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1
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Yuan J, Xu B, Su Y, Zhang P, Zhang X, Gong P. Identification of USP39 as a prognostic and predictive biomarker for determining the response to immunotherapy in pancreatic cancer. BMC Cancer 2025; 25:758. [PMID: 40264098 PMCID: PMC12016207 DOI: 10.1186/s12885-025-14096-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/07/2025] [Indexed: 04/24/2025] Open
Abstract
Ubiquitin-Specific Protease 39 (USP39) has been implicated in numerous malignancies, however, its pathogenic mechanisms and impact on the tumor immune microenvironment (TIME) remain incompletely characterized. Based on The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we investigated the diagnostic and prognostic values of USP39 across various cancer types. Additionally, we examined the correlation between USP39 expression and immune-related gene signature, immune cell infiltration pattern, tumor microsatellite instability (MSI), and tumor mutation burden (TMB). This study specifically focused on exploring the clinical relevance and molecular functions of USP39 in pancreatic adenocarcinoma (PAAD), with particularly emphasis on its role in shaping the TIME and modulating responses to immunotherapy. The results demonstrated that evaluated USP39 expression significantly correlated with advanced tumor stage and unfavorable clinical outcomes across multiple cancer types, most notably in PAAD. Functional enrichment analysis indicated that USP39 potentially promotes tumor progression through multiple oncogenic signaling cascades. In vitro experimental validation confirmed that USP39 knockdown inhibited migration and proliferation of pancreatic cancer cells while inducing apoptosis. Additionally, we identified significant positive correlations between USP39 expression and immune checkpoint molecules, particularly prominent in PAAD. Furthermore, we observed associations between USP39 expression and TMB in 16 cancer types and MSI in 11 cancer types, suggesting that heightened USP39 expression may enhance responsiveness to immunotherapeutic interventions. Collectively, our findings establish USP39 as a valuable immune-related biomarker with both diagnostic and prognostic utility across multiple cancer types, especially PAAD, underscoring its potential as a promising therapeutic target for cancer immunotherapy. Clinical trial number Not applicable.
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Affiliation(s)
- Jiahui Yuan
- Department of General Surgery, Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Beibei Xu
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Yongcheng Su
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Pingping Zhang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xianbin Zhang
- Department of General Surgery, Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Peng Gong
- Department of General Surgery, Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China.
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2
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Zhang Y, Ge M, Chen Y, Yang Y, Chen W, Wu D, Cai H, Chen X, Wu X. NDUFA4 promotes cell proliferation by enhancing oxidative phosphorylation in pancreatic adenocarcinoma. J Bioenerg Biomembr 2022; 54:283-291. [DOI: 10.1007/s10863-022-09949-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/28/2022] [Indexed: 11/27/2022]
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3
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The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy. Cancers (Basel) 2022; 14:cancers14010217. [PMID: 35008381 PMCID: PMC8750069 DOI: 10.3390/cancers14010217] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma is a leading cause of cancer death worldwide. Due to the frequently late diagnosis, early metastasis and high therapy resistance curation is rare and prognosis remains poor overall. To provide early diagnostic and therapeutic predictors, various molecules from blood, tissue and other origin e.g., saliva, urine and stool, have been identified as biomarkers. This review summarizes current trends in biomarkers for diagnosis and therapy of pancreatic ductal adenocarcinoma. Abstract Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer.
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4
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Hu C, Yin L, Chen Z, Waldron RT, Lugea A, Lin Y, Zhai X, Wen L, Han YP, Pandol SJ, Deng L, Xia Q. The unique pancreatic stellate cell gene expression signatures are associated with the progression from acute to chronic pancreatitis. Comput Struct Biotechnol J 2021; 19:6375-6385. [PMID: 34938413 PMCID: PMC8649580 DOI: 10.1016/j.csbj.2021.11.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 11/16/2021] [Accepted: 11/20/2021] [Indexed: 02/05/2023] Open
Abstract
Early recognition of chronic pancreatitis (CP) is still lacking. In the setting of CP injury, activated pancreatic stellate cell (PSC) is the central mediator of pancreatic fibrosis. We systematically define highly and uniquely expressed PSC genes and show that these genes are enriched in pancreatic diseases. Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. We demonstrated subset genes that may be associated with the progression from AP to CP. Furthermore, SPARC was identified as a candidate marker for the disease progression. Increased expression of SPARC and canonical PSC genes were verified during AP recovery, especially in recurrent AP mice models. Chronic pancreatitis (CP) is characterized by irreversible fibro-inflammatory changes induced by pancreatic stellate cell (PSC). Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. Here, we systematically identify genes whose expressions are unique to PSC by comparing transcriptome profiles among total pancreas, pancreatic stellate, acinar, islet and immune cells. We then identified candidate genes and correlated them with the pancreatic disease continuum by performing intersection analysis among total PSC and activated PSC genes, and genes persistently differentially expressed during acute pancreatitis (AP) recovery. Last, we examined the association between candidate genes and AP, and substantiated their potential as biomarkers in experimental AP and recurrent AP (RAP) models. A total of 68 genes were identified as highly and uniquely expressed in PSC. The PSC signatures were highly enriched with extracellular matrix remodeling genes and were significantly enriched in AP pancreas compared to healthy control tissues. Among PSC signature genes that comprised a fibrotic phenotype, 10 were persistently differentially expressed during AP recovery. SPARC was determined as a candidate marker for the pancreatic disease continuum, which was not only persistently differentially expressed even five days after AP injury, but also highly expressed in two clinical datasets of CP. Sparc was also validated as highly elevated in RAP compared to AP mice. This work highlights the unique transcriptional profiles of PSC. These PSC signatures’ expression may help to identify patients with high risk of AP progression to CP.
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Affiliation(s)
- Cheng Hu
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Liyuan Yin
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyao Chen
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Richard T Waldron
- Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Aurelia Lugea
- Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Yiyun Lin
- Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center, University of Texas, Houston, TX, United States
| | - Xiaoqian Zhai
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Li Wen
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan-Ping Han
- Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Stephen J Pandol
- Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Lihui Deng
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Xia
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
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5
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Malkova AM, Sharoyko VV, Zhukova NV, Gubal AR, Orlova RV. Laboratory biomarkers of an effective antitumor immune response. Clinical significance. Cancer Treat Res Commun 2021; 29:100489. [PMID: 34837797 DOI: 10.1016/j.ctarc.2021.100489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 10/18/2021] [Accepted: 11/09/2021] [Indexed: 10/19/2022]
Abstract
The modern checkpoint inhibitors block the programmed death-1 receptor and its ligand, cytotoxic T-lymphocyte-associated antigen 4 on tumor cells and lymphocytes, that induces cytotoxic reactions. Nowadays, there are no approved clinical and laboratory predictor markers of immune therapy efficacy, which would allow a more personalized approach to patient selection and treatment. The aim of this review is to analyze possible biomarkers of efficacy for treatment with checkpoint inhibitors according to the pathogenic mechanisms of drug action. The review revealed possible predictive biomarkers, that could be classified to 3 groups: biomarkers of high mutagenic potential of the tumor, biomarkers of high activity of adaptive immunity, biomarkers of low activity of the tumor microenvironment. The determination of the described markers before the start of therapy can be used to formulate a treatment regimen, in which the use of various immunomodulatory drugs, inhibitors of proinflammatory cytokines, angiogenic molecules, and probiotics can be considered.
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Affiliation(s)
- A M Malkova
- Saint Petersburg State University, 7/9 Universitetskaya Emb., St Petersburg 199034, Russian Federation.
| | - V V Sharoyko
- Saint Petersburg State University, 7/9 Universitetskaya Emb., St Petersburg 199034, Russian Federation.
| | - N V Zhukova
- Saint Petersburg State University, 7/9 Universitetskaya Emb., St Petersburg 199034, Russian Federation.
| | - A R Gubal
- Saint Petersburg State University, 7/9 Universitetskaya Emb., St Petersburg 199034, Russian Federation.
| | - R V Orlova
- Saint Petersburg State University, 7/9 Universitetskaya Emb., St Petersburg 199034, Russian Federation.
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6
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Sarantis P, Bokas A, Papadimitropoulou A, Koustas E, Theocharis S, Papakotoulas P, Schizas D, Papalampros A, Felekouras E, Papavassiliou AG, Karamouzis MV. Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer. Int J Mol Sci 2021; 22:7053. [PMID: 34208987 PMCID: PMC8268558 DOI: 10.3390/ijms22137053] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/22/2021] [Accepted: 06/28/2021] [Indexed: 02/05/2023] Open
Abstract
Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.
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Affiliation(s)
- Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (A.B.); (E.K.)
| | - Alexandros Bokas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (A.B.); (E.K.)
- Department of Medical Oncology, ‘Theageneio’ Cancer Hospital, 54639 Thessaloniki, Greece;
| | - Adriana Papadimitropoulou
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (A.B.); (E.K.)
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Pavlos Papakotoulas
- Department of Medical Oncology, ‘Theageneio’ Cancer Hospital, 54639 Thessaloniki, Greece;
| | - Dimitrios Schizas
- First Department of Surgery, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.S.); (A.P.); (E.F.)
| | - Alexandros Papalampros
- First Department of Surgery, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.S.); (A.P.); (E.F.)
| | - Evangelos Felekouras
- First Department of Surgery, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.S.); (A.P.); (E.F.)
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (A.B.); (E.K.)
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (A.B.); (E.K.)
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7
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Hua YQ, Zhang K, Sheng J, Ning ZY, Li Y, Shi WD, Liu LM. NUCB1 Suppresses Growth and Shows Additive Effects With Gemcitabine in Pancreatic Ductal Adenocarcinoma via the Unfolded Protein Response. Front Cell Dev Biol 2021; 9:641836. [PMID: 33855021 PMCID: PMC8041069 DOI: 10.3389/fcell.2021.641836] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/03/2021] [Indexed: 01/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient prognosis. A cellular stress response mechanism called the unfolded protein response (UPR) has been implicated in PDAC progression. More recently, nucleobindin 1 (NUCB1), a calcium-binding protein, has been shown to control the UPR but its precise role in PDAC has not been explored. Here, we found that downregulation of NUCB1 was associated with poor prognosis in patients with PDAC. Functionally, NUCB1 overexpression suppressed pancreatic cancer cell proliferation and showed additive effects with gemcitabine (GEM) in vitro and in vivo. Moreover, by controlling ATF6 activity, NUCB1 overexpression suppressed GEM-induced UPR and autophagy. Last but not least, we uncovered METTL3-mediated m6A modification on NUCB1 5'UTR via the reader YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. Taken together, our study revealed crucial functions of NUCB1 in suppressing proliferation and enhancing the effects of gemcitabine in pancreatic cancer cells and identified METTL3-mediated m6A modification as a mechanism for NUCB1 downregulation in PDAC.
