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The relationship between SPARC expression in primary tumor and metastatic lymph node of resected pancreatic cancer patients and patients' survival. Hepatobiliary Pancreat Dis Int 2017; 16:104-109. [PMID: 28119265 DOI: 10.1016/s1499-3872(16)60168-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Previous researches in pancreatic cancer demonstrated a negative correlation between secreted protein acidic and rich in cysteine (SPARC) expression in primary tumor and survival, but not for SPARC expression in lymph node. In the present study, we aimed to evaluate the SPARC expression in various types of tissues and its impact on patients' prognosis. METHODS The expression of SPARC was examined by immunohistochemistry in resected pancreatic cancer specimens. Kaplan-Meier analyses and Cox proportional hazards regression were applied to assess the mortality risk. RESULTS A total of 222 tissue samples from 73 patients were collected to evaluate the SPARC expression, which included 73 paired primary tumor and adjacent normal tissues, 38 paired metastatic and normal lymph nodes. The proportion of positive SPARC expression in metastatic lymph node was high (32/38), whereas in normal lymph node it was negative (0/38). Positive SPARC expression in primary tumor cells was associated with a significantly decreased overall survival (P=0.007) and disease-free survival (P=0.003), whereas in other types of tissues it did not show a predictive role for prognosis. Univariate and multivariate analyses both confirmed this significance. CONCLUSION SPARC can serve a dual function role as both predictor for prognosis and potentially biomarker for lymph node metastasis in resected pancreatic cancer patients.
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Baines A, Martin P, Rorie C. Current and Emerging Targeting Strategies for Treatment of Pancreatic Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:277-320. [DOI: 10.1016/bs.pmbts.2016.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Goel G, Sun W. Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future. J Hematol Oncol 2015; 8:44. [PMID: 25935754 PMCID: PMC4431030 DOI: 10.1186/s13045-015-0141-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 04/21/2015] [Indexed: 02/08/2023] Open
Abstract
Despite a few breakthroughs in therapy for advanced disease in the recent years, pancreatic ductal adenocarcinoma continues to remain one of the most challenging human malignancies to treat. The overall prognosis for the majority of patients with pancreatic cancer is rather dismal, and therefore, more effective treatment options are being desperately sought. The practical goals of management are to improve the cure rates for patients with resectable disease, achieve a higher conversion rate of locally advanced tumor into potentially resectable disease, and finally, prolong the overall survival for those who develop metastatic disease. Our understanding of the complex genetic alterations, the implicated molecular pathways, and the role of desmoplastic stroma in pancreatic cancer tumorigenesis has increased several folds in the recent years. This has facilitated the development of novel therapeutic strategies against pancreatic cancer, some of which are currently under evaluation in ongoing preclinical and clinical studies. This review will summarize the existing treatment approaches for this devastating disease and also discuss the promising therapeutic approaches that are currently in different stages of clinical development.
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Affiliation(s)
- Gaurav Goel
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA, 15232, USA.
| | - Weijing Sun
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA, 15232, USA.
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Ryall CL, Viloria K, Lhaf F, Walker AJ, King A, Jones P, Mackintosh D, McNeice R, Kocher H, Flodstrom-Tullberg M, Edling C, Hill NJ. Novel role for matricellular proteins in the regulation of islet β cell survival: the effect of SPARC on survival, proliferation, and signaling. J Biol Chem 2014; 289:30614-30624. [PMID: 25204658 DOI: 10.1074/jbc.m114.573980] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Understanding the mechanisms regulating islet growth and survival is critical for developing novel approaches to increasing or sustaining β cell mass in both type 1 and type 2 diabetes patients. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that is important for the regulation of cell growth and adhesion. Increased SPARC can be detected in the serum of type 2 diabetes patients. The aim of this study was to investigate the role of SPARC in the regulation of β cell growth and survival. We show using immunohistochemistry that SPARC is expressed by stromal cells within islets and can be detected in primary mouse islets by Western blot. SPARC is secreted at high levels by pancreatic stellate cells and is regulated by metabolic parameters in these cells, but SPARC expression was not detectable in β cells. In islets, SPARC expression is highest in young mice, and is also elevated in the islets of non-obese diabetic (NOD) mice compared with controls. Purified SPARC inhibits growth factor-induced signaling in both INS-1 β cells and primary mouse islets, and inhibits IGF-1-induced proliferation of INS-1 β cells. Similarly, exogenous SPARC prevents IGF-1-induced survival of primary mouse islet cells. This study identifies the stromal-derived matricellular protein SPARC as a novel regulator of islet survival and β cell growth.
