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Park SE, Hong TH. Establishment of an orthotopic nude mouse model for recurrent pancreatic cancer after complete resection: an experimental animal study. Ann Surg Treat Res 2025; 108:317-324. [PMID: 40352799 PMCID: PMC12059248 DOI: 10.4174/astr.2025.108.5.317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 05/14/2025] Open
Abstract
Purpose This study created a nude mouse model to study pancreatic cancer recurrence. Circumstances leading to the highest recurrence rates after curative surgery were also analyzed. Methods A total of 135 nude mice were divided into 3 groups: sham, metastasis, and resection (45 mice in each group). In sham and resection groups, AsPc-1 cells suspended in a synthetic extracellular matrix were injected into the tail of the pancreas of each mouse. In the metastasis group, cells were injected into the spleen. After 3 weeks, the resection group underwent distal pancreatectomy and the metastasis group underwent diagnostic laparotomy to confirm metastasis. To assess disease recurrence, the resection group was monitored weekly using luminescence imaging. Diagnostic exploration was conducted 3 weeks after surgery. Recurrence rate was evaluated and histological examination was performed for the resection group. Results Among 45 mice, 43 developed cancerous masses in the tail of the pancreas without invading adjacent organs 3 weeks after the initial orthotopic injection. Of those 43 mice, one died due to intraoperative bleeding during complete surgical resection. Pancreatic cancer recurrence was observed in 37 of 42 mice (88.1%) at an average of 21.8 ± 2.2 days. Histological examination showed high nuclear pleomorphism and neoangiogenesis. Conclusion We developed an efficient model that could demonstrate recurrence after complete resection of pancreatic cancer. By confirming that recurrence occurs after surgery using this protocol, our model is expected to contribute to the development of various treatment strategies.
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Affiliation(s)
- Sung Eun Park
- Division of Trauma and Surgical Critical Care, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Tae Ho Hong
- Division of Trauma and Surgical Critical Care, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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2
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Zhu M, Luo F, Xu B, Xu J. Research Progress of Neural Invasion in Pancreatic Cancer. Curr Cancer Drug Targets 2024; 24:397-410. [PMID: 37592782 DOI: 10.2174/1568009623666230817105221] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/13/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023]
Abstract
Pancreatic cancer is one of the highly malignant gastrointestinal tumors in humans, and patients suffer from cancer pain in the process of cancer. Most patients suffer from severe pain in the later stages of the disease. The latest studies have shown that the main cause of pain in patients with pancreatic cancer is neuroinflammation caused by tumor cells invading nerves and triggering neuropathic pain on this basis, which is believed to be the result of nerve invasion. Peripheral nerve invasion (PNI), defined as the presence of cancer cells along the nerve or in the epineurial, perineural, and endoneurial spaces of the nerve sheath, is a special way for cancer to spread to distant sites. However, due to limited clinical materials, the research on the mechanism of pancreatic cancer nerve invasion has not been carried out in depth. In addition, perineural invasion is considered to be one of the underlying causes of recurrence and metastasis after pancreatectomy and an independent predictor of prognosis. This article systematically reviewed the neural invasion of pancreatic cancer through bioinformatics analysis, clinical manifestations and literature reviews.
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Affiliation(s)
- Mengying Zhu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China
| | - Feng Luo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, China
| | - Bin Xu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, P.R. China
| | - Jian Xu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China
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3
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de Lima PO, Broit N, Huang JD, Lim JH, Gardiner DJ, Brown IS, Panizza BJ, Boyle GM, Simpson F. Development of an in vivo murine model of perineural invasion and spread of cutaneous squamous cell carcinoma of the head and neck. Front Oncol 2023; 13:1231104. [PMID: 37746297 PMCID: PMC10513369 DOI: 10.3389/fonc.2023.1231104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/06/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction Cutaneous squamous cell carcinoma of the head and neck (cSCCHN) can metastasize by invading nerves and spread toward the central nervous system. This metastatic process is called perineural invasion (PNI) and spread (PNS). An in vivo sciatic nerve mouse model is used for cSCCHN PNI/PNS. Here we describe a complementary whisker pad model which allows for molecular studies investigating drivers of PNI/PNS in the head and neck environment. Methods A431 cells were injected into the whisker pads of BALB/c Foxn1nu and NSG-A2 mice. Tumor progression was monitored by bioluminescence imaging and primary tumor resection was performed. PNI was detected by H&E and IHC. Tumor growth and PNI were assessed with inducible ablation of LOXL2. Results The rate of PNI development in mice was 10%-28.6%. Tumors exhibited PNI/PNS reminiscent of the morphology seen in the human disease. Our model's utility was demonstrated with inducible ablation of LOXL2 reducing primary tumor growth and PNI. Discussion This model consists in a feasible way to test molecular characteristics and potential therapies, offers to close a gap in the described in vivo methods for PNI/PNS of cSCCHN and has uses in concert with the established sciatic nerve model.
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Affiliation(s)
| | - Natasa Broit
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Johnson D. Huang
- Frazer Institute, University of Queensland, Brisbane, QLD, Australia
| | - Jae H. Lim
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Damien J. Gardiner
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Ian S. Brown
- Envoi Pathology, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Benedict J. Panizza
- Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
- Department of Otolaryngology-Head and Neck Surgery, Kaiser Moanalua Medical Center, Honolulu, HI, United States
| | - Glen M. Boyle
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Fiona Simpson
- Frazer Institute, University of Queensland, Brisbane, QLD, Australia
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Zhang Q, Xia F, Sun Q, Cao W, Mo A, He W, Chen J, Zhang W, Chen W. Recurrence and Prognostic Value of Circulating Tumor Cells in Resectable Pancreatic Head Cancer: A Single Center Retrospective Study. Front Surg 2022; 9:832125. [PMID: 35465422 PMCID: PMC9019076 DOI: 10.3389/fsurg.2022.832125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 03/15/2022] [Indexed: 02/04/2023] Open
Abstract
Background and Aim To investigate the effect of preoperative circulation tumor cells (CTCs) on postoperative recurrence and overall survival prognosis of pancreatic head cancer after pancreaticoduodenectomy (PD). Methods From March 2014 to January 2018, 73 patients with pancreatic head cancer underwent radical resection (R0) in Zhongshan People's Hospital. CTCs in peripheral blood of patients with pancreatic head cancer were detected by “Cyttel” method before PD. Seventy-three patients were divided into positive and negative groups according to the positive criteria. To explore the relationship between the clinical data of CTCs and disease-free survival (DFS) and overall survival (OS). Cox proportional hazards model was used to analyzing the risk factors affecting the postoperative recurrence and the survival prognosis of patients. Results 41 patients (56.2%) were in the CTC-positive group. Preoperative CTCs were correlated with tumor vascular invasion, CA199 level and postoperative liver metastasis (P < 0.05). Preoperative CTC-positive, lymph node metastasis, vascular invasion, and nerve invasion were independent risk factors for DFS (P < 0.05). Preoperative CTC-positive, tumor diameter > 2 cm and vascular invasion were independent risk factors for OS of patients (P < 0.05). Conclusion The detection of CTCs before PD is an important factor affecting the DFS and OS of pancreatic head cancer, which is significant in guiding clinical work.