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Affiliation(s)
- Yong-Qiang Hua
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ke Zhang
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jie Sheng
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhou-Yu Ning
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ye Li
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wei-Dong Shi
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lu-Ming Liu
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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8
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Increased SPARC expression is associated with neoadjuvant therapy in resectable pancreatic ductal adenocarcinoma. Pract Lab Med 2020; 21:e00171. [PMID: 32548230 PMCID: PMC7284134 DOI: 10.1016/j.plabm.2020.e00171] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 03/27/2020] [Accepted: 05/18/2020] [Indexed: 01/04/2023] Open
Abstract
Secreted Protein Acid and Rich in Cysteine (SPARC) is an extracellular glycoprotein secreted by fibroblasts and osteoblasts in normal tissues. SPARC overexpression occurs in multiple tumors including pancreatic ductal adenocarcinoma (PDAC) and may predict favorable response to nab-paclitaxel. The prognostic significance of SPARC expression in PDAC is unclear - some reports indicate SPARC overexpression associates with poor outcomes and others find no correlation. Considering neoadjuvant therapy enhances the stromal fibrosis of PDAC and taking into account that SPARC is a component of PDAC stromal fibrosis, we hypothesized that SPARC expression would be greater in neoadjuvant-treated versus treatment-naive PDAC. Quantitative immunohistochemistry was used to measure SPARC expression in resected PDAC in 74 cases of neoadjuvant treated PDAC and 95 cases of treatment-naïve PDAC. SPARC expression was increased 54% in neoadjuvant treated PDAC compared to treatment-naïve PDAC. These data indicate that increased SPARC expression correlates with neoadjuvant therapy in PDAC.
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9
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Ghanemi A, Yoshioka M, St-Amand J. Secreted protein acidic and rich in cysteine and inflammation: Another homeostatic property? Cytokine 2020; 133:155179. [PMID: 32619797 DOI: 10.1016/j.cyto.2020.155179] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/12/2020] [Accepted: 06/13/2020] [Indexed: 02/08/2023]
Affiliation(s)
- Abdelaziz Ghanemi
- Functional Genomics Laboratory, Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Center, Québec, Québec G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Québec G1V 0A6, Canada
| | - Mayumi Yoshioka
- Functional Genomics Laboratory, Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Center, Québec, Québec G1V 4G2, Canada
| | - Jonny St-Amand
- Functional Genomics Laboratory, Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Center, Québec, Québec G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Québec G1V 0A6, Canada.
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10
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Byrling J, Sasor A, Nilsson J, Said Hilmersson K, Andersson R, Andersson B. Expression of peritumoral SPARC during distal cholangiocarcinoma progression and correlation with outcome. Scand J Gastroenterol 2020; 55:725-731. [PMID: 32543919 DOI: 10.1080/00365521.2020.1774923] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/18/2020] [Accepted: 05/23/2020] [Indexed: 02/04/2023]
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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Affiliation(s)
- Johannes Byrling
- Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden
| | - Agata Sasor
- Department of Clinical Sciences Lund, Pathology, Lund University and Skåne University Hospital, Lund, Sweden
| | - Johan Nilsson
- Department of Clinical Sciences Lund, Cardiothoracic Surgery, Lund University and Skåne University Hospital, Lund, Sweden
| | - Katarzyna Said Hilmersson
- Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden
| | - Roland Andersson
- Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden
| | - Bodil Andersson
- Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden
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11
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Munasinghe A, Malik K, Mohamedi F, Moaraf S, Kocher H, Jones L, Hill NJ. Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer. Cancer Lett 2020; 477:88-96. [DOI: 10.1016/j.canlet.2020.02.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/30/2020] [Accepted: 02/23/2020] [Indexed: 12/11/2022]
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12
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Serum extracellular vesicles contain SPARC and LRG1 as biomarkers of colon cancer and differ by tumour primary location. EBioMedicine 2019; 50:211-223. [PMID: 31753726 PMCID: PMC6921233 DOI: 10.1016/j.ebiom.2019.11.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 11/03/2019] [Accepted: 11/04/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Recently, the distinction between left- and right-sided colon cancer (LCC and RCC) has been brought into focus. RCC is associated with an inferior overall survival and progression-free survival. We aimed to perform a detailed analysis of the diversity of extracellular vesicles (EV) between LCC and RCC using quantitative proteomics and to identify for new diagnostic and prognostic biomarkers. METHODS We isolated EVs from patients with LCC, RCC and healthy volunteers, and treated colorectal cancer cell line with serum-derived EVs. We then performed a quantitative proteomics analysis of the serum-derived EVs and cell line treated with EVs. Proteomic data are available via ProteomeXchange with the identifiers PXD012283 and PXD012304. In addition, we assessed the performance of EV SPARC and LRG1 as diagnosis and prognosis biomarkers in colon cancer. FINDINGS The expression profile of the serum EV proteome in patients with RCC was different from that of patients with LCC. Serum-derived EVs in RCC promoted cellular mobility more significantly than EVs derived from LCC. EV SPARC and LRG1 expression levels demonstrated area under the receiver-operating characteristic curve values of 0.95 and 0.93 for discriminating patients with colon cancer from healthy controls. Moreover, the expression levels of SPARC and LRG1 correlated with tumour sidedness and were predictive of tumour recurrence. INTERPRETATION We identified differences in EV protein profiles between LCC and RCC. Serum-derived EVs of RCC may promote metastasis via upregulation of extracellular matrix (ECM)-related proteins, especially SPARC and LRG1, which may serve as diagnosis and prognosis biomarkers in colon cancer.
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13
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Khetan K, Baloda V, Sahoo RK, Vishnubhathla S, Yadav R, Saraya A, Sharma A, Gupta SD, Das P. SPARC expression in desmoplastic and non desmoplastic pancreatic carcinoma and cholangiocarcinoma. Pathol Res Pract 2019; 215:152685. [PMID: 31727501 DOI: 10.1016/j.prp.2019.152685] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/24/2019] [Accepted: 10/06/2019] [Indexed: 01/03/2023]
Abstract
BACKGROUND The pancreatobiliary carcinomas are characterized by presence of desmoplastic stroma. Overexpression of secreted protein acid and rich in cysteine (SPARC), a matrix producing agent has been documented in pancreatic ductal adenocarcinomas, with survival benefits. This study was targeted to see if SPARC expression in pancreatobiliary carcinomas is responsible for stromal desmoplasia and its prognostic significance. METHODS In this retrospective study 48 cases of pancreatic cancer and 27 cases of cholangiocarcinoma were analyzed. The expression pattern of SPARC and vascular endothelial growth factor (VEGF) (angiogenic factors) was evaluated by immunohistochemistry on formalin fixed paraffin embedded tissues. Immunoreactivity was scored semi quantitatively based on stain intensity and stain distribution. SPARC expression was correlated with tumor histology, stromal desmoplasia, VEGF expression, various histological parameters and overall survival in patients. Real time polymerase chain reaction was performed in few cases to validate the immunohistochemistry expression pattern. RESULTS SPARC expression was high in peritumoral stroma in pancreatic carcinoma than in pancreatic controls; however, SPARC expression pattern was not grossly different in desmoplastic and non-desmoplastic pancreatobiliary carcinomas and in cholangiocarcinomas. No definite correlation was noted between SPARC expression and histological markers of severity and overall survival data. CONCLUSIONS The relevance of SPARC expression in pancreato-biliary carcinomas though may still be important for therapeutic decision making, it is not responsible for peritumoral stromal desmoplasia in these tumors and it does not have any significant prognostic implication.
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Affiliation(s)
- Khusbu Khetan
- Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Vandana Baloda
- Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Ranjit K Sahoo
- Departments of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Rajni Yadav
- Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Departments of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Atul Sharma
- Departments of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Prasenjit Das
- Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India.
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14
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Ramu I, Buchholz SM, Patzak MS, Goetze RG, Singh SK, Richards FM, Jodrell DI, Sipos B, Ströbel P, Ellenrieder V, Hessmann E, Neesse A. SPARC dependent collagen deposition and gemcitabine delivery in a genetically engineered mouse model of pancreas cancer. EBioMedicine 2019; 48:161-168. [PMID: 31597597 PMCID: PMC6838446 DOI: 10.1016/j.ebiom.2019.09.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/07/2019] [Accepted: 09/13/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is characterised by extensive matrix deposition that has been implicated in impaired drug delivery and therapeutic resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates collagen deposition and is highly upregulated in the activated stroma subtype with poor prognosis in PDAC patients. METHODS KrasG12D;p48-Cre;SPARC-/- (KC-SPARC-/-) and KrasG12D;p48-Cre;SPARCWT (KC-SPARCWT) were generated and analysed at different stages of carcinogenesis by histological grading, immunohistochemistry for epithelial and stromal markers, survival and preclinical analysis. Pharmacokinetic and pharmacodynamic studies were conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunohistochemistry following gemcitabine treatment (100 mg/kg) in vivo. FINDINGS Global genetic ablation of SPARC in a KrasG12D driven mouse model resulted in significantly reduced overall and mature collagen deposition around early and advanced pancreatic intraepithelial neoplasia (PanIN) lesions and in invasive PDAC (p < .001). However, detailed pathological scoring and molecular analysis showed no effects on PanIN to PDAC progression, vessel density (CD31), tumour incidence, grading or metastatic frequency. Despite comparable tumour kinetics, ablation of SPARC resulted in a significantly shortened survival in KC-SPARC-/- mice (280 days versus 485 days, p < .03, log-rank-test). Using LC-MS/MS, we show that SPARC dependent collagen deposition does not affect intratumoural gemcitabine accumulation or immediate therapeutic response in tumour bearing KC-SPARCWT and KC-SPARC-/-mice. INTERPRETATION Global SPARC ablation reduces the collagen-rich microenvironment in murine PDAC. Moreover, global SPARC depletion did not affect tumour growth kinetics, grading or metastatic frequency. Notably, the dense-collagen matrix did not restrict access of gemcitabine to the tumour. These findings may have direct translational implications in clinical trial design.
