| 1. |
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| 2. |
- Akbarshahi, Hamid, et al.
(författare)
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TLR4 dependent heparan sulphate-induced pancreatic inflammatory response is IRF3-mediated
- 2011
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 9:219
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Tidskriftsartikel (refereegranskat)abstract
- Background: Degraded extracellular matrix can stimulate the innate immune system via the Toll-Like Receptor-4 (TLR4). In the pancreas, syndecan-anchored heparan sulphate (HS) on the ductal epithelium can be cleaved off its protein cores by the proteases (trypsin and elastase) and potentially activate TLR4 signalling. Methods: To investigate this signalling event, a low sulphated HS (500 mu g/ml) was infused into the biliary-pancreatic duct of C57BL/6J wild-type mice. Phosphate buffered saline (PBS) and lipopolysaccharide (LPS) were used as negative and positive controls, respectively. Mice were sacrificed after 1, 3, 6, 9, and 48 hours and tissues were analysed for neutrophil and cytokine contents. In order to study the TLR4 signalling pathway of HS in the pancreas, genetically engineered mice lacking TLR4, Myeloid Differentiation primary response gene (88) (MyD88) or Interferon Regulatory Factor 3 (IRF3) were subjected to pancreatic infusion of HS. Results: Neutrophil sequestration and corresponding myeloperoxidase (MPO) activity in the pancreas were increased 9 hours following HS challenge. In wild-type mice, the monocyte chemoattractant protein-1(MCP-1) increased at 3 hours after infusion, while RANTES increased after 9 hours. TLR4, MyD88, and IRF3 knockout mice showed an abrogated neutrophil recruitment and myeloperoxidase activity in the HS group, while the LPS response was only abolished in TLR4 and MyD88 knockouts. Conclusions: The results of this study show that HS is capable of initiating a TLR4-dependent innate immune response in the pancreas which is distinctly different from that induced by LPS. This inflammatory response was mediated predominantly through IRF3-dependent pathway. Release of HS into the pancreatic duct may be one important mediator in the pancreatic ductal defence.
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| 3. |
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| 4. |
- Axelsson, Jakob B, et al.
(författare)
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Proposed protective mechanism of the pancreas in the rat
- 2010
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Ingår i: Journal of Inflammation. - : Springer Science and Business Media LLC. - 1476-9255. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heparan sulphate is known to have various functions in the animal body, including surveillance of tissue integrity. Administered intraperitoneally, it induces a systemic inflammatory response syndrome and when given locally in the pancreas it initiates a protective inflammatory response. The aim of the present study was to investigate the underlying mechanisms behind cell recruitment following intra-ductal infusion of heparan sulphate. Methods: Rats were subjected to intraductal-infusion of heparan sulphate, lipopolysaccharide and phosphate buffered saline into the pancreas. Pancreatic tissue was harvested 1, 3, 6, 9 or 48 hours after infusion and stained immunohistochemically for myeloperoxidase, ED-1, CINC-1 and MCP-1, as well as using eosin hematoxylin staining. Furthermore, MPO activity and MCP-1 and CINC-1 concentrations of tissue homogenates were measured. All differences were analyzed statistically using the Mann-Whitney U-test. Results: During HS infusion, a rapid influx of macrophages/monocytes, as visualized as ED-1 positive cells, was seen reaching a maximum at 6 hours. After 48 hours, the same levels of ED-1 positive cells were noted in the pancreatic tissue, but with different location and morphology. Increased neutrophil numbers of heparan sulphate treated animals compared to control could be detected only 9 hours after infusion. The number of neutrophils was lower than the number of ED-1 positive cells. On the contrary, LPS infusion caused increased neutrophil numbers to a larger extent than heparan sulphate. Furthermore, this accumulation of neutrophils preceded the infiltration of ED-1 positive cells. Chemokine expression correlates very well to the cell infiltrate. MCP-1 was evident in the ductal cells of both groups early on. MCP-1 preceded monocyte infiltration in both groups, while the CINC-1 increase was only noticeable in the LPS group. Conclusions: Our data suggest that heparan and LPS both induce host defense reactions, though by using different mechanisms of cell-recruitment. This implies that the etiology of pancreatic inflammation may influence how the subsequent events will develop.