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Affiliation(s)
- Qiao Zhang
- Guangdong Medical College, Zhanjiang, China
| | - Feng Xia
- Department of Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Qiang Sun
- Department of Hepatobiliary Surgery, Zhongshan Hospital Affiliated to Sun Yat-sen University, Zhongshan, China
| | - Wenjing Cao
- Southern Medical University Graduate School, Guangzhou, China
| | - Ali Mo
- Guangdong Medical College, Zhanjiang, China
| | - Weiming He
- Guangdong Medical College, Zhanjiang, China
| | | | | | - Weiqiang Chen
- Guangdong Medical College, Zhanjiang, China
- *Correspondence: Weiqiang Chen
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Smith JJ, Xiao Y, Parsan N, Medwig-Kinney TN, Martinez MAQ, Moore FEQ, Palmisano NJ, Kohrman AQ, Chandhok Delos Reyes M, Adikes RC, Liu S, Bracht SA, Zhang W, Wen K, Kratsios P, Matus DQ. The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo. PLoS Genet 2022; 18:e1009981. [PMID: 34982771 PMCID: PMC8759636 DOI: 10.1371/journal.pgen.1009981] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 01/14/2022] [Accepted: 12/07/2021] [Indexed: 12/15/2022] Open
Abstract
Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and chromatin regulating factors that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis. Cellular invasion is required for animal development and homeostasis. Inappropriate activation of invasion however can result in cancer metastasis. Invasion programs are orchestrated by complex gene regulatory networks (GRN) that function in a coordinated fashion to turn on and off pro-invasive genes. While the core of GRNs are DNA binding transcription factors, they require aid from chromatin remodelers to access the genome. To identify the suite of pro-invasive chromatin remodelers, we paired high resolution imaging with RNA interference to individually knockdown 269 chromatin factors, identifying the evolutionarily conserved SWItching defective/Sucrose Non-Fermenting (SWI/SNF) ATP-dependent chromatin remodeling complex as a new regulator of Caenorhabditis elegans anchor cell (AC) invasion. Using a combination of CRISPR/Cas9 genome engineering and targeted protein degradation we demonstrate that the core SWI/SNF complex functions in a dose-dependent manner to control invasion. Further, we determine that the accessory SWI/SNF complexes, BAF and PBAF, contribute to invasion via distinctive mechanisms: BAF is required to prevent inappropriate proliferation while PBAF promotes AC attachment and remodeling of the basement membrane. Together, our data provide insights into how the SWI/SNF complex, which is mutated in many human cancers, can function in a dose-dependent fashion to regulate switching from invasive to proliferative fates.
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Affiliation(s)
- Jayson J. Smith
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Yutong Xiao
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Nithin Parsan
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
- Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Taylor N. Medwig-Kinney
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Michael A. Q. Martinez
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Frances E. Q. Moore
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Nicholas J. Palmisano
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Abraham Q. Kohrman
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America
| | - Mana Chandhok Delos Reyes
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Rebecca C. Adikes
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
- Biology Department, Siena College, Loudonville, New York, United States of America
| | - Simeiyun Liu
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
- Molecular, Cellular and Developmental Biology, University of California Santa Cruz, Santa Cruz, California, United States of America
| | - Sydney A. Bracht
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
- Department of Cell Biology, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Wan Zhang
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
| | - Kailong Wen
- The Grossman Institute for Neuroscience, Quantitative Biology, and Human Behavior, University of Chicago, Chicago, Illinois, United States of America
- Department of Neurobiology, University of Chicago, Chicago, Illinois, United States of America
| | - Paschalis Kratsios
- The Grossman Institute for Neuroscience, Quantitative Biology, and Human Behavior, University of Chicago, Chicago, Illinois, United States of America
- Department of Neurobiology, University of Chicago, Chicago, Illinois, United States of America
| | - David Q. Matus
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America
- * E-mail:
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Micheletti L, Borella F, Preti M, Frau V, Cosma S, Privitera S, Bertero L, Benedetto C. Perineural Invasion in Vulvar Squamous-Cell Carcinoma Is an Independent Risk Factor for Cancer-Specific Survival, but Not for Locoregional Recurrence: Results from a Single Tertiary Referral Center. Cancers (Basel) 2021; 14:cancers14010124. [PMID: 35008288 PMCID: PMC8750970 DOI: 10.3390/cancers14010124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Vulvar squamous cell carcinoma is a rare tumor but represents a serious health issue, especially due to the increasing incidence over the past decades. Many efforts have been made to identify new prognostic and therapeutic factors and, in this context, growing evidence concerning a pivotal role of perineural invasion. With this study, we investigated the role of perineural invasion in a large cohort of FIGO stage Ib-IIIc vulvar squamous cell carcinomas and found that perineural invasion-positive tumors have more aggressive biological behaviors and showed reduced cancer-specific survival as compared to perineural invasion-negative tumors, while this feature does not appear to be related to a greater risk to develop loco-regional recurrence. Further evaluations are warranted to confirm the prognostic role of perineural invasion and its potential use to tailor adjuvant treatment. Abstract The aims of this study were to assess the prevalence of perineural invasion (PNI) in vulvar squamous cell carcinoma (VSCC) and its prognostic role in locoregional recurrence (LRR) and cancer-specific survival (CSS). We performed a retrospective analysis of 223 consecutive stage IB–IIIC surgically treated VSCCs at S. Anna Hospital, University of Turin, from 2000 to 2019. We identified 133/223 (59.6%) patients with PNI-positive VSCCs. PNI was associated with aggressive biological features (i.e., advanced FIGO stage, larger tumor diameter, greater depth of invasion, a higher number of metastatic lymph nodes, and lymphovascular invasion) and shorter 5-year CSS (78% vs. 90%, log-rank p = 0.02) compared with PNI-negative VSCCs. Multivariate analysis showed that PNI (HR 2.99 CI 95% 1.17–7.63; p = 0.02) and the presence of tumor cells on pathological surgical margins (HR 3.13 CI 95% 1.37–7.13; p = 0.007) are independent prognostic factors for CSS. PNI does not appear to be related to LRR, but is an independent prognostic factor for worse survival outcomes. Future studies are necessary to explore the possible value of PNI in tailoring the choice of adjuvant treatment.
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Affiliation(s)
- Leonardo Micheletti
- Division of Gynecology and Obstetrics 1, Department of Surgical Sciences, City of Health and Science University Hospital, University of Turin, 10126 Turin, Italy; (L.M.); (M.P.); (V.F.); (S.C.); (C.B.)
| | - Fulvio Borella
- Division of Gynecology and Obstetrics 1, Department of Surgical Sciences, City of Health and Science University Hospital, University of Turin, 10126 Turin, Italy; (L.M.); (M.P.); (V.F.); (S.C.); (C.B.)
- Correspondence: ; Tel.: +39-34-7047-2715
| | - Mario Preti
- Division of Gynecology and Obstetrics 1, Department of Surgical Sciences, City of Health and Science University Hospital, University of Turin, 10126 Turin, Italy; (L.M.); (M.P.); (V.F.); (S.C.); (C.B.)
| | - Valentina Frau
- Division of Gynecology and Obstetrics 1, Department of Surgical Sciences, City of Health and Science University Hospital, University of Turin, 10126 Turin, Italy; (L.M.); (M.P.); (V.F.); (S.C.); (C.B.)
| | - Stefano Cosma
- Division of Gynecology and Obstetrics 1, Department of Surgical Sciences, City of Health and Science University Hospital, University of Turin, 10126 Turin, Italy; (L.M.); (M.P.); (V.F.); (S.C.); (C.B.)
| | - Sebastiana Privitera
- Pathology Unit, Department of Medical Science, University of Turin, 10126 Turin, Italy; (S.P.); (L.B.)
| | - Luca Bertero
- Pathology Unit, Department of Medical Science, University of Turin, 10126 Turin, Italy; (S.P.); (L.B.)
| | - Chiara Benedetto
- Division of Gynecology and Obstetrics 1, Department of Surgical Sciences, City of Health and Science University Hospital, University of Turin, 10126 Turin, Italy; (L.M.); (M.P.); (V.F.); (S.C.); (C.B.)