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Affiliation(s)
- Iswarya Ramu
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany
| | - Sören M Buchholz
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany
| | - Melanie S Patzak
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany
| | - Robert G Goetze
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany
| | - Shiv K Singh
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany
| | - Frances M Richards
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, The University of Cambridge, United Kingdom
| | - Duncan I Jodrell
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, The University of Cambridge, United Kingdom
| | - Bence Sipos
- Institute of Pathology and Neuropathology, University Clinic Tübingen, Germany
| | - Philipp Ströbel
- Institute of Pathology, University Medical Centre Göttingen, Germany
| | - Volker Ellenrieder
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany
| | - Elisabeth Hessmann
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany
| | - Albrecht Neesse
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany.
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15
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Murakawa M, Aoyama T, Miyagi Y, Kobayashi S, Ueno M, Morimoto M, Numata M, Yamamoto N, Tamagawa H, Yukawa N, Rino Y, Masuda M, Morinaga S. The impact of SPARC expression on the survival of pancreatic ductal adenocarcinoma patients after curative resection. J Cancer 2019; 10:627-633. [PMID: 30719160 PMCID: PMC6360433 DOI: 10.7150/jca.28660] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 11/07/2018] [Indexed: 01/27/2023] Open
Abstract
Background: The predictive roles of secreted protein acidic and rich in cysteine (SPARC) in pancreatic ductal adenocarcinoma (PDAC) patients after curative resection have not been clarified. We investigated the correlations between the SPARC expression and the postoperative prognosis. Methods: We retrospectively analyzed the clinical data from consecutive patients who underwent curative resection for pancreatic cancer in our institution from 2005 to 2014. Stromal SPARC expression was analyzed by immunohistochemistry on tumor tissue microarrays (TMAs) from the patients. Results: A total of 179 patients were enrolled to this study. The median follow-up period of the present study was 62.1 months. Seventy patients had positive SPARC expression (39.1%). There were no significant differences between the positive SPARC-positive group and the SPARC-negative group. In the survival analysis, there was a significant difference between the SPARC-positive and SPARC-negative groups in the 5-year overall survival (OS) rates after surgery, which were 8.1% and 19.8%, respectively (p=0.0316). A univariate analysis showed that the SPARC expression, size of tumor, lymph node metastasis, and residual tumor were possible prognostic factors. A multivariate analysis showed that the SPARC expression (hazard ratio [HR]: 1.44, 95% confidence interval [CI]: 1.017-2.051), lymph node metastasis (HR: 2.019, 95% CI: 1.318-3.091), and residual tumor (HR: 1.648, 95% CI: 1.132-2.401) were independent prognostic factors. Conclusions: The stromal SPARC expression in resectable pancreatic cancer patients might be useful as a prognostic marker.
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Affiliation(s)
- Masaaki Murakawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
- ✉ Corresponding author: Masaaki Murakawa, Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ward, Yokohama city, 241-8515, Japan TEL: 81-45-520-2222, E-mail:
| | - Toru Aoyama
- Department of Surgery, Yokohama City University
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute
| | - Satoshi Kobayashi
- Department of Hepatobiliary Pancreatic Oncology, Kanagawa Cancer Center
| | - Makoto Ueno
- Department of Hepatobiliary Pancreatic Oncology, Kanagawa Cancer Center
| | - Manabu Morimoto
- Department of Hepatobiliary Pancreatic Oncology, Kanagawa Cancer Center
| | | | - Naoto Yamamoto
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | | | | | | | | | - Soichiro Morinaga
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
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16
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Hou MX, Gao YL, Liu JX, Dai LY, Kong XZ, Shang J. Network analysis based on low-rank method for mining information on integrated data of multi-cancers. Comput Biol Chem 2018; 78:468-473. [PMID: 30563751 DOI: 10.1016/j.compbiolchem.2018.11.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 11/30/2018] [Accepted: 11/30/2018] [Indexed: 02/01/2023]
Abstract
The noise problem of cancer sequencing data has been a problem that can't be ignored. Utilizing considerable way to reduce noise of these cancer data is an important issue in the analysis of gene co-expression network. In this paper, we apply a sparse and low-rank method which is Robust Principal Component Analysis (RPCA) to solve the noise problem for integrated data of multi-cancers from The Cancer Genome Atlas (TCGA). And then we build the gene co-expression network based on the integrated data after noise reduction. Finally, we perform nodes and pathways mining on the denoising networks. Experiments in this paper show that after denoising by RPCA, the gene expression data tend to be orderly and neat than before, and the constructed networks contain more pathway enrichment information than unprocessed data. Moreover, learning from the betweenness centrality of the nodes in the network, we find some abnormally expressed genes and pathways proven that are associated with many cancers from the denoised network. The experimental results indicate that our method is reasonable and effective, and we also find some candidate suspicious genes that may be linked to multi-cancers.
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Affiliation(s)
- Mi-Xiao Hou
- School of Information Science and Engineering, Qufu Normal University, Rizhao, China
| | - Ying-Lian Gao
- Library of Qufu Normal University, Qufu Normal University, Rizhao, China
| | - Jin-Xing Liu
- School of Information Science and Engineering, Qufu Normal University, Rizhao, China; Co-Innovation Center for Information Supply & Assurance Technology, Anhui University, Hefei, China.
| | - Ling-Yun Dai
- School of Information Science and Engineering, Qufu Normal University, Rizhao, China
| | - Xiang-Zhen Kong
- School of Information Science and Engineering, Qufu Normal University, Rizhao, China
| | - Junliang Shang
- School of Information Science and Engineering, Qufu Normal University, Rizhao, China
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17
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Chen H, He R, Shi X, Zhou M, Zhao C, Zhang H, Qin R. Meta-analysis on resected pancreatic cancer: a comparison between adjuvant treatments and gemcitabine alone. BMC Cancer 2018; 18:1034. [PMID: 30352573 PMCID: PMC6199735 DOI: 10.1186/s12885-018-4948-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 10/14/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Pancreatic cancer is a highly malignant tumor with a poor prognosis. Chemotherapy such as gemcitabine is still an important treatment. Gemcitabine (Gem) may prolong survival time and delay the development of recurrent disease after complete resection of pancreatic cancer. Currently, some control studies have been performed between certain drugs and gemcitabine monotherapy after pancreatic cancer surgery, but the outcomes were uncertain. Here, we implemented meta-analysis to compare the efficacy between adjuvant treatments and gemcitabine monotherapy in patients with resected pancreatic cancer. METHODS PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library searches were undertaken to identify randomized controlled trials (RCTs). Date of search ranged from January 1997 to December 2017. The meta-analysis included six RCTs. The major endpoints involved overall survival (OS), disease-free survival/progress free survival/relapse-free survival (DFS/PFS/RFS) and grade 3-4 toxicity. RESULTS Pooled meta-analytic estimates were derived using random-effects model. Subgroup analysis used fixed-effects model. The outcome showed that there was no difference in OS (hazard ratio (HR), 0.87; 95% CI, 0.70-1.07; P = 0.19) and DFS (HR, 0.85; 95% CI, 0.71-1.02; P = 0.08) between the adjuvant treatments group (fluorouracil+folinic acid, S-1, gemcitabine+capecitabine, gemcitabine+erlotinib and gemcitabine+uracil/tegafur) and Gem monotherapy group. However, the subgroup analysis showed that only S-1 chemotherapy, which is an oral fluoropyrimidine agent containing tegafur, gimeracil and oteracil, was significant in OS (HR, 0.59; 95% CI, 0.46-0.74; P < 0.0001) and DFS (HR, 0.63; 95% CI, 0.52-0.75; P < 0.00001) compared with Gem alone. Toxicity analysis showed there was an increased incidence of grade 3/4 diarrhea (risk ratio (RR), 5.11; 95%CI, 3.24-8.05; P < 0.00001) and decreased incidence of grade 3/4 leucopenia (RR, 0.55; 95%CI, 0.31-0.98; P = 0.04), thrombocytopenia (RR, 0.61; 95%CI, 0.39-0.97; P = 0.04) in adjuvant treatments group. Neutropenia (RR, 0.69; 95%CI, 0.36-1.29; P = 0.24) and fatigue (RR, 1.29; 95%CI, 0.95-1.77; P = 0.11) for patients between the two groups were not significantly different. CONCLUSIONS In our meta-analysis, a significant survival benefit is only observed in the S-1 regimen, but the results are yet to be determined. Optimal cytotoxicity or targeted drug regimens need further validation in clinical trials in the future.
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Affiliation(s)
- Hua Chen
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Ruizhi He
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Xiuhui Shi
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Min Zhou
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Chunle Zhao
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Hang Zhang
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
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18
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The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship. Cancers (Basel) 2018; 10:cancers10090316. [PMID: 30200666 PMCID: PMC6162452 DOI: 10.3390/cancers10090316] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 08/31/2018] [Accepted: 09/02/2018] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has an extraordinarily dense fibrotic stroma that impedes tumor perfusion and delivery of anticancer drugs. Since the extracellular matrix (ECM) comprises the bulk of the stroma, it is primarily responsible for the increased interstitial tissue pressure and stiff mechanical properties of the stroma. Besides its mechanical influence, the ECM provides important biochemical and physical cues that promote survival, proliferation, and metastasis. By serving as a nutritional source, the ECM also enables PDAC cells to survive under the nutrient-poor conditions. While therapeutic strategies using stroma-depleting drugs have yielded disappointing results, an increasing body of research indicates the ECM may offer a variety of potential therapeutic targets. As preclinical studies of ECM-targeted drugs have shown promising effects, a number of clinical trials are currently investigating agents with the potential to advance the future treatment of PDAC. Thus, the present review seeks to give an overview of the complex relationship between the ECM and PDAC.