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| 5. |
- Byrling, Johannes, et al.
(författare)
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Expression of fibroblast activation protein and the clinicopathological relevance in distal cholangiocarcinoma
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 55:1, s. 82-89
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The current survival of patients with distal cholangiocarcinoma (dCCA) is poor. There is a need to develop new prognostic and predictive biomarkers to improve the survival of patients. Fibroblast activation protein (FAP) expression has been associated with survival in several solid malignancies. The goal of this study was to evaluate the expression pattern and prognostic significance of FAP in dCCA. Materials and methods: FAP expression was examined in 57 resected dCCA specimens and 28 paired lymph node metastasis specimens, as well as 10 benign bile ducts using immunohistochemistry. FAP expression was scored in the epithelial and stromal component of the dCCA specimens. The association between FAP expression and prognosis was evaluated using univariable and multivariable statistical modeling. Results: FAP expression was absent in the benign controls. FAP expression was evident in the epithelial 43 (75%) and stromal compartment 34 (60%) of dCCA. There was no association between epithelial or stromal FAP expression and clinicopathological factors. Epithelial FAP expression (HR 0.4 95% CI 0.20–0.78; p=.007) but not stromal FAP expression was significantly associated with better survival in univariable and multivariable analysis. Conclusions: FAP overexpression is evident in dCCA. There was a positive association between epithelial FAP expression and better survival which merits further evaluation.
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| 6. |
- Byrling, Johannes, et al.
(författare)
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Expression of peritumoral SPARC during distal cholangiocarcinoma progression and correlation with outcome
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 55:6, s. 725-731
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Distal cholangiocarcinoma (dCCA) is a malignancy with a dismal prognosis. One of the hallmarks is the presence of a rich desmoplastic stroma believed to contribute to tumor progression and treatment resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein implicated in tumor-stroma interaction with prognostic correlation across several malignancies. The aim of the present study was to evaluate the expression pattern and prognostic significance of SPARC in resected dCCA and paired lymph node metastasis. Materials and methods: SPARC expression was evaluated in 59 resected dCCA samples and 25 paired lymph node metastases as well as 10 benign bile duct samples using immunohistochemistry. Stromal SPARC expression was scored semi quantitatively. Survival was estimated using the Kaplan–Meier method with associated log-rank test. Results: SPARC expression was absent in normal bile ducts. In dCCA, peritumoral stromal SPARC was detectable in 47/59 (80%) of samples with 40/59 (68%) classified as high stromal SPARC expression. There was a significantly lower proportion of SPARC positive stroma in paired lymph node metastasis 17/25 (68%) than the corresponding primary tumors 24/25 (96%) (p =.016). Stromal SPARC expression was associated with the presence of lymph node metastasis; high SPARC expression 31/40 (78%) versus low SPARC expression 9/19 (47%) (p =.013). In the present material there was no significant association between stromal SPARC expression and survival. Conclusions: Stromal SPARC expression occurs frequently in dCCA. Although significantly lower than in primary tumors stromal SPARC is frequently retained in paired lymph node metastasis suggesting a possible role in the metastatic process of dCCA.
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| 7. |
- Gundewar, Chinmay, et al.
(författare)
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The role of SPARC expression in pancreatic cancer progression and patient survival.
- 2015
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 50:9, s. 1170-1174
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Tidskriftsartikel (refereegranskat)abstract
- Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that has been implicated in tumor-stroma interactions in pancreatic cancer. Here we evaluated the expression of SPARC during the progression of pancreatic cancer and its correlation with survival following curative intent surgery.
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| 8. |
- Hu, Dingyuan, et al.
