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Gao X, Zhang G, Wang F, Ruan W, Sun S, Zhang Q, Liu X. Emerging roles of EGFL family members in neoplastic diseases: Molecular mechanisms and targeted therapies. Biochem Pharmacol 2025; 236:116847. [PMID: 40044051 DOI: 10.1016/j.bcp.2025.116847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/13/2025] [Accepted: 03/03/2025] [Indexed: 03/09/2025]
Abstract
Epidermal growth factor-like proteins (EGFLs) contain more than a single EGF/EGF-like domain within their protein structure. To date, ten EGFL family members (EGFL1-10) have been characterized across diverse tissues and developmental stages under different conditions. In this review, we conclude that EGFLs are instrumental in regulating biological activities and pathological processes. Under physiological conditions, EGFLs participate in angiogenesis, neurogenesis, osteogenesis, and other processes. Under pathological conditions, EGFLs are linked with different diseases, particularly cancers. Furthermore, we highlight recent advancements in the study of EGFLs in biological conditions and cancers. In addition, the regulatory role and key underlying mechanism of EGFLs in mediating tumorigenesis are discussed. This paper also examines potential antagonists that target EGFL family members in cancer therapeutics. In summary, this comprehensive review elucidates the critical role of EGFLs in neoplastic diseases and highlights their potential as therapeutic targets.
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Affiliation(s)
- Xiaoge Gao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Guopeng Zhang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Feitong Wang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Wenhui Ruan
- School of Medical Imaging, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, PR China
| | - Shishuo Sun
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Qing Zhang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Xiangye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, PR China; Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, PR China.
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Doctor A, Laube M, Meister S, Kiss OC, Kopka K, Hauser S, Pietzsch J. Combined PET Radiotracer Approach Reveals Insights into Stromal Cell-Induced Metabolic Changes in Pancreatic Cancer In Vitro and In Vivo. Cancers (Basel) 2024; 16:3393. [PMID: 39410013 PMCID: PMC11475921 DOI: 10.3390/cancers16193393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/25/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
Background/Objective Pancreatic stellate cells (PSCs) in pancreatic adenocarcinoma (PDAC) are producing extracellular matrix, which promotes the formation of a dense fibrotic microenvironment. This makes PDAC a highly heterogeneous tumor-stroma-driven entity, associated with reduced perfusion, limited oxygen supply, high interstitial fluid pressure, and limited bioavailability of therapeutic agents. Methods In this study, spheroid and tumor xenograft models of human PSCs and PanC-1 cells were characterized radiopharmacologically using a combined positron emission tomography (PET) radiotracer approach. [18F]FDG, [18F]FMISO, and [18F]FAPI-74 were employed to monitor metabolic activity, hypoxic metabolic state, and functional expression of fibroblast activation protein alpha (FAPα), a marker of activated PSCs. Results In vitro, PanC-1 and multi-cellular tumor spheroids demonstrated comparable glucose uptake and hypoxia, whereas FAPα expression was significantly higher in PSC spheroids. In vivo, glucose uptake as well as the transition to hypoxia were comparable in PanC-1 and multi-cellular xenograft models. In mice injected with PSCs, FAPα expression decreased over a period of four weeks post-injection, which was attributed to the successive death of PSCs. In contrast, FAPα expression increased in both PanC-1 and multi-cellular xenograft models over time due to invasion of mouse fibroblasts. Conclusion The presented models are suitable for subsequently characterizing stromal cell-induced metabolic changes in tumors using noninvasive molecular imaging techniques.