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7
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Abstract
Although pancreatic cancer remains to be a leading cause of cancer-related deaths in many industrialized countries, there have been major advances in research over the past two decades that provided a detailed insight into the molecular and developmental processes that govern the genesis of this highly malignant tumor type. There is a continuous need for the development and analysis of preclinical and genetically engineered pancreatic cancer models to study the biological significance of new molecular targets that are identified using various genome-wide approaches and to better understand the mechanisms by which they contribute to pancreatic cancer onset and progression. Following an introduction into the etiology of pancreatic cancer, the molecular subtypes, and key signaling pathways, this review provides an overview of the broad spectrum of models for pancreatic cancer research. In addition to conventional and patient-derived xenografting, this review highlights major milestones in the development of chemical carcinogen-induced and genetically engineered animal models to study pancreatic cancer. Particular emphasis was placed on selected research findings of ligand-controlled tumor models and current efforts to develop genetically engineered strains to gain insight into the biological functions of genes at defined developmental stages during cancer initiation and metastatic progression.
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Mallya K, Gautam SK, Aithal A, Batra SK, Jain M. Modeling pancreatic cancer in mice for experimental therapeutics. Biochim Biophys Acta Rev Cancer 2021; 1876:188554. [PMID: 33945847 DOI: 10.1016/j.bbcan.2021.188554] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/19/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy that is characterized by early metastasis, low resectability, high recurrence, and therapy resistance. The experimental mouse models have played a central role in understanding the pathobiology of PDAC and in the preclinical evaluation of various therapeutic modalities. Different mouse models with targetable pathological hallmarks have been developed and employed to address the unique challenges associated with PDAC progression, metastasis, and stromal heterogeneity. Over the years, mouse models have evolved from simple cell line-based heterotopic and orthotopic xenografts in immunocompromised mice to more complex and realistic genetically engineered mouse models (GEMMs) involving multi-gene manipulations. The GEMMs, mostly driven by KRAS mutation(s), have been widely accepted for therapeutic optimization due to their high penetrance and ability to recapitulate the histological, molecular, and pathological hallmarks of human PDAC, including comparable precursor lesions, extensive metastasis, desmoplasia, perineural invasion, and immunosuppressive tumor microenvironment. Advanced GEMMs modified to express fluorescent proteins have allowed cell lineage tracing to provide novel insights and a new understanding about the origin and contribution of various cell types in PDAC pathobiology. The syngeneic mouse models, GEMMs, and target-specific transgenic mice have been extensively used to evaluate immunotherapies and study therapy-induced immune modulation in PDAC yielding meaningful results to guide various clinical trials. The emerging mouse models for parabiosis, hepatic metastasis, cachexia, and image-guided implantation, are increasingly appreciated for their high translational significance. In this article, we describe the contribution of various experimental mouse models to the current understanding of PDAC pathobiology and their utility in evaluating and optimizing therapeutic modalities for this lethal malignancy.
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Affiliation(s)
- Kavita Mallya
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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9
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Lohse I, Brothers SP. Pathogenesis and Treatment of Pancreatic Cancer Related Pain. Anticancer Res 2020; 40:1789-1796. [PMID: 32234867 DOI: 10.21873/anticanres.14133] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/18/2020] [Accepted: 02/19/2020] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer is often diagnosed due to the patient seeking medical attention for abdominal pain. It is among the most painful cancers, with pain severity strongly correlating with prognosis. Perineural invasion is a prominent feature of pancreatic cancer and often the first route of metastasis resulting in neuropathic pain. While surgical pain is present, it is generally short-lived; chemo- and radio-therapy associated side effect pain is often longer lasting and more difficult to manage. Treatment-induced mucositis in response to chemotherapy occurs throughout the GI tract resulting in infection-prone ulcers on the lip, buccal mucosa, palate or tongue. Cisplatin treatment is associated with axonal neuropathy in the dorsal root ganglion, although other large sensory fibers can be affected. Opioid-induced hyperalgesia can also emerge in patients. Along with traditional means to address pain, neurolytic celiac plexus block of afferent nociceptive fibers has been reported to be effective in 74% of patients. Moreover, as cancer treatments become more effective and result in improved survival, treatment-related side effects become more prevalent. Here, pancreatic cancer and treatment associated pain are reviewed along with current treatment strategies. Potential future therapeutic strategies to target the pathophysiology underlying pancreatic cancer and pain induction are also presented.
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Affiliation(s)
- Ines Lohse
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, U.S.A.,Department of Psychiatry and Behavioral Sciences, University of Miami, FL, U.S.A.,Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, FL, U.S.A
| | - Shaun P Brothers
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, U.S.A. .,Department of Psychiatry and Behavioral Sciences, University of Miami, FL, U.S.A.,Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, FL, U.S.A
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10
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Kong K, Guo M, Liu Y, Zheng J. Progress in Animal Models of Pancreatic Ductal Adenocarcinoma. J Cancer 2020; 11:1555-1567. [PMID: 32047562 PMCID: PMC6995380 DOI: 10.7150/jca.37529] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/10/2019] [Indexed: 12/22/2022] Open
Abstract
As a common gastrointestinal tumor, the incidence of pancreatic cancer has been increasing in recent years. The disease shows multi-gene, multi-step complex evolution from occurrence to dissemination. Furthermore, pancreatic cancer has an insidious onset and an extremely poor prognosis, so it is difficult to obtain cinical specimens at different stages of the disease, and it is, therefore, difficult to observe tumorigenesis and tumor development in patients with pancreatic cancer. At present, no standard protocols stipulate clinical treatment of pancreatic cancer, and the benefit rate of new targeted therapies is low. For this reason, a well-established preclinical model of pancreatic cancer must be established to allow further exploration of the occurrence, development, invasion, and metastasis mechanism of pancreatic cancer, as well as to facilitate research into new therapeutic targets. A large number of animal models of pancreatic cancer are currently available, including a cancer cell line-based xenograft, a patient-derived xenograft, several mouse models (including transgenic mice), and organoid models. These models have their own characteristics, but they still cannot perfectly predict the clinical outcome of the new treatment. In this paper, we present the distinctive features of the currently popular pancreatic cancer models, and discuss their preparation methods, clinical relations, scientific purposes and limitations.
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Affiliation(s)
- Kaiwen Kong
- Pathology Department of Changhai Hospital, Second Military Medical University
| | - Meng Guo
- Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China; National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University
| | - Yanfang Liu
- Pathology Department of Changhai Hospital, Second Military Medical University; National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University
| | - Jianming Zheng
- Pathology Department of Changhai Hospital, Second Military Medical University
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11
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Gasparini G, Pellegatta M, Crippa S, Lena MS, Belfiori G, Doglioni C, Taveggia C, Falconi M. Nerves and Pancreatic Cancer: New Insights into a Dangerous Relationship. Cancers (Basel) 2019; 11:E893. [PMID: 31248001 PMCID: PMC6678884 DOI: 10.3390/cancers11070893] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer-particularly in pancreatic ductal adenocarcinoma (PDAC)-PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously ("present" or "absent"). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.
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Affiliation(s)
- Giulia Gasparini
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Marta Pellegatta
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Stefano Crippa
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
| | - Marco Schiavo Lena
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Giulio Belfiori
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Claudio Doglioni
- Vita Salute San Raffaele University, 20132 Milan, Italy.