(författare)
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Calcium-activated chloride channel regulator 1 as a prognostic biomarker in pancreatic ductal adenocarcinoma
- 2018
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In a previous study utilizing mass spectrometry-based proteomics, we identified calcium-activated chloride channel regulator 1 (CLCA1) as a potential tumor suppressor in pancreatic cancer and the expression was inversely correlated with patient survival. The aim of the study was to further validate the prognostic significance of CLCA1 in pancreatic cancer. METHODS: CLCA1 expression was evaluated with tissue microarrays and immunohistochemistry in 140 patients with pancreatic ductal adenocarcinoma that underwent surgical resection at Skåne University Hospital, Sweden. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between CLCA1 and clinicopathological factors and survival. RESULTS: CLCA1 expression was denoted as positive in 90 tumors (64.3%), with positive staining being limited to the tumor cells. There were no significant association between CLCA1 expression and established clinicopathological parameters. Low CLCA1 expression correlated significantly with shorter disease-free survival (11.9 vs 17.5 months, P = 0.042). Multivariable Cox regression analysis confirmed the results (HR 0.61, 95% CI-0.40-0.92, P = 0.019). CONCLUSIONS: Low CLCA1 expression is an independent factor of poor disease-free survival in pancreatic cancer.
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| 9. |
- Hu, Dingyuan, et al.
(författare)
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Galectin 4 is a biomarker for early recurrence and death after surgical resection for pancreatic ductal adenocarcinoma
- 2019
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 54:1, s. 95-100
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Tidskriftsartikel (refereegranskat)abstract
- Background: Galectins are a group of carbohydrate-binding proteins that are involved in neoplastic development and progression. In a previous mass spectrometry-based study, we identified galectin 4 as a down-regulated protein in short-term survivors of pancreatic cancer. This study was performed to validate the prognostic value of galectin 4 in a larger cohort of pancreatic cancer patients undergoing surgical resection. Methods: Galectin 4 expression was evaluated by tissue microarrays and immunohistochemistry in 140 patients with surgically resected pancreatic cancer. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between galectin 4 and survival. Results: Galectin 4 staining expression was positive in 111 cases (79.3%). The expression of galectin 4 was significantly associated with tumor size (p =.008) and differentiation (p =.001). Galectin 4 expression was significantly correlated with disease recurrence within 1 year of surgery (adjusted HR 0.485, p =.027). There was also a significant association between galectin 4 and overall survival at 1 year (adjusted HR 0.482, p =.047) and at 3 years (adjusted HR 0.550, p =.025). Conclusion: Galectin 4 expression is a novel biomarker for early recurrence and mortality after surgical resection for pancreatic cancer.
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| 10. |
- Hu, Dingyuan, et al.
(författare)
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Low P4HA2 and high PRTN3 expression predicts poor survival in patients with pancreatic cancer
- 2019
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 54:2, s. 246-251
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Tidskriftsartikel (refereegranskat)abstract
- Background: The tumor microenvironment in pancreatic cancer has a multifaceted role in disease development and progression. Prolyl 4-hydroxylase subunit alpha 2 (P4HA2) and proteinase 3 (PRTN3) are involved in the synthesis and degradation of collagen in the tumor microenvironment and have been identified as prognostic biomarker candidates for pancreatic cancer in our previous mass spectro-metric study. This study aimed at validating prognostic performance of P4HA2 and PRTN3 in a larger cohort of patients. Methods: The expression of P4HA2 and PRTN3 was evaluated with tissue microarrays and immunohis-tochemistry in 140 patients with pancreatic cancer who underwent surgical resection. Kaplan–Meier and Cox proportional hazards regression modeling were used to explore the association of P4HA2 and PRTN3, either separately or combined, with clinicopathological factors and survival. Results: Most tumors were positive for P4HA2 (133/140, 95%), whereas 77 tumors (55%) were positive for PRTN3. Expression levels of P4HA2 and PRTN3 did not separately correlate with disease-free or overall survival, in either uni-or multivariable analysis. However, a low P4HA2 and high PRTN3 expression correlated with shorter disease-free survival (median 7.0 vs. 13.4 months, adjusted HR 3.24, 95% CI: 1.13–9.25, p ¼.028) and overall survival (median 8.5 vs. 25.8 months, adjusted HR 8.14, 95% CI: 3.41–19.44, p <.001). Conclusion: Our data show that a low P4HA2 and high PRTN3 expression correlates with poor survival in patients with pancreatic cancer, indicating the involvement of collagen deposition in the restraint of the tumor. The tumoral expression of PRTN3 reinforces the therapeutic potential of PR1-targeting immunotherapy in pancreatic cancer.