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Affiliation(s)
- Alina Doctor
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
- School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstraße 4, 01069 Dresden, Germany
| | - Markus Laube
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
| | - Sebastian Meister
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
| | - Oliver C. Kiss
- Department of Targetry, Target Chemistry and Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany;
| | - Klaus Kopka
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
- School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstraße 4, 01069 Dresden, Germany
- National Center for Tumor Diseases (NCT) Dresden, Partner Site Dresden, University Cancer Center (UCC), Fetscherstraße 74, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Sandra Hauser
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
- School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstraße 4, 01069 Dresden, Germany
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Qin A, Shi K, Tindall RR, Li J, Cheng B, Li J, Yang B, Yu Q, Zhang Y, Hong B, Kaur B, Younes M, Shen Q, Bailey-Lundberg JM, Cao Y, Ko TC. Characterization of Pancreatic Collagen-Expressing Fibroblasts in Mouse Acute Pancreatitis. GASTRO HEP ADVANCES 2024; 4:100557. [PMID: 39866719 PMCID: PMC11761323 DOI: 10.1016/j.gastha.2024.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 09/16/2024] [Indexed: 01/28/2025]
Abstract
Background and Aims Pancreatic stellate cells (PSCs) are critical mediators in chronic pancreatitis with an undefined role in acute pancreatitis (AP). PSCs consist of a heterogenous group of cells and are considered interchangeable with pancreatic fibroblasts. This study explored the heterogeneous nature of PSCs by characterizing pancreatic collagen-expressing fibroblasts (PCFs) via lineage tracing in mouse normal and AP pancreas and determining the effect of PCF depletion in AP. Methods Tandem dimer Tomato (tdTom+) PCFs in collagen type 1 (Col1)a2CreERtdTomato (Tom) mice receiving tamoxifen were characterized via fluorescence, Oil Red staining, and flow cytometry. AP was induced by cerulein, AP injury was assessed, and tdTom+ PCFs were monitored. The effect of PCF depletion on AP injury was evaluated in Col1a2CreERdiphtheria toxin A mice. Results Approximately 13% of pancreatic cells in Col1a2CreERTom mice were labeled by tdTom (tdTom+ PCFs), which surrounded acini, ducts, and blood vessels, and stained with Oil Red, collagen type I, vimentin, and desmin. tdTom+ PCFs increased 2-fold during AP, correlating with AP score, amylase, and alpha-smooth muscle actin+ and Ki67+ staining. PCF depletion in Col1a2CreERdiphtheria toxin A mice receiving tamoxifen resulted in enhanced inflammation compared to control. Conclusion PCFs may constitute a subset of PSCs and can be activated during AP. PCF depletion aggravates AP, suggesting a protective role for PCFs.
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Affiliation(s)
- Amy Qin
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Kevin Shi
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | | | - Jiajing Li
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Binglu Cheng
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Jing Li
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Baibing Yang
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Qiang Yu
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Yinjie Zhang
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Bangxing Hong
- Department of Pathology, Georgia Cancer Center, Augusta University, Augusta, Georgia
| | - Balveen Kaur
- Department of Pathology, Georgia Cancer Center, Augusta University, Augusta, Georgia
| | - Mamoun Younes
- Department of Pathology, George Washington University, Washington, District of Columbia
| | - Qiang Shen
- Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | | | - Yanna Cao
- Department of Surgery, UTHealth at Houston, Houston, Texas
| | - Tien C. Ko
- Department of Surgery, UTHealth at Houston, Houston, Texas
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Liu M, Xing Y, Tan J, Chen X, Xue Y, Qu L, Ma J, Jin X. Comprehensive summary: the role of PBX1 in development and cancers. Front Cell Dev Biol 2024; 12:1442052. [PMID: 39129784 PMCID: PMC11310070 DOI: 10.3389/fcell.2024.1442052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 07/16/2024] [Indexed: 08/13/2024] Open
Abstract
PBX1 is a transcription factor that can promote the occurrence of various tumors and play a reg-ulatory role in tumor growth, metastasis, invasion, and drug resistance. Furthermore, a variant generated by fusion of E2A and PBX1, E2A-PBX1, has been found in 25% of patients with childhood acute lymphoblastic leukemia. Thus, PBX1 is a potential therapeutic target for many cancers. Here, we describe the structure of PBX1 and E2A-PBX1 as well as the molecular mecha-nisms whereby these proteins promote tumorigenesis to provide future research directions for developing new treatments. We show that PBX1 and E2A-PBX1 induce the development of highly malignant and difficult-to-treat solid and blood tumors. The development of specific drugs against their targets may be a good therapeutic strategy for PBX1-related cancers. Furthermore, we strongly recommend E2A-PBX1 as one of the genes for prenatal screening to reduce the incidence of childhood hematological malignancies.