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Carla Taveggia
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Massimo Falconi
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
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12
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Deborde S, Yu Y, Marcadis A, Chen CH, Fan N, Bakst RL, Wong RJ. An In Vivo Murine Sciatic Nerve Model of Perineural Invasion. J Vis Exp 2018. [PMID: 29733315 DOI: 10.3791/56857] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Cancer cells invade nerves through a process termed perineural invasion (PNI), in which cancer cells proliferate and migrate in the nerve microenvironment. This type of invasion is exhibited by a variety of cancer types, and very frequently is found in pancreatic cancer. The microscopic size of nerve fibers within mouse pancreas renders the study of PNI difficult in orthotopic murine models. Here, we describe a heterotopic in vivo model of PNI, where we inject syngeneic pancreatic cancer cell line Panc02-H7 into the murine sciatic nerve. In this model, sciatic nerves of anesthetized mice are exposed and injected with cancer cells. The cancer cells invade in the nerves proximally toward the spinal cord from the point of injection. The invaded sciatic nerves are then extracted and processed with OCT for frozen sectioning. H&E and immunofluorescence staining of these sections allow quantification of both the degree of invasion and changes in protein expression. This model can be applied to a variety of studies on PNI given its versatility. Using mice with different genetic modifications and/or different types of cancer cells allows for investigation of the cellular and molecular mechanisms of PNI and for different cancer types. Furthermore, the effects of therapeutic agents on nerve invasion can be studied by applying treatment to these mice.
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Affiliation(s)
- Sylvie Deborde
- Department of Surgery, Memorial Sloan Kettering Cancer Center;
| | - Yasong Yu
- Department of Surgery, Memorial Sloan Kettering Cancer Center
| | - Andrea Marcadis
- Department of Surgery, Memorial Sloan Kettering Cancer Center
| | - Chun-Hao Chen
- Department of Surgery, Memorial Sloan Kettering Cancer Center
| | - Ning Fan
- Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center
| | | | - Richard J Wong
- Department of Surgery, Memorial Sloan Kettering Cancer Center
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13
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Wei WF, Han LF, Liu D, Wu LF, Chen XJ, Yi HY, Wu XG, Zhong M, Yu YH, Liang L, Wang W. Orthotopic Xenograft Mouse Model of Cervical Cancer for Studying the Role of MicroRNA-21 in Promoting Lymph Node Metastasis. Int J Gynecol Cancer 2017; 27:1587-1595. [PMID: 28945212 DOI: 10.1097/igc.0000000000001059] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cervical cancer is the most frequent cause of gynecologic cancer-associated death worldwide. Animal models that demonstrate metastatic patterns consistent with the clinical course of cervical cancer are urgently needed to conduct studies focused on understanding the mechanisms of the disease and identifying optimal treatments. To address this, we established an orthotopic xenograft model of cervical cancer in female NOD-SCID mice using SiHa and ME180 cell lines stably expressing green fluorescent protein to evaluate the role of microRNA-21 (miR-21) in spontaneous lymph node metastasis in vivo. In this case, SiHa and ME180 cells were transduced by lentivirus to stably express green fluorescent protein and miR-21. Overexpression of miR-21 promoted proliferation, migration, and invasion of SiHa and ME180 cells in vitro. Finally, an orthotopic xenograft model of human cervical cancer was successfully established in NOD-SCID mice. Using this model, we confirmed that overexpression of miR-21 resulted in an increase in the size of primary tumors and in the frequency of spontaneous lymph node metastasis at the time of excision. Therefore, the use of the orthotopic xenograft model should allow for the investigation of novel factors that affect metastasis of cervical cancer and presents an opportunity to evaluate potential therapeutic agents that may inhibit the spread of the disease.
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Affiliation(s)
- Wen-Fei Wei
- *Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong; †Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai; ‡Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan; and §Department of Obstetrics and Gynecology, Third Affiliated Hospital, and ∥Department of Pathology, Nanfang Hospital, Southern Medical University; and ¶Department of Obstetrics and Gynecology, Shenzhen Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
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Wang H, Cai J, Du S, Guo Z, Xin B, Wang J, Wei W, Shen X. Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF-κB cascade in pancreatic cancer cells. Cell Biochem Funct 2017; 35:315-326. [PMID: 28845524 DOI: 10.1002/cbf.3278] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/23/2017] [Accepted: 07/03/2017] [Indexed: 12/27/2022]
Abstract
Fractalkine (FKN, CX3CL1) is highly expressed in a majority of malignant solid tumours. Fractalkine is the only known ligand for CX3CR1. In this study, we performed an analysis to determine the effects of fractalkine/CX3CR1 on modulating apoptosis and explored the related mechanisms. The expression of fractalkine/CX3CR1 was detected by immunohistochemistry and western blotting. The levels of AKT/p-AKT, BCL-xl, and BCL-2 were detected by western blotting. Then, the effects of exogenous and endogenous fractalkine on the regulation of tumour apoptosis and proliferation were investigated. The mechanism of fractalkine/CX3CR1 on modulating apoptosis in cancer cells through the activation of AKT/NF-κB/p65 signals was evaluated. The effect of fractalkine on regulating cell cycle distribution was also tested. Fractalkine, AKT/p-AKT, and apoptotic regulatory proteins BCL-xl and BCL-2 were highly expressed in human pancreatic cancer tissues. In vitro, fractalkine/CX3CR1 promoted proliferation and mediated resistance to apoptosis in pancreatic cancer cells. The antiapoptotic effect of fractalkine was induced by the activation of AKT/NF-κB/p65 signalling in pancreatic cancer cells. The NF-κB/p65 contributes to promote the expressions of BCL-xl and BCL-2 and reduce caspase activity, thereby inhibiting apoptotic processes. Treatment with fractalkine resulted in the enrichment of pancreatic cancer cells in S phase with a concomitant decrease in the number of cells in G1 phase. The present study demonstrated the function of fractalkine in the activation of the AKT/NF-κB/p65 signalling cascade and mediation of apoptosis resistance in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as a diagnostic marker and as a potential target for chemotherapy in early stage pancreatic cancer. Pancreatic cancer is characterized by local recurrence, neural invasion, or distant metastasis. The present study demonstrated the overexpression of fractalkine/CX3CR1 in pancreatic cancer tissues, indicating its important role in the tumourigenesis of pancreatic cancer, and suggested that the overexpression of fractalkine/CX3CR1 could serve as a diagnostic marker for pancreatic cancer. Moreover, we reveal the mechanism that fractalkine functions on the activation of the AKT/NF-κB/p65 signalling cascade and regulation of the antiapoptosis process in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as an effective therapeutic target of chemotherapeutic and biologic agents in early stage pancreatic cancer.
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Affiliation(s)
- Hui Wang
- School of Medicine, Nankai University, Tianjin, China
| | - Jun Cai
- School of Medicine, Nankai University, Tianjin, China
| | - Shaoxia Du
- School of Medicine, Nankai University, Tianjin, China
| | - Zhongkui Guo
- School of Medicine, Nankai University, Tianjin, China
| | - Beibei Xin
- School of Medicine, Nankai University, Tianjin, China
| | - Juan Wang
- School of Medicine, Nankai University, Tianjin, China
| | - Wei Wei
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiaohong Shen
- School of Medicine, Nankai University, Tianjin, China
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Abstract
Recent studies have demonstrated a critical role for nerves in enabling tumor progression. The association of nerves with cancer cells is well established for a variety of malignant tumors, including pancreatic, prostate and the head and neck cancers. This association is often correlated with poor prognosis. A strong partnership between cancer cells and nerve cells leads to both cancer progression and expansion of the nerve network. This relationship is supported by molecular pathways related to nerve growth and repair. Peripheral nerves form complex tumor microenvironments, which are made of several cell types including Schwann cells. Recent studies have revealed that Schwann cells enable cancer progression by adopting a de-differentiated phenotype, similar to the Schwann cell response to nerve trauma. A detailed understanding of the molecular and cellular mechanisms involved in the regulation of cancer progression by the nerves is essential to design strategies to inhibit tumor progression.