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| 11. |
- Hu, Dingyuan, et al.
(författare)
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Stromal fibronectin expression in patients with resected pancreatic ductal adenocarcinoma
- 2019
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Ingår i: World Journal of Surgical Oncology. - : Springer Science and Business Media LLC. - 1477-7819. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense stroma, which has a fundamental role in tumor progression. Fibronectin (FN1) is the main constituent of the tumor stroma in pancreatic cancer. This study aimed to explore the association between FN1 and clinicopathological characteristics and disease survival. Methods: Formalin-fixed paraffin-embedded tissue samples from 138 patients with PDAC were constructed into a tissue microarray, followed by immunohistochemical analysis with a recombinant monoclonal FN1 antibody. Chi-square test or Fisher's exact test were used for comparison of FN1 expression and relevant clinicopathological parameters. Kaplan-Meier survival curves and Cox regression analyses were used to assess the association between FN1 and survival. Results: FN1 was detected in the stromal compartment in most cases (117/138, 84.8%). Compared to the low FN1 expression group, the high FN1 expression group had significantly larger tumor size (P = 0.002), more advanced T stage (P = 0.039) and N stage (P = 0.009), and also worse AJCC stage (P = 0.003). However, stromal FN1 expression was not associated with disease-free survival or overall survival. Conclusions: This study suggests that high stromal FN1 expression is associated with aggressive tumor characteristics in patients with resected PDAC. However, no association between FN1 expression and survival was found.
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| 12. |
- Isaksson, Karolin, et al.
(författare)
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Cationic polypeptides in a concept of oppositely charged polypeptides as prevention of postsurgical intraabdominal adhesions
- 2011
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Ingår i: Journal of Biomedical Science and Engineering. - : Scientific Research Publishing, Inc.. - 1937-6871 .- 1937-688X. ; 4:3, s. 200-206
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Two differently charged polypeptides, α-poly-L-lysine and poly-L-glutamate, have previ- ously been shown to effectively reduce postoperative intraabdominal adhesions. Though α-poly-L-lysine showed toxicity in doses too close to the lowest the-rapeutic dose, the aim in the present study was to investigate the possible antiadhesive effect of another four cationic polypeptides.
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| 13. |
- Karnevi, Emelie, et al.
(författare)
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Impact by pancreatic stellate cells on epithelial-mesenchymal transition and pancreatic cancer cell invasion : Adding a third dimension in vitro
- 2016
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 346:2, s. 206-215
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic cancer is associated with a highly abundant stroma and low-grade inflammation. In the local tumour microenvironment, elevated glucose levels, the presence of tumour-associated stellate cells and macrophages are hypothesised to promote the tumour progression and invasion. The present study investigated the influence by the microenvironment on pancreatic cancer cell invasion in vitro. After co-culture with tumour-associated pancreatic stellate cells (TPSCs), pancreatic cancer cells displayed up to 8-fold reduction in levels of epithelial-mesenchymal transition (EMT) markers E-cadherin and ZO-1, while β-catenin and vimentin levels were increased. A 3D organotypic model showed that TPSCs stimulated pancreatic cancer cell invasion, both as single cell (PANC-1) and cohort (MIAPaCa-2) invasion. The combined presence of TPSCs and M2-like macrophages induced invasion of the non-invasive BxPC-3 cells. High glucose conditions further enhanced changes in EMT markers as well as the cancer cell invasion. In summary, co-culture with TPSCs induced molecular changes associated with EMT in pancreatic cancer cells, regardless of differentiation status, and the organotypic model demonstrated the influence of microenvironmental factors, such as glucose, stellate cells and macrophages, on pancreatic cancer cell invasion.
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| 14. |
- Karnevi, Emelie, et al.