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19
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Fan X, Wang Y, Jiang T, Cai W, Jin Y, Niu Y, Zhu H, Bu Y. B-Myb Mediates Proliferation and Migration of Non-Small-Cell Lung Cancer via Suppressing IGFBP3. Int J Mol Sci 2018; 19:ijms19051479. [PMID: 29772705 PMCID: PMC5983693 DOI: 10.3390/ijms19051479] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/06/2018] [Accepted: 05/11/2018] [Indexed: 12/22/2022] Open
Abstract
B-Myb has been shown to play an important oncogenic role in several types of human cancers, including non-small-cell lung cancer (NSCLC). We previously found that B-Myb is aberrantly upregulated in NSCLC, and overexpression of B-Myb can significantly promote NSCLC cell growth and motility. In the present study, we have further investigated the therapeutic potential of B-Myb in NSCLC. Kaplan–Meier and Cox proportional hazards analysis indicated that high expression of B-Myb is significantly associated with poor prognosis in NSCLC patients. A loss-of-function study demonstrated that depletion of B-Myb resulted in significant inhibition of cell growth and delayed cell cycle progression in NSCLC cells. Notably, B-Myb depletion also decreased NSCLC cell migration and invasion ability as well as colony-forming ability. Moreover, an in vivo study demonstrated that B-Myb depletion caused significant inhibition of tumor growth in a NSCLC xenograft nude mouse model. A molecular mechanistic study by RNA-seq analysis revealed that B-Myb depletion led to deregulation of various downstream genes, including insulin-like growth factor binding protein 3 (IGFBP3). Overexpression of IGFBP3 suppressed the B-Myb-induced proliferation and migration, whereas knockdown of IGFBP3 significantly rescued the inhibited cell proliferation and motility caused by B-Myb siRNA (small interfering RNA). Expression and luciferase reporter assays revealed that B-Myb could directly suppress the expression of IGFBP3. Taken together, our results suggest that B-Myb functions as a tumor-promoting gene via suppressing IGFBP3 and could serve as a novel therapeutic target in NSCLC.
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MESH Headings
- Animals
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Cycle/genetics
- Cell Cycle Proteins/genetics
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Proliferation/genetics
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Disease Models, Animal
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Humans
- Insulin-Like Growth Factor Binding Protein 3/genetics
- Insulin-Like Growth Factor Binding Protein 3/metabolism
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Male
- Mice
- Neoplasm Staging
- Prognosis
- Promoter Regions, Genetic
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Small Interfering/genetics
- Trans-Activators/genetics
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Affiliation(s)
- Xiaoyan Fan
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
- Department of Pathology, College of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China.
| | - Yitao Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
| | - Tinghui Jiang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
| | - Wei Cai
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
| | - Yuelei Jin
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
- Department of Cell Biology, College of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China.
| | - Yulong Niu
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
| | - Huifang Zhu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
| | - Youquan Bu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing 400016, China.
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
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20
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Liang C, Shi S, Meng Q, Liang D, Ji S, Zhang B, Qin Y, Xu J, Ni Q, Yu X. Do anti-stroma therapies improve extrinsic resistance to increase the efficacy of gemcitabine in pancreatic cancer? Cell Mol Life Sci 2018; 75:1001-1012. [PMID: 28993833 PMCID: PMC11105455 DOI: 10.1007/s00018-017-2678-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/25/2017] [Accepted: 10/02/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies, with approximately 20-30% of PDAC patients receiving the surgical resection with curative intent. Although many studies have focused on finding ideal "drug chaperones" that facilitate and/or potentiate the effects of gemcitabine (GEM) in pancreatic cancer, a significant benefit in overall survival could not be demonstrated for any of these combination therapies in PDAC. Given that pancreatic cancer is characterized by desmoplasia and the dual biological roles of stroma in pancreatic cancer, we reassess the importance of stroma in GEM-based therapeutic approaches in light of current findings. This review is focused on understanding the role of stromal components in the extrinsic resistance to GEM and whether anti-stroma therapies have a positive effect on the GEM delivery. This work contributes to the development of novel and promising combination GEM-based regimens that have achieved significant survival benefits for the patients with pancreatic cancer.
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Affiliation(s)
- Chen Liang
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Si Shi
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Qingcai Meng
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Dingkong Liang
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Shunrong Ji
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Bo Zhang
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yi Qin
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Jin Xu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Quanxing Ni
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xianjun Yu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China.
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21
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Shintakuya R, Kondo N, Murakami Y, Uemura K, Nakagawa N, Okano K, Takahashi S, Sueda T. The high stromal SPARC expression is independently associated with poor survival of patients with resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine in combination with S-1 or adjuvant gemcitabine alone. Pancreatology 2018; 18:191-197. [PMID: 29295776 DOI: 10.1016/j.pan.2017.12.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 11/19/2017] [Accepted: 12/22/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although postoperative adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC) improves survival, its efficacy varies among individuals. Identification of biomarkers that can predict the efficacy of adjuvant chemotherapy for PDAC is essential. OBJECTIVES To investigate the predictive value of secreted protein acidic and rich in cysteine (SPARC) expression in patients with PDAC treated with adjuvant gemcitabine in combination with S-1 (adjuvant GS) or adjuvant gemcitabine alone (adjuvant G alone). METHODS Stromal SPARC and cytoplasmic SPARC were examined immunohistochemically in 211 PDAC patients treated with adjuvant GS or G alone after resection. The association of SPARC expression with clinicopathological factors, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS In multivariate analysis, borderline resectable with arterial contact (BR-A) (P = .002), higher preoperative CA 19-9 level (≥91 U/ml) (P = .005), moderately or poorly (P = .003), presence of lymph node metastasis (P = .012) and high stromal SPARC expression (P = .013) were independent predictors of poor DFS. Moreover, BR-A (P = .003), higher preoperative CA 19-9 level (≥91 U/ml) (P = .007) and high stromal SPARC expression (P < .001) were identified as independent predictors of poor OS. In contrast, cytoplasmic SPARC expression did not affect DFS and OS. CONCLUSIONS High stromal SPARC expression was an independent predictor of poor DFS and OS in patients treated with adjuvant GS or G alone. Stromal SPARC expression could be a relevant biomarker for prediction of prognosis in PDAC patients after resection treated with adjuvant GS or G alone.
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Affiliation(s)
- Ryuta Shintakuya
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Naru Kondo
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yoshiaki Murakami
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Uemura
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoya Nakagawa
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keisuke Okano
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinya Takahashi
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Taijiro Sueda
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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22
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Li Z, Li AD, Xu L, Bai DW, Hou KZ, Zheng HC, Qu XJ, Liu YP. SPARC expression in gastric cancer predicts poor prognosis: Results from a clinical cohort, pooled analysis and GSEA assay. Oncotarget 2018; 7:70211-70222. [PMID: 28053291 PMCID: PMC5342547 DOI: 10.18632/oncotarget.12191] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 09/02/2016] [Indexed: 12/18/2022] Open
Abstract
Background The prognostic role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in gastric cancer (GC) remains controversial. We investigated the clinical significance, the survival relevance, and potential function of SPARC in GC with resected samples, online gene set GSE62254, and cell line SGC7901. Results High immunostaining of SPARC significantly correlated with tumor differentiation (P = 0.004), and independently predicted shorter overall survival (OS) (HR = 1.446, P = 0.022), based on the current IHC evaluation. The accuracy of the results was further validated with 1000 times bootstrapping and the time-dependent receiver-operating characteristics (ROC) curves. The meta-analysis (pooled HR = 1.60, 95% CI: 1.01−2.53) confirmed SPARC as the predictor for reduced OS in GC. Moreover, the association between enhanced SPARC expression and Adriamycin (Adr) sensitivity was revealed by GSEA, and then confirmed by comparative cellular experiments, such as the protein level analysis of SGC7901and SGC7901/Adr cell line. Materials and Methods Immunohistochemistry (IHC) method was used to detect SPARC expression in 137 GC cases. Meta-analysis was performed based on 5 studies published in English on PubMed up to March 2016. GSEA was performed using online data set GSE62254 and GC-related functional gene sets derived from molecular signatures database (MSigDB). Western Blot was carried out to compare protein-level differences between gastric carcinoma SGC7901 cell line and Adr resistant SGC7901/Adr cell line. MTT assay was done to confirm the induction of SPARC on Adr sensitivity Conclusions Increased SPARC expression in GC led to a worse clinical outcome of patients and might induce Adr sensitivity of GC cells.
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Affiliation(s)
- Zhi Li
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Ao-Di Li
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Lu Xu
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - De-Wei Bai
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Department of Cell Biological Treatment Ward, Dalian Centre Hospital, Dalian, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Ke-Zuo Hou
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Hua-Chuan Zheng
- Life Science Institute of Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Xiu-Juan Qu
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
| | - Yun-Peng Liu
- Department of Medical Oncology, The First Hospital, China Medical University, Shenyang, Liaoning Province, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province
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23
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Fiorino S, Bacchi-Reggiani ML, Birtolo C, Acquaviva G, Visani M, Fornelli A, Masetti M, Tura A, Sbrignadello S, Grizzi F, Patrinicola F, Zanello M, Mastrangelo L, Lombardi R, Benini C, Di Tommaso L, Bondi A, Monetti F, Siopis E, Orlandi PE, Imbriani M, Fabbri C, Giovanelli S, Domanico A, Accogli E, Di Saverio S, Grifoni D, Cennamo V, Leandri P, Jovine E, de Biase D. Matricellular proteins and survival in patients with pancreatic cancer: A systematic review. Pancreatology 2018; 18:122-132. [PMID: 29137857 DOI: 10.1016/j.pan.2017.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 10/29/2017] [Accepted: 11/01/2017] [Indexed: 02/05/2023]
Abstract
Extracellular matrix (ECM) plays a fundamental role in tissue architecture and homeostasis and modulates cell functions through a complex interaction between cell surface receptors, hormones, several bioeffector molecules, and structural proteins like collagen. These components are secreted into ECM and all together contribute to regulate several cellular activities including differentiation, apoptosis, proliferation, and migration. The so-called "matricellular" proteins (MPs) have recently emerged as important regulators of ECM functions. The aim of our review is to consider all different types of MPs family assessing the potential relationship between MPs and survival in patients with pancreatic ductal adenocarcinoma (PDAC). A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) Statement issued in 2009 was conducted through Ovid interface, and literature review was performed in May 2017. The search text words were identified by means of controlled vocabulary, such as the National Library of Medicine's MESH (Medical Subject Headings) and Keywords. Collected data showed an important role of MPs in carcinogenesis and in PDAC prognosis even though the underlying mechanisms are still largely unknown and data are not univocal. Therefore, a better understanding of MPs role in regulation of ECM homeostasis and remodeling of specific organ niches may suggest potential novel extracellular targets for the development of efficacious therapeutic strategies.