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16
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Rossini Z, Pessina F. Perineural Spread or Neural Tropism? Discussion of a Paper and Description of an Unusual Case of Cervical Intradural Extramedullary Dumbbell Metastasis from Renal Cell Carcinoma. World Neurosurg 2017; 100:696-698. [PMID: 28437878 DOI: 10.1016/j.wneu.2016.11.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 11/01/2016] [Indexed: 11/18/2022]
Affiliation(s)
- Zefferino Rossini
- Division of Neurosurgical Oncology, Humanitas Research Hospital, Rozzano, Milan, Italy; Division of Neurosurgery, Università degli Studi di Milano, Milan, Italy.
| | - Federico Pessina
- Division of Neurosurgery, Università degli Studi di Milano, Milan, Italy
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17
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Lu Z, Dong TH, Si PR, Shen W, Bi YL, Min M, Chen X, Liu Y. Continuous Low-dose-rate Irradiation of Iodine-125 Seeds Inhibiting Perineural Invasion in Pancreatic Cancer. Chin Med J (Engl) 2017; 129:2460-2468. [PMID: 27748339 PMCID: PMC5072259 DOI: 10.4103/0366-6999.191777] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: Perineural invasion (PNI) is a histopathological characteristic of pancreatic cancer (PanCa). The aim of this study was to observe the treatment effect of continuous low-dose-rate (CLDR) irradiation to PNI and assess the PNI-related pain relief caused by iodine-125 (125I) seed implantation. Methods: The in vitro PNI model established by co-culture with dorsal root ganglion (DRG) and cancer cells was interfered under 2 and 4 Gy of 125I seeds CLDR irradiation. The orthotopic models of PNI were established, and 125I seeds were implanted in tumor. The PNI-related molecules were analyzed. In 30 patients with panCa, the pain relief was assessed using a visual analog scale (VAS). Pain intensity was measured before and 1 week, 2 weeks, and 1, 3, and 6 months after 125I seed implantation. Results: The co-culture of DRG and PanCa cells could promote the growth of PanCa cells and DRG neurites. In co-culture groups, the increased number of DRG neurites and pancreatic cells in radiation group was significantly less. In orthotopic models, the PNI-positive rate in radiation and control group was 3/11 and 7/11; meanwhile, the degrees of PNI between radiation and control groups was significant difference (P < 0.05). At week 2, the mean VAS pain score in patients decreased by 50% and significantly improved than the score at baseline (P < 0.05). The pain scores were lower in all patients, and the pain-relieving effect was retained about 3 months. Conclusions: The CLDR irradiation could inhibit PNI of PanCa with the value of further study. The CLDR irradiation could do great favor in preventing local recurrence and alleviating pain.
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Affiliation(s)
- Zheng Lu
- Liver Cirrhosis Diagnosis and Therapy Center, 302 Hospital of People's Liberation Army, Beijing 100039, China
| | - Teng-Hui Dong
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Pei-Ren Si
- Department of Gastroenterology and Hepatology, 107 Hospital of People's Liberation Army, Yantai, Shandong 264002, China
| | - Wei Shen
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Yi-Liang Bi
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Min Min
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143-0912, USA
| | - Yan Liu
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
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18
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19
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Lahoud MJ, Kourie HR, Antoun J, El Osta L, Ghosn M. Road map for pain management in pancreatic cancer: A review. World J Gastrointest Oncol 2016; 8:599-606. [PMID: 27574552 PMCID: PMC4980650 DOI: 10.4251/wjgo.v8.i8.599] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 03/25/2016] [Accepted: 05/13/2016] [Indexed: 02/05/2023] Open
Abstract
Beside its poor prognosis and its late diagnosis, pancreatic cancer remains one of the most painful malignancies. Optimal management of pain in this cancer represents a real challenge for the oncologist whose objective is to ensure a better quality of life to his patients. We aimed in this paper to review all the treatment modalities incriminated in the management of pain in pancreatic cancer going from painkillers, chemotherapy, radiation therapy and interventional techniques to agents under investigation and alternative medicine. Although specific guidelines and recommendations for pain management in pancreatic cancer are still absent, we present all the possible pain treatments, with a progression from medical multimodal treatment to radiotherapy and chemotherapy then interventional techniques in case of resistance. In addition, alternative methods such as acupuncture and hypnosis can be added at any stage and seems to contribute to pain relief.
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20
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He D, Manzoni A, Florentin D, Fisher W, Ding Y, Lee M, Ayala G. Biologic effect of neurogenesis in pancreatic cancer. Hum Pathol 2016; 52:182-9. [DOI: 10.1016/j.humpath.2016.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 01/20/2016] [Accepted: 02/04/2016] [Indexed: 12/15/2022]
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21
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Zou Y, Li J, Chen Z, Li X, Zheng S, Yi D, Zhong A, Chen J. miR-29c suppresses pancreatic cancer liver metastasis in an orthotopic implantation model in nude mice and affects survival in pancreatic cancer patients. Carcinogenesis 2015; 36:676-84. [PMID: 25863127 DOI: 10.1093/carcin/bgv027] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 03/17/2015] [Indexed: 12/22/2022] Open
Abstract
We investigated mechanisms of pancreatic cancer metastasis and defined the biological role of miR-29c in pancreatic cancer metastasis. After two rounds of cell selection in vivo, pancreatic cancer cells with various metastatic potentials derived from spontaneous liver metastases were used as a model of pancreatic cancer to determine the role of miR-29c in pancreatic cancer metastasis. Pancreatic cancer samples were analyzed for miRNA-29c expression, and these levels were associated with survival between groups. miR-29c suppresses cell migration and invasion by targeting the MMP2 3'UTR. Overexpression of miR-29c suppresses pancreatic cancer liver metastasis in a nude mouse orthotopic implantation model. miR-29c expression was associated with metastasis and pancreatic cancer patient survival. miR-29c plays an important role in mediating pancreatic cancer metastasis to the liver by targeting MMP2. Therefore, miR-29c may serve as a novel marker of pancreatic cancer metastasis and possibly as a therapeutic target to treat pancreatic cancer liver metastasis.
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Affiliation(s)
- Yongkang Zou
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Jianwei Li
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Zhiyu Chen
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Xiaowu Li
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Shuguo Zheng
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Dong Yi
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Ai Zhong
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Jian Chen
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China
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22
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Kim-Fuchs C, Winterhalder S, Winter A, Malinka T, Born D, Schäfer S, Stroka D, Gloor B, Candinas D, Angst E. The silencing of N-myc downstream-regulated gene-1 in an orthotopic pancreatic cancer model leads to more aggressive tumor growth and metastases. Dig Surg 2014; 31:135-42. [PMID: 24970329 DOI: 10.1159/000363065] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 04/19/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence. METHODS Capan-1 cells were silenced for NDRG1 (C(sil)) or transfected with scrambled shRNA (C(scr)) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis. RESULTS The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015). CONCLUSION NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.
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Affiliation(s)
- Corina Kim-Fuchs
- Department of Visceral Surgery and Medicine, Inselspital University of Bern, Bern, Switzerland
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Zheng X, Jiang L, Schroeder J, Stopeck A, Zohar Y. Isolation of viable cancer cells in antibody-functionalized microfluidic devices. BIOMICROFLUIDICS 2014; 8:024119. [PMID: 24803968 PMCID: PMC4008759 DOI: 10.1063/1.4873956] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 04/18/2014] [Indexed: 06/03/2023]
Abstract
Microfluidic devices functionalized with EpCAM antibodies were utilized for the capture of target cancer cells representing circulating tumor cells (CTCs). The fraction of cancer cells captured from homogeneous suspensions is mainly a function of flow shear rate, and can be described by an exponential function. A characteristic shear rate emerges as the most dominant parameter affecting the cell attachment ratio. Utilizing this characteristic shear rate as a scaling factor, all attachment ratio results for various combinations of receptor and ligand densities collapsed onto a single curve described by the empirical formula. The characteristic shear rate increases with both cell-receptor and surface-ligand densities, and empirical formulae featuring a product of two independent cumulative distributions described well these relationships. The minimum detection limit in isolation of target cancer cells from binary mixtures was experimentally explored utilizing microchannel arrays that allow high-throughput processing of suspensions about 0.5 ml in volume, which are clinically relevant, within a short time. Under a two-step attachment/detachment flow rate, both high sensitivity (almost 1.0) and high specificity (about 0.985) can be achieved in isolating target cancer cells from binary mixtures even for the lowest target/non-target cell concentration ratio of 1:100 000; this is a realistic ratio between CTCs and white blood cells in blood of cancer patients. Detection of CTCs from blood samples was also demonstrated using whole blood from healthy donors spiked with cancer cells. Finally, the viability of target cancer cells released after capture was confirmed by observing continuous cell growth in culture.