(författare)
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Intratumoural leukocyte infiltration is a prognostic indicator among pancreatic cancer patients with type 2 diabetes
- 2018
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Ingår i: Pancreatology. - : Elsevier BV. - 1424-3903. ; 18:1, s. 85-93
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Tidskriftsartikel (refereegranskat)abstract
- Background: The life expectancy of pancreatic cancer patients remains minimal. The disease progression may be influenced by type 2 diabetes (T2D) and inflammatory status, although important gaps persist around their joint effects on disease outcome. The aim of this study was to investigate the clinical significance of the tumour immune microenvironment on pancreatic cancer prognosis in relation to T2D status. Method: Tumour-infiltrating macrophages, neutrophils and eosinophils were studied in primary pancreatic tumours and paired lymph node metastases in relation to patient and tumour characteristics, T2D status and overall survival in a retrospective cohort of patients with resectable pancreatic cancer in Sweden. Results: Of the 80 included pancreatic cancer patients, 22 (27.2%) had T2D. The diabetic pancreatic cancer patients had significantly higher systemic high white blood cell count than those without diabetes (P = 0.028). Macrophage infiltration levels were higher in lymph node metastases compared with primary tumours (P = 0.040) among pancreatic cancer patients with diabetes. Type 2 diabetes or intra-tumoural leukocyte (macrophage, neutrophil or eosinophil) infiltration alone did not significantly influence pancreatic cancer prognosis. However, among cancer patients with T2D high macrophage or neutrophil tumour-infiltration was associated with a significant reduction in overall survival (adjusted hazard ratio [HR] 7.2; 95% CI 1.5-35.0 and HR 5.4; 95% CI 1.1-26.3, respectively). Conclusion: These results demonstrate associations between T2D and enhanced inflammatory processes with significant implications on survival among pancreatic cancer patients with T2D. Validation in larger independent patient cohorts may identify additional prognostic tools and improved treatment strategies for specific patient subsets.
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| 15. |
- Karnevi, Emelie, et al.
(författare)
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Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells.
- 2013
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13:May,10
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated.
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| 16. |
- Rosendahl, Ann, et al.
(författare)
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Celecoxib synergizes human pancreatic ductal adenocarcinoma cells to sorafenib-induced growth inhibition.
- 2012
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Ingår i: Pancreatology. - : Elsevier BV. - 1424-3903. ; 12:3, s. 219-226
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreatic ductal adenocarcinoma is frequently associated with aberrant activation of the Ras/Raf/MAPK pathway and cyclooxygenase-2 (COX-2) overexpression. This study evaluated the potential for combining the multikinase inhibitor sorafenib and the specific COX-2 inhibitor celecoxib as therapy in pancreatic ductal adenocarcinoma cells. METHODS: BxPC-3, MIAPaCa-2, PANC-1 and AsPC-1 pancreatic adenocarcinoma cells were exposed to sorafenib and celecoxib combined treatment in vitro. Cell viability and various growth promoting and survival signaling pathways were monitored by MTT, flow cytometry and Western blotting. RESULTS: Combined treatment with sorafenib and celecoxib synergistically inhibited pancreatic adenocarcinoma cell proliferation. This regimen produced combination index (CI) values between 0.67 and 0.92 for the various cell lines, indicating significant synergistic interactions between sorafenib and celecoxib, which also markedly inhibited the migratory capacity. The growth inhibition was associated with an accumulation of cells in the G(0)/G(1) phase of the cell cycle and induction of apoptosis. These changes were accompanied by a significant reduction of p21(WAF1/Cip1) levels, where celecoxib sensitized the cells to sorafenib-mediated p21(WAF1/Cip1) suppression. CONCLUSION: These results suggest that combined treatment with sorafenib and celecoxib synergistically induce growth inhibition and apoptosis in pancreatic adenocarcinoma cells through a process involving p21(WAF1/Cip1) suppression
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| 17. |
- Rosendahl, Ann, et al.
(författare)
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Conditionally immortalized human pancreatic stellate cell lines demonstrate enhanced proliferation and migration in response to IGF-I.