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Affiliation(s)
- Sirio Fiorino
- Internal Medicine Unit C, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy.
| | - Maria Letizia Bacchi-Reggiani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Cardiology Unit, Policlinico S. Orsola-Malpighi, University of Bologna, via Massarenti 9, Bologna, Italy
| | - Chiara Birtolo
- Internal Medicine Unit A, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Giorgia Acquaviva
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), University of Bologna, Azienda USL di Bologna, Largo Nigrisoli 3, Bologna, Italy
| | - Michela Visani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), University of Bologna, Azienda USL di Bologna, Largo Nigrisoli 3, Bologna, Italy
| | - Adele Fornelli
- Anatomic Pathology Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Michele Masetti
- Surgery Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Andrea Tura
- CNR Institute of Neuroscience, Via Giuseppe Moruzzi 1, Padova, Italy
| | | | - Fabio Grizzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milano, Italy
| | - Federica Patrinicola
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milano, Italy
| | - Matteo Zanello
- Surgery Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Laura Mastrangelo
- Surgery Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Raffaele Lombardi
- Surgery Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Claudia Benini
- Surgery Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Luca Di Tommaso
- Department of Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, Milano, Italy
| | - Arrigo Bondi
- Anatomic Pathology Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Francesco Monetti
- Radiology Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Elena Siopis
- Radiology Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Paolo Emilio Orlandi
- Radiology Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Michele Imbriani
- Radiology Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Carlo Fabbri
- Unit of Gastroenterology and Digestive Endoscopy, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Silvia Giovanelli
- Unit of Gastroenterology and Digestive Endoscopy, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Andrea Domanico
- Internal Medicine Unit A, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Esterita Accogli
- Internal Medicine Unit A, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Salomone Di Saverio
- Surgical Emergency Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Daniela Grifoni
- Department of Pharmacy and Biotechnology, University of Bologna, via San Donato 15, Bologna, Italy
| | - Vincenzo Cennamo
- Unit of Gastroenterology and Digestive Endoscopy, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Paolo Leandri
- Surgical Emergency Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Elio Jovine
- Surgery Unit, Azienda USL-Maggiore Hospital, Largo Nigrisoli 3, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology, University of Bologna, via San Donato 15, Bologna, Italy.
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24
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Nakajima M, Yoshino S, Kanekiyo S, Maeda N, Sakamoto K, Tsunedomi R, Suzuki N, Takeda S, Yamamoto S, Hazama S, Hoshii Y, Oga A, Itoh H, Ueno T, Nagano H. High secreted protein acidic and rich in cysteine expression in peritumoral fibroblasts predicts better prognosis in patients with resectable gastric cancer. Oncol Lett 2017; 15:803-812. [PMID: 29403557 PMCID: PMC5780739 DOI: 10.3892/ol.2017.7418] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 09/22/2017] [Indexed: 02/06/2023] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein that may serve an important role in epithelial-mesenchymal transition. Recent studies have demonstrated that SPARC status is a prognostic indicator in various cancer types; however, its value remains unclear in gastric cancer (GC). In the present study, the localization and prognostic impact of SPARC expression were evaluated in patients with GC. Immunohistochemical analysis of SPARC expression was performed in 117 surgically resected GC specimens, and the localization of SPARC positive cells, as well as the rassociation between SPARC expression and clinicopathological characteristics were evaluated. High SPARC expression was observed in 47 cases; the glycoprotein was localized in the peritumoral fibroblasts, but was rarely observed in the cytoplasm of cancer cells. Heterogeneity of SPARC expression was observed in 52 cases. High stromal SPARC expression was identified to be an independent predictor of more favorable prognosis (overall survival and recurrence free survival) in all patients (P<0.001). On subgroup analysis, this association remained significant in patients who received adjuvant chemotherapy, but not in patients who did not (P<0.001). Stromal SPARC expression predicts better prognosis in GC patients who underwent curative resection; this appears to be associated with improved response to chemotherapy.
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Affiliation(s)
- Masao Nakajima
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Shigefumi Yoshino
- Oncology Center, Yamaguchi University Hospital, Yamaguchi 755-8505, Japan
| | - Shinsuke Kanekiyo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Noriko Maeda
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Kazuhiko Sakamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Ryoichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Nobuaki Suzuki
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Shigeru Takeda
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Shigeru Yamamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Shoichi Hazama
- Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan
| | - Yoshinobu Hoshii
- Department of Diagnostic Pathology, Yamaguchi University Hospital, Yamaguchi 755-8505, Japan
| | - Atsunori Oga
- Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Hiroshi Itoh
- Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Tomio Ueno
- Department of Surgery, Kawasaki Medical School, Okayama 701-0192, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
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25
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Liao X, Huang K, Huang R, Liu X, Han C, Yu L, Yu T, Yang C, Wang X, Peng T. Genome-scale analysis to identify prognostic markers in patients with early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy. Onco Targets Ther 2017; 10:4493-4506. [PMID: 28979141 PMCID: PMC5602474 DOI: 10.2147/ott.s142557] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Molecular analysis is a promising source of clinically useful prognostic biomarkers. The aim of this investigation was to identify prognostic biomarkers for patients with early-stage pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy. METHODS An RNA sequencing dataset of PDAC was obtained from The Cancer Genome Atlas. Survival analysis and weighted gene co-expression network analysis were used to investigate the prognostic markers of early-stage PDAC after pancreaticoduodenectomy. RESULTS Using whole genome expression level screening, we identified 1,238 markers that were related to the prognosis of PDAC after pancreaticoduodenectomy, and identified 9 hub genes (ARHGAP30, HCLS1, CD96, FAM78A, ARHGAP15, SLA2, CD247, GVINP1, and IL16) using the weighted gene co-expression network analysis approach. We also constructed a signature comprising the 9 hub genes and weighted by the regression coefficient derived from a multivariate Cox proportional hazards regression model to divide patients into a high-risk group, with increased risk of death, and a low-risk group, with significantly improved overall survival (adjusted P=0.026, adjusted HR =0.513, 95% CI =0.285-0.924). The prognostic signature of the 9 genes demonstrated good performance for predicting 1-year overall survival (area under the respective receiver operating characteristic curves =0.641). CONCLUSION Our results have provided a new prospect for prognostic biomarkers of PDAC after pancreaticoduodenectomy, and may have a value in clinical application.
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Affiliation(s)
- Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University
| | - Rui Huang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University.,Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University
| | - Long Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University
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26
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SPARC gene variants predict clinical outcome in locally advanced and metastatic pancreatic cancer patients. Med Oncol 2017; 34:136. [DOI: 10.1007/s12032-017-0993-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 07/01/2017] [Indexed: 01/09/2023]
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27
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Verdaguer H, Saurí T, Macarulla T. Predictive and prognostic biomarkers in personalized gastrointestinal cancer treatment. J Gastrointest Oncol 2017; 8:405-417. [PMID: 28736628 DOI: 10.21037/jgo.2016.11.15] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Biomarkers play an important role in the detection and management of cancer patients. In gastrointestinal cancer, there is increasing interest in their development and validation according to specific tumor type. Prognostic biomarkers enable identification of patients with a more aggressive tumor evolution, while predictive biomarkers permit the identification of patients with a higher probability of responding or not to a specific treatment. Several biomarkers are currently widely employed in gastrointestinal cancers. These include rat sarcoma-2 virus (RAS) which is used to identify colorectal cancer (CRC) patients who will not respond to anti-epidermal growth factor receptor (EGFR) agents, while in gastric cancer, anti-human epidermal growth factor receptor 2 (HER2) therapy has been shown to only be active in HER2-positive patients. In pancreatic cancer, BRCA is a tool used to differentiate patients who are likely to respond to platinum-based combination therapies and to benefit from poly (ADP-ribose) polymerase (PARP) inhibitors. This review provides an update of the main biomarkers currently used in colorectal, gastric and pancreatic cancers, and reviews those that are being developed.
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Affiliation(s)
- Helena Verdaguer
- Vall d'Hebrón University Hospital (HUVH) and Vall d'Hebrón Institute of Oncology (VHIO), Barcelona, Spain
| | - Tamara Saurí
- Vall d'Hebrón University Hospital (HUVH) and Vall d'Hebrón Institute of Oncology (VHIO), Barcelona, Spain
| | - Teresa Macarulla
- Vall d'Hebrón University Hospital (HUVH) and Vall d'Hebrón Institute of Oncology (VHIO), Barcelona, Spain
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28
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Impact of Secreted Protein Acidic and Rich in Cysteine (SPARC) Expression on Prognosis After Surgical Resection for Biliary Carcinoma. J Gastrointest Surg 2017; 21:990-999. [PMID: 28342122 DOI: 10.1007/s11605-017-3407-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 03/16/2017] [Indexed: 01/31/2023]
Abstract
BACKGROUND Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that influences chemotherapy effectiveness and prognosis. The aim of this study was to investigate whether SPARC expression correlates with the postoperative survival of patients treated with surgical resection for biliary carcinoma. METHODS SPARC expression in resected biliary carcinoma specimens was investigated immunohistochemically in 175 patients. The relationship between SPARC expression and prognosis after surgery was evaluated using univariate and multivariate analyses. RESULTS High SPARC expression in peritumoral stroma was found in 61 (35%) patients. In all patients, stromal SPARC expression was significantly associated with overall survival (OS) (P = 0.006). Multivariate analysis revealed that high stromal SPARC expression was an independent risk factor for poor OS (HR 1.81, P = 0.006). Moreover, high stromal SPARC expression was independently associated with poor prognosis in a subset of 118 patients treated with gemcitabine-based adjuvant chemotherapy (HR 2.04, P = 0.010) but not in the 57 patients who did not receive adjuvant chemotherapy (P = 0.21). CONCLUSIONS Stromal SPARC expression correlated with the prognosis of patients with resectable biliary carcinoma, and its significance was enhanced in patients treated with adjuvant gemcitabine-based chemotherapy.
