Pancreatic cancer: from molecular pathogenesis to targeted therapy

Strimpakos, Alexios S; Saif, Muhammad Wasif; Syrigos, Kostas

doi:10.1007/s10555-008-9134-y

Cited by 77 publications

(62 citation statements)

References 203 publications

(234 reference statements)

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“…Its activity has been found to be elevated in different cancers including lymphomas, melanomas, breast and prostate Stanfel et al, 2009). Elevated mTOR signalling in human tumours is correlated with poor tumour prognosis, and inhibitors of this pathway are showing promising results in clinical trials (Le et al, 2008;Strimpakos et al, 2008;Yap et al, 2008). Additionally, intermediate phenotype insulin resistance in human diabetes can be prevented by mTOR inhibitors (Krebs et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Gene expression analysis of mTOR pathway: association with human longevity

et al. 2012

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SummarymTOR signalling is implicated in the development of disease and in lifespan extension in model organisms. This pathway has been associated with human diseases such as diabetes and cancer, but has not been investigated for its impact on longevity per se. Here, we investigated whether transcriptional variation within the mTOR pathway is associated with human longevity using whole‐blood samples from the Leiden Longevity Study. This is a unique cohort of Dutch families with extended survival across generations, decreased morbidity and beneficial metabolic profiles in middle‐age. By comparing mRNA levels of nonagenarians and middle‐aged controls, the mTOR signalling gene set was found to associate with old age (P = 4.6 × 10−7). Single gene analysis showed that seven of 40 mTOR pathway genes had a significant differential expression of at least 5%. Of these, the RPTOR (Raptor) gene was found to be differentially expressed also when the offspring of nonagenarians was compared with their spouses, indicating association with familial longevity in middle‐age. This association was not explained by variation between the groups in the prevalence of type 2 diabetes and cancer or glucose levels. Thus, the mTOR pathway not only plays a role in the regulation of disease and aging in animal models, but also in human health and longevity.

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Section: Introductionmentioning

confidence: 99%

Gene expression analysis of mTOR pathway: association with human longevity

et al. 2012

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“…However, even if pancreatic cancer is surgically resected in stage I or II, it may recur at a metastatic site (1,2). Currently, patients diagnosed with PDA have less than a 5% chance of surviving past 5 years (3). Through proteomic analysis of pancreatic cancer patient plasma, we discovered a peptide form, quiescin sulfhydryl oxidase 1 (QSOX1), that maps back to the C-terminus of the long isoform of QSOX1 (QSOX1-L; ref.…”

Section: Introductionmentioning

confidence: 99%

Quiescin Sulfhydryl Oxidase 1 Promotes Invasion of Pancreatic Tumor Cells Mediated by Matrix Metalloproteinases

Katchman

Antwi

Hostetter

et al. 2011

Molecular Cancer Research

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Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma (PDA) patients back to an overexpressed QSOX1 parent protein. In addition to overexpression in pancreatic cancer cell lines, 29 of 37 patients diagnosed with PDA expressed QSOX1 protein in tumor cells, but QSOX1 was not detected in normal adjacent tissues or in a transformed, but nontumorigenic cell line. To begin to evaluate the advantage QSOX1 might provide to tumors, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in two pancreatic cancer cell lines. Growth, cell cycle, apoptosis, invasion, and matrix metalloproteinase (MMP) activity were evaluated. QSOX1 shRNA suppressed both short and long isoforms of the protein, showing a significant effect on cell growth, cell cycle, and apoptosis. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC-3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 plays an important role in activation of MMP-2 and MMP-9. Taken together, our results suggest that the mechanism of QSOX1-mediated tumor cell invasion is by activation of MMP-2 and MMP-9. Mol Cancer Res; 9(12); 1621-31. Ó2011 AACR.

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“…It remains the fourth most common cause of cancer-related death in the western world [1] . The annual incidence rate of pancreatic cancer is almost identical to the mortality rate; approximately 37 000 new cases are diagnosed each year in the United States, and approximately 33 000 patients die from this disease [2] . Due to the aggressive natural history of this disease, less than 10% of these cases constitute candidates for surgical resection at the time of diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Lentivirus-mediated shRNA interference targeting STAT3 inhibits human pancreatic cancer cell invasion

Yang

Huang²,

Cao³

et al. 2009

WJG

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AIM:To investigate RNA interference targeting signal transducer and activator of transcription-3 (STAT3) on invasion of human pancreatic cancer cells. METHODS:We constructed three plasmids of RNA interference targeting the STAT3 gene. After LV (lentivirus)-STAT3siRNA (STAT3 small interfering RNA) the vector was transfected into the human pancreatic cell line, SW1990 and cell proliferation was measured by the MTT assay. Flow cytometry was used to assess cell cycle. Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) mRNA and protein expression were examined by quantitative PCR and western blotting, respectively. The invasion ability of SW1990 cells was determined by cell invasion assay. RESULTS:We successfully constructed the LVSTAT3siRNA lentivirus vector and proved that it can suppress expression of STAT3 gene in SW1990 cells. RNA interference of STAT3 by the LV-STAT3siRNA construct significantly inhibited the growth of SW1990 cells, in addition to significantly decreasing both VEGF and MMP-2 mRNA and protein expression. Moreover, suppression of STAT3 by LV-STAT3siRNA decreased the invasion ability of SW1990 cells. CONCLUSION:The STAT3 signaling pathway may provide a novel therapeutic target for the treatment of pancreatic cancer since it inhibits the invasion ability of pancreatic cancer cells.

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Pancreatic cancer: from molecular pathogenesis to targeted therapy

Cited by 77 publications

References 203 publications

Gene expression analysis of mTOR pathway: association with human longevity

Gene expression analysis of mTOR pathway: association with human longevity

Quiescin Sulfhydryl Oxidase 1 Promotes Invasion of Pancreatic Tumor Cells Mediated by Matrix Metalloproteinases

Lentivirus-mediated shRNA interference targeting STAT3 inhibits human pancreatic cancer cell invasion

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