- 2015
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 330:2, s. 300-310
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic stellate cells (PSCs) play a key role in the dense desmoplastic stroma associated with pancreatic ductal adenocarcinoma. Studies on human PSCs have been minimal due to difficulty in maintaining primary PSC in culture. We have generated the first conditionally immortalized human non-tumor (NPSC) and tumor-derived (TPSC) pancreatic stellate cells via transformation with the temperature-sensitive SV40 large T antigen and human telomerase (hTERT). These cells proliferate at 33°C. After transfer to 37°C, the SV40LT is switched off and the cells regain their primary PSC phenotype and growth characteristics. NPSC contained cytoplasmic vitamin A-storing lipid droplets, while both NPSC and TPSC expressed the characteristic markers αSMA, vimentin, desmin and GFAP. Proteome array analysis revealed that of the 55 evaluated proteins, 27 (49%) were upregulated ≥3-fold in TPSC compared to NPSC, including uPA, pentraxin-3, endoglin and endothelin-1. Two insulin-like growth factor binding proteins (IGFBPs) were inversely expressed. Although discordant IGFBP-2 and -3 levels, IGF-I was found to stimulate proliferation of both NPSC and TPSC. Both basal and IGF-I stimulated motility was significantly enhanced in TPSC compared to NPSC. In conclusion, these cells provide a unique resource that will facilitate further study of the active stroma compartment associated with pancreatic cancer.
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| 18. |
- Spelt, Lidewij, et al.
(författare)
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The prognostic role of cancer stem cell markers for long-term outcome after resection of colonic liver metastases
- 2018
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 38:1, s. 313-320
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: To assess the expression of cancer stem cell (CSC) markers CD44, CD133 and CD24 in colon cancer liver metastases and analyse their predictive value for overall survival (OS) and disease-free survival (DFS) after liver resection. Materials and Methods: Patients operated on for colon cancer liver metastases were included. CSC marker expression was determined through immunohistochemistry analysis. OS and DFS were compared between marker-positive and marker-negative patients. Multivariate analysis was performed to select predictive variables for OS and DFS. Results: CD133-positive patients had a worse DFS than CD133-negative patients, with a median DFS of 12 and 25 months (p=0.051). Multivariate analysis selected CD133 expression as a significant predictor for DFS. CD44 and CD24 were not found to predict OS or DFS. Conclusion: CD133 expression in colonic liver metastases is a negative prognostic factor for DFS after liver resection. In the future, CD133 could be used as a biomarker for risk stratification, and possibly for developing novel targeted therapy.
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| 19. |
- Urey, Carlos, et al.
(författare)
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Low MUC4 expression is associated with survival benefit in patients with resectable pancreatic cancer receiving adjuvant gemcitabine
- 2017
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 52:5, s. 595-600
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous in vitro studies have shown that mucin 4 (MUC4) confers resistance toward gemcitabine in pancreatic cancer cells. To date, there are few clinical studies corroborating these findings. The aim of this study was to evaluate the predictive impact of MUC4 expression on survival in patients with resectable pancreatic cancer receiving adjuvant gemcitabine. Materials and methods: MUC4 expression was investigated by immunohistochemistry in 78 tissue sections from patients with pancreatic ductal adenocarcinoma undergoing Whipple resection. The H-score was used to evaluate MUC4 expression. The Kaplan–Meier method and Cox proportional hazards regression analysis were used to assess the predictive role of MUC4 expression. Results: The MUC4 protein was expressed in 93.6% (73/78) of pancreatic cancer tissue specimens. None of the normal control pancreatic tissues had any MUC4 expression. Low MUC4 expression (H-score ≤100) was detectable in 42 (53.8%) of tumors and high MUC4 expression (H-score >100) was detectable in 36 (46.2%) of tumors. Low expression of MUC4 was associated with favorable survival (p = .027), whereas high MUC4 expression did not correlate with survival (p = .87) in patients receiving adjuvant gemcitabine treatment. Conclusions: This is the first study indicating a predictive role of MUC4 expression for gemcitabine treatment in the clinical setting.
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| 20. |
- Zhou, Qimin, et al.