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Yu XZ, Guo ZY, Di Y, Yang F, Ouyang Q, Fu DL, Jin C. 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] [MESH Headings] [Grants] [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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Affiliation(s)
- Xin-Zhe Yu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
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30
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Su JR, Kuai JH, Li YQ. Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression. World J Gastroenterol 2016; 22:10053-10063. [PMID: 28018113 PMCID: PMC5143752 DOI: 10.3748/wjg.v22.i45.10053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/07/2016] [Accepted: 10/26/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the influence of Smoc2 on hepatocellular carcinoma (HCC) cell proliferation and to find a possible new therapeutic target for preventing HCC progression. METHODS We detected expression of Smoc2 in HCC tissues and corresponding non-tumor liver (CNL) tissues using PCR, western blot, and immunohistochemistry methods. Subsequently, we down-regulated and up-regulated Smoc2 expression using siRNA and lentivirus transfection assay, respectively. Then, we identified the effect of Smoc2 on cell proliferation and cell cycle using CCK-8 and flow cytometry, respectively. The common cell growth signaling influenced by Smoc2 was detected by western blot assay. RESULTS The expression of Smoc2 was significantly higher in HCC tissues compared with CNL tissues. Overexpression of Smoc2 promoted HCC cell proliferation and cell cycle progression. Down-regulation of Smoc2 led to inhibition of cell proliferation and cell cycle progression. Smoc2 had positive effect on ERK and AKT signaling. CONCLUSION Smoc2 promotes the proliferation of HCC cells through accelerating cell cycle progression and might act as an anti-cancer therapeutic target in the future.
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31
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Impact of SPARC expression on outcome in patients with advanced pancreatic cancer not receiving nab-paclitaxel: a pooled analysis from prospective clinical and translational trials. Br J Cancer 2016; 115:1520-1529. [PMID: 27802454 PMCID: PMC5155356 DOI: 10.1038/bjc.2016.355] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 10/04/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Conflicting results on the role of secreted protein acidic and rich in cysteins (SPARC) expression have been reported in resected pancreatic ductal adenocarcinoma (PDAC), and its prognostic and/or predictive role in advanced PDAC (aPDAC) has not been extensively investigated yet. This study was designed to evaluate SPARC expression as a biomarker in aPDAC patients (pts) not receiving nab-paclitaxel. METHODS Using immunohistochemistry, we examined the stromal as well as the tumoral (i.e., cytoplasmic) SPARC expression in tumour tissue (primary tumours and metastases) of 134 aPDAC pts participating in completed prospective clinical and biomarker trials. The SPARC expression levels were correlated to the pts' clinicopathological parameters and survival times. RESULTS Sixty-seven per cent of the analysed tumours showed high stromal SPARC expression, which was not associated with overall survival (OS, median 9.1 vs 7.6 months, P=0.316). A positive cytoplasmic SPARC expression was detected in 55% of the tumours and correlated significantly with inferior progression-free survival (PFS, 6.2 vs 8.6 months, P=0.004) and OS (7.8 vs 8.4 months, P=0.032). This association was strongest for pts, where primary tumour tissue was examined (PFS: 6.7 vs 10.8 months, P=0.004; OS: 7.9 vs 11.9 months, P=0.030), whereas no significant correlation was detected for pts, where only metastatic tissue was available (PFS: 5.8 vs 6.6 months, P=0.502; OS: 7.0 vs 7.8 months, P=0.452). In pts receiving gemcitabine-based chemotherapy cytoplasmic SPARC expression was significantly associated with an inferior PFS and OS (PFS: 6.2 vs 9.2 months, P=0.002; OS 7.3 vs 9.9 months, P=0.012), whereas no such association was detected for stromal SPARC expression or for pts receiving fluoropyrimidine-based chemotherapy. CONCLUSION We identified cytoplasmic SPARC expression in the primary tumour as a biomarker associated with inferior PFS and OS in aPDAC. Cytoplasmic SPARC expression may furthermore act as a negative predictive biomarker in pts treated with gemcitabine-based chemotherapy.
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Can Molecular Biomarkers Change the Paradigm of Pancreatic Cancer Prognosis? BIOMED RESEARCH INTERNATIONAL 2016; 2016:4873089. [PMID: 27689078 PMCID: PMC5023838 DOI: 10.1155/2016/4873089] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/28/2016] [Accepted: 08/03/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal types of tumour, and its incidence is rising worldwide. Although survival can be improved when these tumours are detected at an early stage, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. The only prognostic biomarker approved by the FDA to date is carbohydrate antigen 19-9 (CA19-9); however, the specificity of this biomarker has been called into question, and diagnosis is usually based on clinical parameters. Tumour size, degree of differentiation, lymph node status, presence of distant metastasis at diagnosis, protein levels of KI-67 or C-reactive protein, and mutational status of P53, KRAS, or BRCA2 are the most useful biomarkers in clinical practice. In addition to these, recent translational research has provided evidence of new biomarkers based on different molecules involved in endoplasmic reticulum stress, epithelial-to-mesenchymal transition, and noncoding RNA panels, especially microRNAs and long noncoding RNAs. These new prospects open new paths to tumour detection using minimally or noninvasive techniques such as liquid biopsies. To find sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.
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Hsueh CT, Selim JH, Tsai JY, Hsueh CT. Nanovectors for anti-cancer drug delivery in the treatment of advanced pancreatic adenocarcinoma. World J Gastroenterol 2016; 22:7080-7090. [PMID: 27610018 PMCID: PMC4988316 DOI: 10.3748/wjg.v22.i31.7080] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/13/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovector-based anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma.
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Davis EJ, Zhao L, Lucas DR, Schuetze SM, Baker LH, Zalupski MM, Thomas D, Chugh R. SPARC expression in patients with high-risk localized soft tissue sarcoma treated on a randomized phase II trial of neo/adjuvant chemotherapy. BMC Cancer 2016; 16:663. [PMID: 27544129 PMCID: PMC4992190 DOI: 10.1186/s12885-016-2694-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 08/09/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Treatment for localized soft tissue sarcoma includes surgery and radiation, while the role of chemotherapy is controversial. Biomarkers that could predict therapeutic response or prognosticate overall survival (OS) are needed to define patients most likely to benefit from systemic treatment. Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that has been evaluated as a potential biomarker in numerous malignancies given its involvement in cell adhesion, proliferation, migration, and tissue remodeling. METHODS Using primary biopsy and resection specimens from patients with high-risk localized, soft tissue sarcoma treated on a neo/adjuvant chemotherapy study, SPARC expression was assessed and compared to patient and tumor characteristics, treatment, and outcomes. Survival functions were estimated using the Kaplan-Meier method and compared using the log-rank test. The Cox model was used for multivariate analysis. RESULTS Fifty patients had primary tumor specimens available. High, low, and no SPARC expression was found in 22, 13, and 15 patients, respectively. There was no significant difference in time to recurrence or OS between patients in these three groups. Comparing lack of SPARC expression with any SPARC expression, there was no significant difference in time to recurrence in patients without SPARC expression (n = 15) compared to patients with SPARC expression (n = 35). Likewise, there was no statistically significant difference in OS in patients without SPARC expression versus patients whose tumors expressed SPARC. CONCLUSIONS Although we did not find a statistically significant difference in time to recurrence and OS in patients with high-risk soft tissue sarcoma, we did identify a trend toward improved time to recurrence and OS in patients whose tumors lacked SPARC expression. However, SPARC did not demonstrate the ability to discern which high-risk patients may have a worse prognosis or greater benefit from chemotherapy. TRIAL REGISTRATION The trial was registered on September 13, 2005 with ClinicalTrials.gov, number https://clinicaltrials.gov/ct2/show/NCT00189137?term=sarcoma&id=NCT00189137&state1=NA%3AUS%3AMI&phase=1&rank=1 .
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Affiliation(s)
- Elizabeth J Davis
- Division of Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA. .,Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.
| | - Lili Zhao
- Department of Biostatistics, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - David R Lucas
- Department of Pathology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - Scott M Schuetze
- Division of Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - Laurence H Baker
- Division of Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - Mark M Zalupski
- Division of Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - Dafydd Thomas
- Department of Pathology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - Rashmi Chugh
- Division of Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
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Westphalen CB, Kruger S, Haas M, Heinemann V, Boeck S. Safety of palliative chemotherapy in advanced pancreatic cancer. Expert Opin Drug Saf 2016; 15:947-54. [PMID: 27070177 DOI: 10.1080/14740338.2016.1177510] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Pancreatic cancer is a major health burden. Currently, the majority of patients is diagnosed at advanced stages and thus qualifies for palliative chemotherapy. Gemcitabine monotherapy has been the gold standard for many years. Recently, more effective chemotherapeutic regimens have shown meaningful clinical activity in patients with metastatic pancreatic cancer. AREAS COVERED In this review we have aimed to give an overview on the treatment options for patients diagnosed with metastatic pancreatic cancer with an emphasis on the safety and toxicity of the applied regimens. We have conducted a pubmed search using the terms 'metastatic pancreatic cancer', 'palliative chemotherapy', 'safety' and 'toxicity'. Our special focus rested on randomized phase III trials to provide readers with the highest level of available evidence. EXPERT OPINION The emergence of new and more effective chemotherapy regimens gives clinicians more freedom in the treatment of metastatic pancreatic cancer. While being more effective, these regiments have a considerable degree of toxicity. Choosing the right treatment for any individual will be the next major challenge treating patients with pancreatic cancer.
