 3%. Symptoms of early pancreas cancer are nonspecific. As such, only a fraction of patients are candidates for surgery. While surgical resection provides the only curative option, most patients will develop tumor recurrence and die of their disease. To date, the clinical benefits of chemotherapy and radiation therapy have been important but have led to modest improvements. Tumor vaccines have the potential to specifically target the needle of pancreas cancer cells amidst the haystack of normal tissue. The discovery of pancreas tumor-specific antigens and the subsequent ability to harness this technology has become an area of intense interest for tumor immunologists and clinicians alike. Without knowledge of specific antigen targets, the whole tumor cell represents the best source of immunizing antigens. This chapter will focus on the development of whole tumor cell vaccine strategies for pancreas cancer.
Methods Mol Med 2005
PMID:Development of a cytokine-modified allogeneic whole cell pancreatic cancer vaccine. 1554 14

Linkage analysis has aided in the identification of genes involved in many diseases, including several cancers. It relies on using family-based data to detect genetic loci that may harbor disease predisposing genes. Although linkage studies were first designed to find the genes responsible for simple Mendelian diseases (diseases caused by alterations in a single gene), today it is more common for investigators to use linkage analysis to locate genes involved in complex diseases (diseases caused by the independent and joint effects of multiple genes often in conjunction with environmental factors), such as pancreatic cancer. During the past decade linkage analysis has been key step in the identification of several cancer genes, including BRCA2 and STK11, which additional studies have shown also carry an increased risk of pancreatic cancer. However, these known genes explain very little of the observed familial aggregation of pancreatic cancer. While the foundations of linkage analysis are relatively straightforward, the actual implementation of linkage studies, especially for complex diseases such as pancreatic cancer, can be quite difficult. This chapter focuses on the basics of linkage analysis for qualitative traits (affected/unaffected) as could be applied to the study of pancreatic cancer.
Methods Mol Med 2005
PMID:Overview of linkage analysis: application to pancreatic cancer. 1554 15

The RAS-activated RAF-->MEK-->extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3'-kinase)-->PDK1-->AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells. To explore the mechanisms that underlie such cooperation, we have derived cells harboring conditionally active, steroid hormone-regulated forms of RAF and AKT. These cells permit the assessment of the biological and biochemical effects of activation of these protein kinases either alone or in combination with one another. Under conditions where activation of neither RAF nor AKT alone promoted S-phase progression, coactivation of both kinases elicited a robust proliferative response. Moreover, under conditions where high-level activation of RAF induced G(1) cell cycle arrest, activation of AKT bypassed the arrest and promoted S-phase progression. At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27(Kip1) expression. Repression of p27(Kip1) was accompanied by a dramatic reduction in KIP1 mRNA and was observed in primary mouse embryo fibroblasts derived from mice either lacking SKP2 or expressing a T187A mutated form of p27(Kip1). Consistent with these observations, pharmacological inhibition of MEK or PI3'-kinase inhibited the effects of activated RAS on the expression of p27(Kip1) in NIH 3T3 fibroblasts and in a panel of bona fide human pancreatic cancer cell lines. Furthermore, we demonstrated that AKT activation led to sustained activation of cyclin/cdk2 complexes that occurred concomitantly with the removal of RAF-induced p21(Cip1) from cyclin E/cdk2 complexes. Cumulatively, these data strongly suggest that the RAF-->MEK-->ERK and PI3'K-->PDK-->AKT signaling pathways can cooperate to promote G(0)-->G(1)-->S-phase cell cycle progression in both normal and cancer cells.
Mol Cell Biol 2004 Dec
PMID:Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. 1557 89

We examined the anti-tumor effect of cationic multilamellar liposome containing human IFN-beta (huIFN-beta) gene against cultured human pancreatic cancer cells. We also evaluated the combined effect of huIFN-beta gene entrapped in liposomes and gemcitabine. Furthermore, we examined the anti-tumor mechanisms of the therapy, with emphasis on the Ras-related signal pathway. Three human pancreatic cancer cell lines (AsPc-1, MIAPaCa-2, and PANC-1) were used in this study. The growth inhibition together with the therapy were evaluated by WST-1 assay; the production of huIFN-beta protein was measured by ELISA; the cell cycle and apoptosis were analyzed using a FACScan flow cytometer; the protein levels of Son of sevenless (SOS-1) and Ras-GAP were measured by Western blotting; and the activation of Ras-GTP was evaluated by the immunoprecipitation method. As a result, we found that huIFN-beta gene entrapped in liposomes demonstrated a strong anti-tumor effect against human pancreatic cancer cells. The treatment that combined huIFN-beta gene entrapped in liposomes and gemcitabine was more effective than each treatment alone. Although gemcitabine remarkably reduced the level of SOS-1, the above combined therapy reduced the level of SOS-1 even more significantly. Both huIFN-beta gene entrapped in liposomes and the com-bination of huIFN-beta gene entrapped in liposomes and gemcitabine increased the level of Ras-GAP, and decreased the activity of Ras-GTP. These results suggest that this combination therapy can induce strong anti-tumor activity against human pancreatic cancer cells through the regulation of the Ras-related signal pathway.
Int J Mol Med 2005 Feb
PMID:Growth inhibition of human pancreatic cancer cells by human interferon-beta gene combined with gemcitabine. 1564 44

Pancreatic carcinoma is the fifth leading cause of cancer-related deaths in North America and Europe. Major reasons for the high mortality rate include the inability to detect pancreatic cancer at an early stage, extensive local invasion, and early formation of lymphatic and hematogenous metastases. Consequently, novel and effective therapies need to be developed urgently in order to improve the outcome of patients. Since overexpression of the epidermal growth factor receptor (EGFR) in pancreatic tumors correlates with advanced clinical staging, increased tumor size and reduced patient survival, this receptor represents an appropriate target for immunotherapy. We recently generated the recombinant immunotoxin 425(scFv)-ETA' by genetically fusing the anti-EGFR single chain variable fragment 425(scFv) to a truncated version of Pseudomonas aeroginosa exotoxin A (ETA'). The 425(scFv)-ETA' fusion protein was functionally expressed in the periplasmic space of Escherichia coli and was purified using a combination of metal-ion affinity and anion exchange chromatography. The protein showed specific binding to and toxicity against the EGFR-positive, metastatic pancreatic carcinoma cell line L3.6pl, but not to control cell systems. We report the anti-tumor activity of this recombinant immunotoxin in a disseminated human pancreatic cancer nude mouse model. After intravenous (i.v.) injection of L3.6pl cells into immunodeficient nude mice, both single (20 microg on day 1 after challenge) and repeated (10 microg on days 1, 2, 3 and 4 after tumor cell injection) i.v. administration of 425(scFv)-ETA' resulted in a significant reduction in the average number of lung metastases from 56.25 per animal in the control groups to 0.875 per animal (single injection) and 0.286 per animal (repeated injection), respectively, in the experimental groups. In summary, this is the first report showing an in vivo anti-tumor effect caused by the recombinant immunotoxin 425(scFv)-ETA' against disseminated growing metastatic human pancreatic carcinoma cells. Our data suggest that EGFR-specific antibody toxins could be suitable for further clinical investigation in the development of therapies for pancreatic carcinoma.
Int J Mol Med 2005 Feb
PMID:Recombinant anti-EGFR immunotoxin 425(scFv)-ETA' demonstrates anti-tumor activity against disseminated human pancreatic cancer in nude mice. 1564 48


<< Previous 1 2 3 4 5 6 7 8 9 10