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Affiliation(s)
- Claire L Ryall
- Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom
| | - Katrina Viloria
- Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom
| | - Fadel Lhaf
- Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom
| | - Anthony J Walker
- School of Life Sciences, and Kingston University, Kingston upon Thames, United Kingdom
| | - Aileen King
- Diabetes Research Group, Division of Reproduction & Endocrinology, King's College London, London, United Kingdom
| | - Peter Jones
- Diabetes Research Group, Division of Reproduction & Endocrinology, King's College London, London, United Kingdom
| | - David Mackintosh
- Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom
| | - Rosemary McNeice
- School of Mathematics, Kingston University, Kingston upon Thames, United Kingdom
| | - Hemant Kocher
- Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom
| | - Malin Flodstrom-Tullberg
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Charlotte Edling
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, and
| | - Natasha J Hill
- Diabetes and Cardiovascular Research Group, Kingston University, Kingston upon Thames, United Kingdom.
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Rossi ML, Rehman AA, Gondi CS. Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 2014; 20:11142-11159. [PMID: 25170201 PMCID: PMC4145755 DOI: 10.3748/wjg.v20.i32.11142] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/11/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.
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Marzoq AJ, Giese N, Hoheisel JD, Alhamdani MSS. Proteome variations in pancreatic stellate cells upon stimulation with proinflammatory factors. J Biol Chem 2013; 288:32517-32527. [PMID: 24089530 DOI: 10.1074/jbc.m113.488387] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Pancreatic stellate cells are key mediators in chronic pancreatitis and play a central role in the development of pancreatic fibrosis, stromal formation, and progression of pancreatic cancer. This study was aimed at investigating molecular changes at the level of the proteome that are associated with the activation of pancreatic stellate cells by proinflammatory factors, namely TNF-α, FGF2, IL6, and chemokine (C-C motif) ligand 4 (CCL4). They were added individually to cells growing in serum-free medium next to controls in medium supplemented with serum, thus containing a mixture of them all, or in serum-free medium alone. Variations were detected by means of a microarray of 810 antibodies targeting relevant proteins. All tested factors triggered increased proliferation and migration. Further analysis showed that TNF-α is the prime factor responsible for the activation of pancreatic stellate cells. CCL4 is associated with cellular neovascularization, whereas FGF2 and IL6 induction led to better cellular survival and decreased apoptotic activity of the stellate cells. The identified direct effects of individual cytokines on human pancreatic stellate cells provide new insights about their contribution to pancreatic cancer promotion.
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Affiliation(s)
- Aseel J Marzoq
- From the Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Nathalia Giese
- the Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Jörg D Hoheisel
- From the Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Mohamed Saiel Saeed Alhamdani
- From the Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
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Marzoq AJ, Giese N, Hoheisel JD, Alhamdani MSS. Proteome variations in pancreatic stellate cells upon stimulation with proinflammatory factors. J Biol Chem 2013. [PMID: 24089530 DOI: 10.074/jbc.m] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pancreatic stellate cells are key mediators in chronic pancreatitis and play a central role in the development of pancreatic fibrosis, stromal formation, and progression of pancreatic cancer. This study was aimed at investigating molecular changes at the level of the proteome that are associated with the activation of pancreatic stellate cells by proinflammatory factors, namely TNF-α, FGF2, IL6, and chemokine (C-C motif) ligand 4 (CCL4). They were added individually to cells growing in serum-free medium next to controls in medium supplemented with serum, thus containing a mixture of them all, or in serum-free medium alone. Variations were detected by means of a microarray of 810 antibodies targeting relevant proteins. All tested factors triggered increased proliferation and migration. Further analysis showed that TNF-α is the prime factor responsible for the activation of pancreatic stellate cells. CCL4 is associated with cellular neovascularization, whereas FGF2 and IL6 induction led to better cellular survival and decreased apoptotic activity of the stellate cells. The identified direct effects of individual cytokines on human pancreatic stellate cells provide new insights about their contribution to pancreatic cancer promotion.
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Affiliation(s)
- Aseel J Marzoq
- From the Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Nathalia Giese
- the Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Jörg D Hoheisel
- From the Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Mohamed Saiel Saeed Alhamdani
- From the Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
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Rapoport N, Payne A, Dillon C, Shea J, Scaife C, Gupta R. Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model. J Ther Ultrasound 2013; 1:11. [PMID: 25516800 PMCID: PMC4265944 DOI: 10.1186/2050-5736-1-11] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Accepted: 05/19/2013] [Indexed: 01/14/2023] Open
Abstract
Background Many aspects of the mechanisms involved in ultrasound-mediated therapy remain obscure. In particular, the relative roles of drug and ultrasound, the effect of the time of ultrasound application, and the effect of tissue heating are not yet clear. The current study was undertaken with the goal to clarify these aspects of the ultrasound-mediated drug delivery mechanism. Methods Focused ultrasound-mediated drug delivery was performed under magnetic resonance imaging guidance (MRgFUS) in a pancreatic ductal adenocarcinoma (PDA) model grown subcutaneously in nu/nu mice. Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA. Poly(ethylene oxide)-co-poly(d,l-lactide) block copolymer stabilized perfluoro-15-crown-5-ether nanoemulsions were used as drug carriers. MRgFUS was applied at sub-ablative pressure levels in both continuous wave and pulsed modes, and only a fraction of the tumor was treated. Results Positive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug. The MRgFUS treatment enhanced the action of the drug presumably through enhanced tumor perfusion and blood vessel and cell membrane permeability that increased the drug supply to tumor cells. The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation. The time of the MRgFUS application after drug injection also proved to be an important factor with the best results observed when ultrasound was applied at least 6 h after the injection of drug-loaded nanodroplets. Some collateral damage was observed with particular ultrasound protocols supposedly associated with enhanced inflammation. Conclusion This presented data suggest that there exists an optimal range of ultrasound application parameters and drug injection time. Decreased tumor growth, or complete resolution, was achieved with continuous wave ultrasound pressures below or equal to 3.1 MPa and drug injection times of at least 6 h prior to treatment. Increased acoustic pressure or ultrasound application before or shortly after drug injection gave increased tumor growth when compared to other protocols.