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Affiliation(s)
- C Benedikt Westphalen
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Stephan Kruger
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Michael Haas
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Volker Heinemann
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Stefan Boeck
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
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36
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Nielsen MFB, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016; 22:2678-2700. [PMID: 26973408 PMCID: PMC4777992 DOI: 10.3748/wjg.v22.i9.2678] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/19/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and non-cellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a context-dependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.
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37
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Le N, Sund M, Vinci A. Prognostic and predictive markers in pancreatic adenocarcinoma. Dig Liver Dis 2016; 48:223-30. [PMID: 26769569 DOI: 10.1016/j.dld.2015.11.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 10/27/2015] [Accepted: 11/01/2015] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, despite improvements observed for many other solid tumours. Intensive research efforts have been undertaken during the last decades to discover new prognostic and treatment predictive biomarkers for pancreatic ductal adenocarcinoma. The mainstay of medical treatment for the disease has been the well-tolerated nucleoside analogue, gemcitabine. The only targeted agent currently used in pancreatic ductal adenocarcinoma patients is the epithelial growth factor receptor inhibitor erlotinib in combination with gemcitabine. Recently, treatment regimens such as a combination of fluorouracil-leucovorin-irinotecan-oxaliplatin (FOLFIRINOX) and the combination of nab-paclitaxel with gemcitabine have been introduced for metastatic pancreatic ductal adenocarcinoma. Although these treatment regimens significantly improve survival of patients, there are no good predictive biomarkers available that can be used to identify who would benefit most from them. Therefore, the search for predictive biomarkers that would facilitate personalization of chemotherapy is highly relevant.
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Affiliation(s)
- Nha Le
- Semmelweis University, Second Internal Medicine Department, Gastroenterology Division, Budapest, Hungary
| | - Malin Sund
- University of Umeå, Department of Surgical and Perioperative Sciences, Umeå, Sweden.
| | - Alessio Vinci
- University of Pavia, Department of Surgery, IRCCS S. Matteo University Hospital Foundation, Pavia, Italy
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Kao SC, Kirschner MB, Cooper WA, Tran T, Burgers S, Wright C, Korse T, van den Broek D, Edelman J, Vallely M, McCaughan B, Pavlakis N, Clarke S, Molloy MP, van Zandwijk N, Reid G. A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma. Br J Cancer 2016; 114:524-31. [PMID: 26889976 PMCID: PMC4782201 DOI: 10.1038/bjc.2015.470] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 10/26/2015] [Accepted: 11/19/2015] [Indexed: 12/29/2022] Open
Abstract
Background: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM). Methods: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts. Results: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC. Conclusions: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.
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Affiliation(s)
- Steven C Kao
- Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.,Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia.,Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
| | - Michaela B Kirschner
- Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia
| | - Wendy A Cooper
- Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.,Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.,University of Western Sydney, Sydney, NSW 2150, Australia
| | - Thang Tran
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
| | - Sjaak Burgers
- Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Casey Wright
- Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia
| | - Tiny Korse
- Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Daan van den Broek
- Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - James Edelman
- Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
| | - Michael Vallely
- Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.,Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.,Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia
| | - Brian McCaughan
- Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.,Sydney Cardiothoracic Surgeons, RPAH Medical Centre, Sydney, NSW 2050, Australia
| | - Nick Pavlakis
- Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.,Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia
| | - Stephen Clarke
- Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.,Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia
| | - Mark P Molloy
- Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109, Australia
| | - Nico van Zandwijk
- Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.,Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
| | - Glen Reid
- Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.,Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
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Viterbo D, Gausman V, Gonda T. Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy. World J Gastrointest Endosc 2016; 8:128-142. [PMID: 26862363 PMCID: PMC4734972 DOI: 10.4253/wjge.v8.i3.128] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/17/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are two malignancies that carry significant morbidity and mortality. The poor prognoses of these cancers are strongly related to lack of effective screening modalities as well as few therapeutic options. In this review, we highlight novel biomarkers that have the potential to be used as diagnostic, prognostic and predictive markers. The focus of this review is biomarkers that can be evaluated on endoscopically-obtained biopsies or brush specimens in the pre-operative setting. We also provide an overview of novel serum based markers in the early diagnosis of both PDAC and CCA. In pancreatic cancer, the emphasis is placed on prognostic and theranostic markers, whereas in CCA the utility of molecular markers in diagnosis and prognosis are highlighted.
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Conroy T, Bachet JB, Ayav A, Huguet F, Lambert A, Caramella C, Maréchal R, Van Laethem JL, Ducreux M. Current standards and new innovative approaches for treatment of pancreatic cancer. Eur J Cancer 2016; 57:10-22. [PMID: 26851397 DOI: 10.1016/j.ejca.2015.12.026] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 12/20/2015] [Accepted: 12/29/2015] [Indexed: 12/19/2022]
Abstract
Pancreatic adenocarcinoma remains a devastating disease with a 5-year survival rate not exceeding 6%. Treatment of this disease remains a major challenge. This article reviews the state-of-the-art in the management of this disease and the new innovative approaches that may help to accelerate progress in treating its victims. After careful pre-therapeutic evaluation, only 15-20% of patients diagnosed with a pancreatic cancer (PC) are eligible for upfront radical surgery. After R0 or R1 resection in such patients, evidence suggests a significantly positive impact on survival of adjuvant chemotherapy comprising 6 months of gemcitabine or fluorouracil/folinic acid. Delayed adjuvant chemoradiation is considered as an option in cases of positive margins. Borderline resectable pancreatic cancer (BRPC) is defined as a tumour involving the mesenteric vasculature to a limited extend. Resection of these tumours is technically feasible, yet runs the high risk of a R1 resection. Neoadjuvant treatment probably offers the best chance of achieving successful R0 resection and long-term survival, but the best treatment options should be determined in prospective randomised studies. Gemcitabine has for 15 years been the only validated therapy for advanced PC. Following decades of negative phase III studies, increasing evidence now suggests that further significant improvements to overall survival can be achieved via either Folfirinox or gemcitabine + nab-paclitaxel regimens. Progress in systemic therapy may improve the chances of resection in borderline resectable pancreatic cancer (BRPC) or locally advanced PC. This requires first enhancing knowledge of the genetic events driving carcinogenesis, which may then be translated into clinical studies.
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Affiliation(s)
- Thierry Conroy
- Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, 6 avenue de Bourgogne, CS 30519, 54519, Vandoeuvre-lès-Nancy, France.
| | - Jean-Baptiste Bachet
- Department of Hepato-Gastroenterology, Pitié-Salpétrière University Hospital, 47-83 boulevard de l'hôpital, 75651, Paris Cedex 13, France
| | - Ahmet Ayav
- Department of Surgery, Nancy University Hospital Lorraine and Lorraine University, rue du Morvan, 54511, Vandoeuvre-lès Nancy, France
| | - Florence Huguet
- Department of Radiation Therapy, Tenon Hospital, Paris Est University Hospitals, 4 rue de la Chine, 75020, Paris, France
| | - Aurélien Lambert
- Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, 6 avenue de Bourgogne, CS 30519, 54519, Vandoeuvre-lès-Nancy, France
| | - Caroline Caramella
- Gustave Roussy Cancer Campus Grand Paris, 114 rue Edouard-Vaillant, 94805, Villejuif Cedex, France
| | - Raphaël Maréchal
- Department of Gastroenterology, Erasme University Hospital-ULB-Brussels, Lennikstreet 808, 1070, Brussels, Belgium
| | - Jean-Luc Van Laethem
- Department of Gastroenterology, Erasme University Hospital-ULB-Brussels, Lennikstreet 808, 1070, Brussels, Belgium
| | - Michel Ducreux
- Gustave Roussy Cancer Campus Grand Paris, 114 rue Edouard-Vaillant, 94805, Villejuif Cedex, France
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Han W, Cao F, Chen MB, Lu RZ, Wang HB, Yu M, Shi CT, Ding HZ. Prognostic Value of SPARC in Patients with Pancreatic Cancer: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0145803. [PMID: 26731428 PMCID: PMC4701416 DOI: 10.1371/journal.pone.0145803] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 12/08/2015] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE There is a heated debate on whether the prognostic value of SPARC is favorable or unfavorable. Thus, we carried out a meta-analysis evaluating the relationship between SPARC expression and the prognosis of patients with pancreatic cancer. METHODS We searched PubMed, EMBASE and Web of Science for relevant articles. The pooled hazard ratios (HRs) and corresponding 95%CI of overall survival (OS) were calculated to evaluate the prognostic value of SPARC expression in patients with pancreatic cancer. We also performed subgroup analyses. RESULTS With 1623 patients pooled from 10 available studies, the incorporative HR showed an unfavorable prognosis of patients with pancreatic cancer in the multivariate analysis (HR = 1.55, 95%CI: 1.11-2.17, P = 0.01), but not in univariate analysis (HR = 1.41, 95%CI: 0.47-4.21, P = 0.54) and estimate (HR = 1.24, 95%CI: 0.72-2.13, P = 0.44). And this adverse impact could also be found in the subgroup analyses in multivariate analysis, especially in the stroma (HR = 1.53, 95%CI: 1.05-2.24, P = 0.03). However, the combined HR had the highly significant heterogeneity. No obvious publication bias was found. CONCLUSIONS SPARC might be an unfavorable indicator in patients with pancreatic cancer, especially in the stroma. More and further researches should be conducted to reveal the prognostic value of SPARC.