(författare)
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Quantitative proteomics identifies brain acid soluble protein 1 (BASP1) as a prognostic biomarker candidate in pancreatic cancer tissue
- 2019
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 43, s. 282-294
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pancreatic cancer is a heterogenous disease with a poor prognosis. This study aimed to discover and validate prognostic tissue biomarkers in pancreatic cancer using a mass spectrometry (MS) based proteomics approach. Methods: Global protein sequencing of fresh frozen pancreatic cancer and healthy pancreas tissue samples was conducted by MS to discover potential protein biomarkers. Selected candidate proteins were further verified by targeted proteomics using parallel reaction monitoring (PRM). The expression of biomarker candidates was validated by immunohistochemistry in a large tissue microarray (TMA) cohort of 141 patients with resectable pancreatic cancer. Kaplan-Meier and Cox proportional hazard modelling was used to investigate the prognostic utility of candidate protein markers. Findings: In the initial MS-discovery phase, 165 proteins were identified as potential biomarkers. In the subsequent MS-verification phase, a panel of 45 candidate proteins was verified by the development of a PRM assay. Brain acid soluble protein 1 (BASP1) was identified as a new biomarker candidate for pancreatic cancer possessing largely unknown biological and clinical functions and was selected for further analysis. Importantly, bioinformatic analysis indicated that BASP1 interacts with Wilms tumour protein (WT1) in pancreatic cancer. TMA-based immunohistochemistry analysis showed that BASP1 was an independent predictor of prolonged survival (HR 0.468, 95% CI 0.257–0.852, p =.013) and predicted favourable response to adjuvant chemotherapy, whereas WT1 indicated a worsened survival (HR 1.636, 95% CI 1.083–2.473, p =.019) and resistance to chemotherapy. Interaction analysis showed that patients with negative BASP1 and high WT1 expression had the poorest outcome (HR 3.536, 95% CI 1.336–9.362, p =.011). Interpretation: We here describe an MS-based proteomics platform for developing biomarkers for pancreatic cancer. Bioinformatic analysis and clinical data from our study suggest that BASP1 and its putative interaction partner WT1 can be used as biomarkers for predicting outcomes in pancreatic cancer patients.
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| 21. |
- Zhou, Qimin, et al.
(författare)
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YAP1 is an independent prognostic marker in pancreatic cancer and associated with extracellular matrix remodeling
- 2020
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreatic cancer is a major cause of cancer-related mortality. The identification of effective biomarkers is essential in order to improve management of the disease. Yes-associated protein 1 (YAP1) is a downstream effector of the Hippo pathway, a signal transduction system implicated in tissue repair and regeneration, as well as tumorigenesis. Here we evaluate the biomarker potential of YAP1 in pancreatic cancer tissue.METHODS: YAP1 was selected as a possible biomarker for pancreatic cancer from global protein sequencing of fresh frozen pancreatic cancer tissue samples and normal pancreas controls. The prognostic utility of YAP1 was evaluated using mRNA expression data from 176 pancreatic cancer patients in The Cancer Genome Atlas (TCGA), as well as protein expression data from immunohistochemistry analysis of a local tissue microarray (TMA) cohort comprising 140 pancreatic cancer patients. Ingenuity Pathway Analysis was applied to outline the interaction network for YAP1 in connection to the pancreatic tumor microenvironment. The expression of YAP1 target gene products was evaluated after treatment of the pancreatic cancer cell line Panc-1 with three substances interrupting YAP-TEAD interaction, including Super-TDU, Verteporfin and CA3.RESULTS: Mass spectrometry based proteomics showed that YAP1 is the top upregulated protein in pancreatic cancer tissue when compared to normal controls (log2 fold change 6.4; p = 5E-06). Prognostic analysis of YAP1 demonstrated a significant correlation between mRNA expression level data and reduced overall survival (p = 0.001). In addition, TMA and immunohistochemistry analysis suggested that YAP1 protein expression is an independent predictor of poor overall survival [hazard ratio (HR) 1.870, 95% confidence interval (CI) 1.224-2.855, p = 0.004], as well as reduced disease-free survival (HR 1.950, 95% CI 1.299-2.927, p = 0.001). Bioinformatic analyses coupled with in vitro assays indicated that YAP1 is involved in the transcriptional control of target genes, associated with extracellular matrix remodeling, which could be modified by selected substances disrupting the YAP1-TEAD interaction.CONCLUSIONS: Our findings indicate that YAP1 is an important prognostic biomarker for pancreatic cancer and may play a regulatory role in the remodeling of the extracellular matrix.
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