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Affiliation(s)
- Xiangjun Zheng
- Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, Arizona 85721, USA
| | - Linan Jiang
- Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, Arizona 85721, USA ; College of Optical Science, University of Arizona, Tucson, Arizona 85721, USA
| | - Joyce Schroeder
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721, USA ; Arizona Cancer Center, University of Arizona, Tucson, Arizona 85721, USA ; BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA
| | - Alison Stopeck
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721, USA
| | - Yitshak Zohar
- Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, Arizona 85721, USA ; Arizona Cancer Center, University of Arizona, Tucson, Arizona 85721, USA ; BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA ; Department of Biomedical Engineering, University of Arizona, Tucson, Arizona 85721, USA
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Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma is a devastating disease, with an overall 5-year survival rate of only 3% to 5%. As the current therapies offer very limited survival benefits, novel therapeutic strategies are urgently required to treat this disease. Here, we determined whether metformin administration inhibits the growth of PANC-1 and MiaPaCa-2 tumor xenografts in vivo. METHODS Different xenograft models, including orthotopic implantation, were used to determine whether intraperitoneal or oral administration of metformin inhibits the growth of pancreatic cancer in vivo. RESULTS We demonstrate that metformin given once daily intraperitoneally at various doses (50-250 mg/kg) to nude mice inhibited the growth of PANC-1 xenografts in a dose-dependent manner. A significant effect of metformin was obtained at 50 mg/kg and maximal effect at 200 mg/kg. Metformin administration also caused a significant reduction in the phosphorylation of ribosomal S6 protein and ERK in these xenografts. Metformin also inhibited the growth of pancreatic cancer xenografts when administered orally (2.5 mg/mL) either before or after tumor implantation. Importantly, oral administration of metformin also inhibited the growth of MiaPaCa-2 tumors xenografted orthotopically. CONCLUSIONS The studies presented here provide further evidence indicating that metformin offers a potential novel approach for pancreatic ductal adenocarcinoma prevention and therapy.
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25
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Zhang Y, Chen L, Yang J, Fleming JB, Chiao PJ, Logsdon CD, Li M. Study human pancreatic cancer in mice: how close are they? Biochim Biophys Acta Rev Cancer 2012; 1835:110-8. [PMID: 23147198 DOI: 10.1016/j.bbcan.2012.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 10/31/2012] [Accepted: 11/01/2012] [Indexed: 12/15/2022]
Abstract
Pancreatic cancer is the fourth leading cause of cancer deaths and is characterized by dismal prognosis. Xenograft and genetically engineered mouse (GEM) models have recapitulated critical elements of human pancreatic cancer, providing useful tools to probe the underlying cause of cancer etiology. In this review, we provide a brief description of the common genetic lesions that occur during the development of pancreatic cancer. Next, we describe the strengths and weaknesses of these two models and highlight key discoveries each has made. Although the relative merits of GEM and xenograft pancreatic cancer mouse models are subject to debate, both systems have and will continue to yield essential insights in understanding pancreatic cancer etiology. This information is critical for the development of new methods to screen, treat, and prevent pancreatic cancer.
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Affiliation(s)
- Yuqing Zhang
- Department of Cancer Biology, the University of Texas MD Anderson Cancer Center, USA
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The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. J Gastrointest Cancer 2012; 40:1-9. [PMID: 22710569 DOI: 10.1007/s12029-009-9071-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Accepted: 05/27/2009] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?
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Ni X, Yang J, Li M. Imaging-guided curative surgical resection of pancreatic cancer in a xenograft mouse model. Cancer Lett 2012; 324:179-85. [PMID: 22617626 DOI: 10.1016/j.canlet.2012.05.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Revised: 05/10/2012] [Accepted: 05/13/2012] [Indexed: 12/15/2022]
Abstract
Pancreatic cancer is the fourth leading cause of cancer related deaths in North America. The poor survival statistics are due to the fact that there are no reliable tests for early diagnosis and no effective therapies once metastasis has occurred. Surgical resection is the only curative treatment for pancreatic cancer; however, only less than 15% of the patients are eligible for surgery at diagnosis. New therapies are urgently needed for this malignant disease. And combinational therapy including surgery, chemotherapy and molecular targeted therapy may further improve the efficacy of individual therapies. However, a reliable mouse model which mimics the human disease and can be used for testing the surgical treatment and surgery-based combinational therapy is not available. In this study, we have established a mouse model for curative surgical resection of pancreatic cancer. Human pancreatic cancer cells were used to create orthotopic xenografts in nude mice, distal pancreatectomy was performed using imaging-guided technology to remove the pancreatic tumors, and sham surgery was performed in the control group. All mice survived the operation and no complication was observed. Surgical resection at early stage improved the survival rate and quality of life of the mice compared with the sham surgery and surgical resection at the late stage. If combined with other therapies such as chemotherapy and molecular targeted therapy, it could further improve the outcome of pancreatic cancer. This mouse model is a useful tool to study the surgical therapy and the tumor recurrence of pancreatic cancer, and could potentially impact the therapeutic choices for this deadly disease.
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Affiliation(s)
- Xiaoling Ni
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA
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28
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Abstract
OBJECTIVES Scutellaria baicalensis has been a subject of research interest due to its potential multiple therapeutic benefits. This study was to examine the distribution of baicalein, wogonin, oroxylin A and their glucuronide/sulfate-conjugated metabolites in plasma, colon, small intestine, lung, liver, pancreas, kidney, and prostate tissues and in pancreatic tumor in a xenograft animal model. In addition, we examined metabolic stability of baicalin in these tissues. METHODS A mouse xenograft model was prepared by injection of 3 × 10 human pancreatic cancer MiaPaCa-2 cells subcutaneously into nude mice. Mice were randomly allocated to control diet (AIN-76A) and 1% S. baicalensis diet (n = 8 per group) for 13 weeks. Levels of baicalein, wogonin, oroxylin A, and their conjugates in mouse tissues were measured by high-pressure liquid chromatography after enzymatic hydrolysis and then extraction. RESULTS A substantial amount of baicalin (34%-63%) was methylated to oroxylin A and its conjugates in various organs during absorption. Whereas plasma contained predominantly conjugates of baicalein, wogonin, and oroxylin A, both aglycones and conjugates were found in all other tissues investigated and in tumor. CONCLUSIONS Substantial accumulation of bioactive metabolites are found in target tissues, suggesting strong potential for S. baicalensis use as a preventive or adjuvant supplement for pancreatic cancer.