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Affiliation(s)
- Natalya Rapoport
- Department of Bioengineering, University of Utah, 36 S. Wasatch Dr., Room 3100, Salt Lake City, UT 84112, USA
| | - Allison Payne
- Department of Radiology, University of Utah, Salt Lake City, UT 84112, USA
| | - Christopher Dillon
- Department of Bioengineering, University of Utah, 36 S. Wasatch Dr., Room 3100, Salt Lake City, UT 84112, USA
| | - Jill Shea
- Department of Surgery, University of Utah, Salt Lake City, UT 84112, USA
| | - Courtney Scaife
- Department of Surgery, University of Utah, Salt Lake City, UT 84112, USA
| | - Roohi Gupta
- Department of Bioengineering, University of Utah, 36 S. Wasatch Dr., Room 3100, Salt Lake City, UT 84112, USA ; Current address: Department of Radiation Oncology, Fox Chase Cancer Center, P0103, 333 Cottman Avenue, Philadelphia, PA 19111, USA
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Ebrahimi A, Honegger J, Schluesener H, Schittenhelm J. Osteonectin Expression in Surrounding Stroma of Craniopharyngiomas. Int J Surg Pathol 2013; 21:591-8. [DOI: 10.1177/1066896913486695] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Craniopharyngioma is an epithelial tumor of the sellar region with a high survival rate but a high rate of recurrence, especially in children. Hypothalamic involvement, tumor recurrence, and multiple treatments result in clinical deterioration and impaired quality of life. Using immunohistochemistry, we investigated the expression pattern of osteonectin, a marker of tumor invasion and aggressive behavior, in 43 cases of craniopharyngioma. We observed a positive correlation of osteonectin expression in connective-type stromal tissue surrounding the epithelial tumor cells of craniopharyngioma with the extent of central nervous system infiltration and recurrence rate ( P < .001). Given the previous success of chemotherapeutic agents that target the tumor microenvironment, our findings on osteonectin expression in stroma of craniopharyngiomas might, hopefully, be a guide to find newer prognostic markers capable of estimating the risk of progression or recurrence. They may also aid in the development of therapeutics that target tumor microenvironment to improve patient outcome.
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Affiliation(s)
- Azadeh Ebrahimi
- Division of Immunopathology of the Nervous System
- Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany
| | - Juergen Honegger
- Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany
| | | | - Jens Schittenhelm
- Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tuebingen, Tuebingen, Germany
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Heinemann V, Haas M, Boeck S. Systemic treatment of advanced pancreatic cancer. Cancer Treat Rev 2012; 38:843-53. [PMID: 22226241 DOI: 10.1016/j.ctrv.2011.12.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 12/09/2011] [Accepted: 12/12/2011] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer belongs to the most malignant gastrointestinal cancers and, in its advanced stage, remains a deadly disease for nearly all affected patients. Treatment of metastatic adenocarcinoma of the pancreas not only involves chemotherapy and targeted therapy, but also requires attention to accompanying comorbidities as well as frequently intensive supportive treatment and psychosocial support. Gemcitabine-based combinations with fluoropyrimidines and platin analogs have essentially failed to provide a substantial prolongation of survival and may constitute a treatment option only in patients with a good performance status. Among targeted therapies, only the EGFR tyrosine kinase inhibitor erlotinib has shown activity which is marginal in the overall population, but clinically relevant in patients developing skin rash. New avenues of polychemotherapy are presently explored since the gemcitabine-free FOLFIRINOX-regimen (infusional 5-fluorouracil/folinic acid plus irinotecan and oxaliplatin) was shown to be markedly superior to gemcitabine in selected good-performance patients. Pancreatic cancer is notably characterized as a hypovascular tumor rich in desmoplastic stromal tissue. An innovative approach to treatment therefore focuses on peritumoral fibroblasts and aims to induce a depletion of the stroma either by inhibition of the hedgehog pathway or by targeting SPARC (secreted protein acidic and rich in cysteine) via application of albumin-bound paclitaxel.
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Affiliation(s)
- Volker Heinemann
- Klinikum Grosshadern, Department of Oncology and Comprehensive Cancer Center, Ludwig-Maximilians-Universität München, Germany.
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