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Affiliation(s)
- Wei Han
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, P. R. China
| | - Fang Cao
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, P. R. China
| | - Min-bin Chen
- Department of Radiotherapy and Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, P. R. China
| | - Rong-zhu Lu
- Department of Preventive Medicine, School of Medicine, Jiangsu University, Zhenjiang Jiangsu, 212001, P. R. China
| | - Hua-bing Wang
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, P. R. China
| | - Min Yu
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, P. R. China
| | - Chun-tao Shi
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, P. R. China
| | - Hou-zhong Ding
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, P. R. China
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42
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Liou GY, Storz P. Strategies to Target Pancreatic Cancer. MOLECULAR TARGETS AND STRATEGIES IN CANCER PREVENTION 2016:1-20. [DOI: 10.1007/978-3-319-31254-5_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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43
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Ahn DH, Williams TM, Goldstein DA, El-Rayes B, Bekaii-Saab T. Adjuvant therapy for pancreas cancer in an era of value based cancer care. Cancer Treat Rev 2016; 42:10-7. [PMID: 26620819 PMCID: PMC4976619 DOI: 10.1016/j.ctrv.2015.11.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/08/2015] [Accepted: 11/12/2015] [Indexed: 12/16/2022]
Abstract
In resected pancreas cancer, adjuvant therapy improves outcomes and is considered the standard of care for patients who recover sufficiently post operatively. Chemotherapy or combined chemotherapy and radiation therapy (chemoradiation; CRT) are strategies used in the adjuvant setting. However, there is a lack of evidence to suggest whether the addition of RT to chemotherapy translates to an improvement in clinical outcomes. This is true even when accounting for the subset of patients with a higher risk for recurrence, such as those with R1 and lymph node positive disease. When considering the direct and indirect costs, impact on quality of life and questionable added clinical benefit, the true "net health benefit" from added RT to chemotherapy becomes more uncertain. Future directions, including the utilization of modern RT, integration of novel therapies, and intensifying chemotherapy regimens may improve outcomes in resected pancreas cancer.
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Affiliation(s)
- Daniel H Ahn
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States
| | - Terence M Williams
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States
| | - Daniel A Goldstein
- Winship Cancer Institute, Emory University, 1365-C Clifton Rd NE, Atlanta, GA, United States
| | - Bassel El-Rayes
- Winship Cancer Institute, Emory University, 1365-C Clifton Rd NE, Atlanta, GA, United States
| | - Tanios Bekaii-Saab
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States.
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Treatment regimens of classical and newer taxanes. Cancer Chemother Pharmacol 2015; 77:221-33. [PMID: 26589792 DOI: 10.1007/s00280-015-2893-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 10/19/2015] [Indexed: 10/22/2022]
Abstract
The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. The taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and a substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Still, the optimal dosing regimen (weekly vs 3 weekly) and optimal dose of the taxanes are controversial, as is the value of pharmacological personalization of taxane dosing. In this article, an overview is given on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen, the recommended initial dose and the issue of therapeutic drug dosing.
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Quel traitement adjuvant de l’adénocarcinome du pancréas aujourd’hui : quelles perspectives ? ONCOLOGIE 2015. [DOI: 10.1007/s10269-015-2558-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Grapsa D, Saif MW, Syrigos K. Targeted therapies for pancreatic adenocarcinoma: Where do we stand, how far can we go? World J Gastrointest Oncol 2015; 7:172-177. [PMID: 26483872 PMCID: PMC4606172 DOI: 10.4251/wjgo.v7.i10.172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/10/2015] [Accepted: 08/31/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic adenocarcinoma (usually referred to as pancreatic cancer) is a highly lethal and aggressive malignancy with a disease-related mortality almost equaling its incidence, and one of the most challenging cancers to treat. The notorious resistance of pancreatic cancer not only to conventional cytotoxic therapies but also to almost all targeted agents developed to date, continues to puzzle the oncological community and represents one of the biggest hurdles to reducing the death toll from this ominous disease. This editorial highlights the most important recent advances in preclinical and clinical research, with regards to targeted therapeutics for pancreatic cancer, outlines current challenges and provides an overview of potential future perspectives in this rapidly evolving field.
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Klein F, Bahra M, Schirmeier A, Al-Abadi H, Pratschke J, Pelzer U, Oettle H, Striefler J, Riess H, Sinn M. Prognostic significance of DNA cytometry for adjuvant therapy response in pancreatic cancer. J Surg Oncol 2015; 112:66-71. [PMID: 26193339 DOI: 10.1002/jso.23951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/30/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND OBJECTIVES The continuous progress in treatment options for pancreatic adenocarcinoma has lead to a re-evaluation of prognostic markers. In this study the prognostic relevance of DNA Index and classical histopathological parameters with regard to disease-free (DFS) and overall survival (OS) was analyzed within the CONKO-001 patient population. METHODS One hundred forty three fresh-frozen paraffin-embedded tissue samples of the resected tumor specimen of the CONKO-001 patient population were available for DNA index analysis to evaluate its impact on patient outcome. RESULTS Median DFS (7.3 vs. 14.3 months; P = 0.004) and median OS (16.6 vs. 29.2 months; P = 0.011) were significantly decreased in patients with a high DNA index (>1.4). Multivariate analysis revealed both DNA index (DFS: P = 0.002; OS: P = 0.019) and tumor grading (DFS: P = 0.004; OS: P = 0.004) as individual prognostic markers for DFS and OS. The following prognostic subgroups were identified: good (low DNA Index + G1/2 tumor grading), intermediate (low DNA Index + G3 tumor grading or high DNA Index + G1/2 tumor grading), poor (high DNA Index + G3 tumor grading). CONCLUSION The DNA index/tumor grading constellation may serve as a helpful guide for personalized treatment recommendations for adjuvant therapy of patients with pancreatic adenocarcinoma.
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Affiliation(s)
- Fritz Klein
- Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Marcus Bahra
- Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Anja Schirmeier
- Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hussein Al-Abadi
- Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Uwe Pelzer
- Department of Medical Oncology and Haematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Helmut Oettle
- Department of Outpatient, Medical Oncology, Friedrichshafen, Germany
| | - Jana Striefler
- Department of Medical Oncology and Haematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hanno Riess
- Department of Medical Oncology and Haematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Marianne Sinn
- Department of Medical Oncology and Haematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Bachet JB, Chibaudel B, Bonnetain F, Validire P, Hammel P, André T, Louvet C. A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial. BMC Cancer 2015; 15:653. [PMID: 26445094 PMCID: PMC4596389 DOI: 10.1186/s12885-015-1656-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 09/21/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC. METHODS/DESIGN AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m(2)) plus gemcitabine (1000 mg/m(2)) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m(2)) plus sLV5FU2 (leucovorin 400 mg/m(2) followed by bolus 400 mg/m(2) 5-fluorouracil and by 5-fluorouracil 2400 mg/m(2) as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed. DISCUSSION The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC. TRIAL REGISTRATION AFUGEM is registered at Clinicaltrials.gov: NCT01964534 , October 15, 2013.
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Affiliation(s)
- Jean-Baptiste Bachet
- Paris-Sorbonne University, UPMC University Paris 06, Paris, France.
- Department of hepatogastroenterology, Groupe hospitalier Pitié Salpêtrière, Paris, France.
| | | | - Franck Bonnetain
- Head of methodology and quality of life in oncology department, Hôpital Universitaire de Besancon, EA 3181, Besancon, France.
| | - Pierre Validire
- Department of pathology, Institut Mutualiste Montsouris, Paris, France.
| | - Pascal Hammel
- Department of digestive oncology, Hôpital Beaujon, Clichy, France.
| | - Thierry André
- Paris-Sorbonne University, UPMC University Paris 06, Paris, France.
- Department of oncology, Hôpital Saint Antoine, Paris, France.
| | - Christophe Louvet
- Department of oncology, Institut Mutualiste Montsouris, Paris, France.
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Maréchal R, Puleo F, Demols A, Verset G, Laethem JLV. Personalized medicine in pancreatic cancer: the revolution has begun. Per Med 2015; 12:515-523. [PMID: 29749894 DOI: 10.2217/pme.15.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Pancreatic ductal adenocarcinoma carries a dismal prognosis. Both chemotherapy and targeted therapies have been disappointing when administered to unselected populations. Recently, progress has been made in our understanding of the genomic landscape of this cancer which displays remarkable heterogeneity suggesting a reorientation of management and research strategies based on molecular characterization and adapted personalized therapy. Resectable disease offers new opportunities for translational research through functional imaging response evaluation and tumor tissue acquisition before and after neoadjuvant therapy. There is urgent need for clinical trials based on molecular profiling in pancreatic ductal adenocarcinoma. In this review we discuss opportunities and limitations of these new strategies, underlining the importance of tissue acquisition and integration of molecular biomarkers in future molecularly driven clinical trials.
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Affiliation(s)
- Raphaël Maréchal
- Department of Gastroenterology & Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium.,Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Belgium
| | - Francesco Puleo
- Department of Gastroenterology & Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium.,Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Belgium
| | - Anne Demols
- Department of Gastroenterology & Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Gontran Verset
- Department of Gastroenterology & Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Jean-Luc Van Laethem
- Department of Gastroenterology & Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
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50
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Graham JS, Jamieson NB, Rulach R, Grimmond SM, Chang DK, Biankin AV. Pancreatic cancer genomics: where can the science take us? Clin Genet 2015; 88:213-9. [PMID: 25388820 DOI: 10.1111/cge.12536] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 10/28/2014] [Accepted: 11/07/2014] [Indexed: 01/06/2023]
Abstract
The incidence of pancreatic ductal adenocarcinoma (PDAC) is steadily increasing and the annual death-to-incidence ratio approaches one. This is a figure that has not changed for several decades. Surgery remains the only chance of cure; however, only less than 20% of patients are amenable to operative resection. Despite successful surgical resection, the majority of the patients still succumb to recurrent metastatic disease. Therefore, there is an urgent need to develop novel therapeutic strategies and to better select patients for current therapies. In this review, we will discuss current management by highlighting the landmark clinical trials that have shaped current care. We will then discuss the challenges of therapeutic development using the current randomized-controlled trial paradigm when confronted with the molecular heterogeneity of PDAC. Finally, we will discuss strategies that may help to shape the management of PDAC in the near future.
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Affiliation(s)
- J S Graham
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - N B Jamieson
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, Glasgow, United Kingdom
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, University of Glasgow, Glasgow, United Kingdom
| | - R Rulach
- Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - S M Grimmond
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - D K Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
- Department of Surgery, Bankstown Hospital, Sydney, Australia
- St Vincent's Clinical School, Faculty of Medicine, Sydney, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - A V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
- Department of Surgery, Bankstown Hospital, Sydney, Australia
- St Vincent's Clinical School, Faculty of Medicine, Sydney, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
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