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29
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Demir IE, Friess H, Ceyhan GO. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Front Physiol 2012; 3:97. [PMID: 22529816 PMCID: PMC3327893 DOI: 10.3389/fphys.2012.00097] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2011] [Accepted: 03/28/2012] [Indexed: 12/21/2022] Open
Abstract
Interaction of cancer cells with diverse cell types in the tumor stroma is today recognized to have a fate-determining role for the progression and outcome of human cancers. Despite the well-described interactions of cancer cells with several stromal components, i.e., inflammatory cells, cancer-associated fibroblasts, endothelial cells, and pericytes, the investigation of their peculiar relationship with neural cells is still at its first footsteps. Pancreatic cancer (PCa) with its abundant stroma represents one of the best-studied examples of a malignant tumor with a mutually trophic interaction between cancer cells and the intratumoral nerves embedded in the desmoplastic stroma. Nerves in PCa are a rich source of neurotrophic factors like nerve growth factor (NGF), glial-cell-derived neurotrophic factor (GDNF), artemin; of neuronal chemokines like fractalkine; and of autonomic neurotransmitters like norepinephrine which can all enhance the invasiveness of PCa cells via matrix-metalloproteinase (MMP) upregulation, trigger neural invasion (NI), and activate pro-survival signaling pathways. Similarly, PCa cells themselves provide intrapancreatic nerves with abundant trophic agents which entail a remarkable neuroplasticity, leading to emergence of more routes for NI and cancer spread, to augmented local neuro-surveillance, neural sensitization, and neuropathic pain. The strong correlation of NI with PCa-associated desmoplasia suggests the potential presence of a triangular relationship between nerves, PCa cells, and other stromal partners like myofibroblasts and pancreatic stellate cells which generate tumor desmoplasia. Hence, although not a classical hallmark of human cancers, nerve-cancer interactions can be considered as an indispensable sub-class of cancer-stroma interactions in PCa. The present article provides an overview of the so far known nerve-cancer interactions in PCa and illustrates their ominous role in the stromal biology of human PCa.
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Affiliation(s)
- Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München Munich, Germany
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30
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NITSCHE CLAUDIA, EDDERKAOUI MOUAD, MOORE RYANM, EIBL GUIDO, KASAHARA NORIYUKI, TREGER JANET, GRIPPO PAULJ, MAYERLE JULIA, LERCH MARKUSM, GUKOVSKAYA ANNAS. The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology 2012; 142:377-87.e1-5. [PMID: 22044669 PMCID: PMC4545256 DOI: 10.1053/j.gastro.2011.10.026] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2011] [Revised: 09/28/2011] [Accepted: 10/17/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC). METHODS We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis. RESULTS PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size. CONCLUSIONS PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.
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Affiliation(s)
- CLAUDIA NITSCHE
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles, Los Angeles, California,Department of Medicine, University of California Los Angeles, Los Angeles, California,Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - MOUAD EDDERKAOUI
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles, Los Angeles, California,Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - RYAN M. MOORE
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles, Los Angeles, California,Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - GUIDO EIBL
- Hirshberg Laboratory of Translational Pancreatic Cancer Research, Department of Surgery, University of California Los Angeles, Los Angeles, California
| | - NORIYUKI KASAHARA
- Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - JANET TREGER
- Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - PAUL J. GRIPPO
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - JULIA MAYERLE
- Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - MARKUS M. LERCH
- Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - ANNA S. GUKOVSKAYA
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles, Los Angeles, California,Department of Medicine, University of California Los Angeles, Los Angeles, California
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31
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Angst E, Chen M, Mojadidi M, Hines OJ, Reber HA, Eibl G. Bioluminescence imaging of angiogenesis in a murine orthotopic pancreatic cancer model. Mol Imaging Biol 2011; 12:570-5. [PMID: 20376570 PMCID: PMC2917614 DOI: 10.1007/s11307-010-0310-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE Angiogenesis is essential for physiological processes as well as for carcinogenesis. New approaches to cancer therapy include targeting angiogenesis. One target is VEGF-A and its receptor VEGFR2. In this study, we sought to investigate pancreatic cancer angiogenesis in a genetically modified VEGFR2-luc-KI mouse. PROCEDURES Live in vivo bioluminescence imaging of angiogenesis was performed continuously until sacrifice in subcutaneous tumors as well as in orthotopically transplanted tumors. Tumor tissue was immunostained for CD-31 and VEGFR2. RESULTS Peritumoral angiogenesis measured by light emission was detected beginning at week 3 following subcutaneous injection. In the orthotopic model, light emission began at day 4, which likely corresponds to wound healing, and continued throughout the experimental period during tumor growth. Peritumoral CD-31 vessel- and VEGFR2-staining were positive. CONCLUSIONS The VEGFR2-luc-KI mouse is a valuable tool to demonstrate tumor angiogenesis and seems to be suitable to evaluate anti-angiogenic approaches in pancreatic cancer.
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Affiliation(s)
- Eliane Angst
- Hirshberg Laboratory for Pancreatic Cancer Research, Department of Surgery, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California-Los Angeles, 675 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
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Neural invasion in pancreatic cancer: the past, present and future. Cancers (Basel) 2010; 2:1513-27. [PMID: 24281170 PMCID: PMC3837319 DOI: 10.3390/cancers2031513] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2010] [Revised: 06/30/2010] [Accepted: 07/07/2010] [Indexed: 12/20/2022] Open
Abstract
In the past 15 years, invasion of nerves by cancer cells has escaped from its role as a mere bystander in cancer biology and turned into an attractive niche to study the heterotypic interaction between cancer cells and neurons. Today, neural invasion (NI) in pancreatic cancer (PCa) stands out due to the recent demonstration of its association with tumor progression, local recurrence and neuropathic pain. Accordingly, recent research on NI in PCa revealed the critical involvement of numerous nerve- or cancer cell-derived molecules in several novel in vitro and in vivo models of NI, which, however, still need further major improvement.
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33
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Zhang L, Angst E, Park JL, Moro A, Dawson DW, Reber HA, Eibl G, Hines OJ, Go VLW, Lu QY. Quercetin aglycone is bioavailable in murine pancreas and pancreatic xenografts. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:7252-7257. [PMID: 20499918 PMCID: PMC2894579 DOI: 10.1021/jf101192k] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Quercetin is a potential chemopreventive and chemotherapeutic agent for pancreatic and other cancers. This study examined the distribution of quercetin in plasma, lung, liver, pancreas, and pancreatic cancer xenografts in a murine in vivo model and the uptake of quercetin in pancreatic cancer MiaPaCa-2 cells in a cellular in vitro model. Mice were randomly allocated to control or 0.2 and 1% quercetin diet groups utilizing the AIN93G-based diet (n = 12 per group) for 6 weeks. In addition, 6 mice from each group were injected weekly with the chemotherapeutic drug gemcitabine (120 mg/kg mouse, ip). MiaPaCa cells were collected from culture medium after cells were exposed to 30 muM quercetin for 0.5, 1, 2, 4, 8, and 24 h. Levels of quercetin and 3-O'-methylquercetin in mouse tissues and MiaPaCa-2 cells were measured by high-pressure liquid chromatography following enzymatic hydrolysis and then extraction. The study showed that quercetin is accumulated in pancreatic cancer cells and is absorbed in the circulating system, tumors, and tissues of pancreas, liver, and lung in vivo. A higher proportion of total quercetin found in tumors and pancreas is aglycones. Gemcitabine cotreatment with quercetin reduced absorption of quercetin in the mouse circulatory system and liver. Results from the study provide important information on the interpretation of the chemotherapeutic efficacy of quercetin.
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Affiliation(s)
- Lifeng Zhang
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Eliane Angst
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Jenny L. Park
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Aune Moro
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - David W. Dawson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Howard A. Reber
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - O. Joe Hines
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Vay-Liang W. Go
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Qing-Yi Lu
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
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Abstract
The dismal prognosis of pancreatic adenocarcinoma is due in part to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used pancreatic adenocarcinoma cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history; in vitro and in vivo growth characteristics; phenotypic characteristics, such as adhesion, invasion, migration, and tumorigenesis; and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.
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35
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Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer 2009; 115:3379-91. [PMID: 19484787 DOI: 10.1002/cncr.24396] [Citation(s) in RCA: 836] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Perineural invasion (PNI) is the process of neoplastic invasion of nerves and is an under-recognized route of metastatic spread. It is emerging as an important pathologic feature of many malignancies, including those of the pancreas, colon and rectum, prostate, head and neck, biliary tract, and stomach. For many of these malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival. PNI is a distinct pathologic entity that can be observed in the absence of lymphatic or vascular invasion. It can be a source of distant tumor spread well beyond the extent of any local invasion; and, for some tumors, PNI may be the sole route of metastatic spread. Despite increasing recognition of this metastatic process, there has been little progress in the understanding of molecular mechanisms behind PNI and, to date, no targeted treatment modalities aimed at this pathologic entity. The objectives of this review were to lay out a clear definition of PNI to highlight its significance in those malignancies in which it has been studied best. The authors also summarized current theories on the molecular mediators and pathogenesis of PNI and introduced current research models that are leading to advancements in the understanding of this metastatic process.
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Affiliation(s)
- Catherine Liebig
- Department of Surgery, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas 77030, USA
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36
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Abstract
A major scientific challenge at the present time for cancer research is the determination of the underlying biological basis for cancer development. It is further complicated by the heterogeneity of cancer's origin. Understanding the molecular basis of cancer requires studying the dynamic and spatial interactions among proteins in cells, signaling events among cancer cells, and interactions between the cancer cells and the tumor microenvironment. Recently, it has been proposed that large-scale protein expression analysis of cancer cell proteomes promises to be valuable for investigating mechanisms of cancer transformation. Advances in mass spectrometry technologies and bioinformatics tools provide a tremendous opportunity to qualitatively and quantitatively interrogate dynamic protein-protein interactions and differential regulation of cellular signaling pathways associated with tumor development. In this review, progress in shotgun proteomics technologies for examining the molecular basis of cancer development will be presented and discussed.
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Affiliation(s)
- Emily I Chen
- Department of Cell Biology, 10550 North Torrey Pines Road, SR11, The Scripps Research Institute, La Jolla, CA 92037, USA
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37
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Torgenson MJ, Shea JE, Firpo MA, Dai Q, Mulvihill SJ, Scaife CL. Natural history of pancreatic cancer recurrence following "curative" resection in athymic mice. J Surg Res 2007; 149:57-61. [PMID: 18222475 DOI: 10.1016/j.jss.2007.08.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2007] [Revised: 07/02/2007] [Accepted: 08/22/2007] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We present a mouse model of pancreatic cancer recurrence following "curative" resection using a novel technique of implanting red fluorescent protein transfected tumor cells within a hyaluronan-based synthetic extracellular matrix into the distal pancreas of nude mice. Following "curative" pancreatic resection, we demonstrate postoperative disease recurrence by fluorescence imaging. METHODS Forty athymic nude mice underwent pancreatic injection with red fluorescent protein transfected MiaPaCa-2 or AsPc-1 cells suspended in a synthetic extracellular matrix. In 20 animals, the distal pancreas and primary tumor were resected at 2 or 5 wk following injection. The remaining 20 mice underwent sham resection. Eight weeks following resection, necropsy and fluorescence imaging were performed to assess disease recurrence. RESULTS At exploration, 39 of 40 mice had primary tumors. Eighteen of 20 mice were eligible for curative resection. Eight weeks following "curative" resection, 10 of 18 mice had recurrent disease. Of these, six developed local recurrence, two had distant metastases, and two had both. CONCLUSIONS Using an orthotopic animal model, we are able to reliably develop primary tumors, safely perform "curative" resection, and demonstrate a 56% recurrence rate 8 wk following resection. We confirmed disease-free resection using fluorescence imaging. This model may prove useful for preclinical adjuvant therapeutic trials.
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Affiliation(s)
- Marcus J Torgenson
- Department of Surgery, University of Utah, Salt Lake City, Utah 84132, USA.
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Bornmann C, Graeser R, Esser N, Ziroli V, Jantscheff P, Keck T, Unger C, Hopt UT, Adam U, Schaechtele C, Massing U, von Dobschuetz E. A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging. Cancer Chemother Pharmacol 2007; 61:395-405. [PMID: 17554540 DOI: 10.1007/s00280-007-0482-z] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2006] [Accepted: 03/16/2007] [Indexed: 10/23/2022]
Abstract
Despite its rapid enzymatic inactivation and therefore limited activity in vivo, Gemcitabine is the standard drug for pancreatic cancer treatment. To protect the drug, and achieve passive tumor targeting, we developed a liposomal formulation of Gemcitabine, GemLip (Ø: 36 nm: 47% entrapment). Its anti-tumoral activity was tested on MIA PaCa-2 cells growing orthotopically in nude mice. Bioluminescence measurement mediated by the stable integration of the luciferase gene was employed to randomize the mice, and monitor tumor growth. GemLip (4 and 8 mg/kg), Gemcitabine (240 mg/kg), and empty liposomes (equivalent to 8 mg/kg GemLip) were injected intravenously once weekly for 5 weeks. GemLip (8 mg/kg) stopped tumor growth, as measured via in vivo bioluminescence, reducing the primary tumor size by 68% (SD +/- 8%; p < 0.02), whereas Gemcitabine hardly affected tumor size (-7%; +/- 1.5%). In 80% of animals, luciferase activity in the liver indicated the presence of metastases. All treatments, including the empty liposomes, reduced the metastatic burden. Thus, GemLip shows promising antitumoral activity in this model. Surprisingly, empty liposomes attenuate the spread of metastases similar to Gemcitabine and GemLip. Further, luciferase marked tumor cells are a powerful tool to observe tumor growth in vivo, and to detect and quantify metastases.
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Affiliation(s)
- C Bornmann
- Department of General and Visceral Surgery, Albert-Ludwigs-University Freiburg, Freiburg, Germany
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Kleeff J, Reiser C, Hinz U, Bachmann J, Debus J, Jaeger D, Friess H, Büchler MW. Surgery for recurrent pancreatic ductal adenocarcinoma. Ann Surg 2007; 245:566-72. [PMID: 17414605 PMCID: PMC1877037 DOI: 10.1097/01.sla.0000245845.06772.7d] [Citation(s) in RCA: 181] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE This study evaluates the outcome of patients who underwent surgery for recurrent pancreatic cancer. SUMMARY BACKGROUND DATA Recurrence of pancreatic ductal adenocarcinoma occurs in up to 80% of pancreatic cancer patients within 2 years of a potential curative resection because, in most cases, occult (local and/or distant) micrometastases are present at the time of the initial resection. METHODS Thirty patients were operated for recurrent pancreatic cancer between October 2001 and April 2005. Median time between the initial resection and recurrence was 12.0 months. While 15 patients were resected, 15 patients either underwent palliative bypass or only exploration. Prospectively recorded data were analyzed retrospectively. Survival analysis was performed using Kaplan-Meier estimation and log-rank test. RESULTS The overall median survival of patients with recurrent disease was 29.0 months. After the first reresection/exploration for recurrent disease, the median survival was 11.4 months. There was a tendency of increased median survival in the group of patients undergoing resection (17.0 months) compared with the bypass/exploration group (9.4 months), although this difference was not significant (P = 0.084). In addition, patients with a prolonged interval (>9 months) from resection to recurrence were more likely to benefit from reresection compared with patients with recurrence within 9 months (median survival 17.0 vs. 7.4 months; P = 0.004). The in-hospital morbidity and mortality rate of resected patients was 20% and 6.7% compared with 13.3% and 0% of patients who underwent only exploration/palliative bypass. CONCLUSION Resection for recurrent pancreatic cancer can be carried out safely. Further studies are required to address the question whether a subgroup of patients might actually benefit from this procedure.
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Affiliation(s)
- Jörg Kleeff
- Department of General Surgery, National Cancer Center, University of Heidelberg, Heidelberg, Germany
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