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Affiliation(s)
- Mingsheng Liu
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Yan Xing
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Jiufeng Tan
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Xiaoliang Chen
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Yaming Xue
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Licheng Qu
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Jianchao Ma
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Xuefei Jin
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
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Mottini C, Auciello FR, Manni I, Pilarsky C, Caputo D, Caracciolo G, Rossetta A, Di Gennaro E, Budillon A, Blandino G, Roca MS, Piaggio G. The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers. J Exp Clin Cancer Res 2024; 43:198. [PMID: 39020414 PMCID: PMC11256648 DOI: 10.1186/s13046-024-03117-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 07/06/2024] [Indexed: 07/19/2024] Open
Abstract
Pancreatic cancer (PC) is a clinically challenging tumor to combat due to its advanced stage at diagnosis as well as its resistance to currently available therapies. The absence of early symptoms and known detectable biomarkers renders this disease incredibly difficult to detect/manage. Recent advances in the understanding of PC biology have highlighted the importance of cancer-immune cell interactions, not only in the tumor micro-environment but also in distant systemic sites, like the bone marrow, spleen and circulating immune cells, the so-called macro-environment. The response of the macro-environment is emerging as a determining factor in tumor development by contributing to the formation of an increasingly immunogenic micro-environment promoting tumor homeostasis and progression. We will summarize the key events associated with the feedback loop between the tumor immune micro-environment (TIME) and the tumor immune macroenvironment (TIMaE) in pancreatic precancerous lesions along with how it regulates disease development and progression. In addition, liquid biopsy biomarkers capable of diagnosing PC at an early stage of onset will also be discussed. A clearer understanding of the early crosstalk between micro-environment and macro-environment could contribute to identifying new molecular therapeutic targets and biomarkers, consequently improving early PC diagnosis and treatment.
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Affiliation(s)
- Carla Mottini
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Francesca Romana Auciello
- UOC Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Isabella Manni
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | | | | | - Giulio Caracciolo
- Dipartimento Di Medicina Molecolare Sapienza, Università Di Roma, Rome, Italy
| | | | - Elena Di Gennaro
- Experimental Pharmacology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via M. Semmola, 80131, Naples, Italy
| | - Alfredo Budillon
- Scientific Directorate, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy
| | - Giovanni Blandino
- UOC Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Maria Serena Roca
- Experimental Pharmacology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via M. Semmola, 80131, Naples, Italy.
| | - Giulia Piaggio
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
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Saleh O, Shihadeh H, Yousef A, Erekat H, Abdallh F, Al-Leimon A, Elsalhy R, Altiti A, Dajani M, AlBarakat MM. The Effect of Intratumor Heterogeneity in Pancreatic Ductal Adenocarcinoma Progression and Treatment. Pancreas 2024; 53:e450-e465. [PMID: 38728212 DOI: 10.1097/mpa.0000000000002342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
BACKGROUND AND OBJECTIVES Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis. MATERIALS AND METHODS The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered. RESULTS The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations. CONCLUSION Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.
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Affiliation(s)
- Othman Saleh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | - Hana Erekat
- School of medicine, University of Jordan, Amman
| | - Fatima Abdallh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | | | - Majd Dajani
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | - Majd M AlBarakat
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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Han L, Wu Y, Fang K, Sweeney S, Roesner UK, Parrish M, Patel K, Walter T, Piermattei J, Trimboli A, Lefler J, Timmers CD, Yu XZ, Jin VX, Zimmermann MT, Mathison AJ, Urrutia R, Ostrowski MC, Leone G. The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis. Nat Commun 2023; 14:1. [PMID: 36596776 PMCID: PMC9810714 DOI: 10.1038/s41467-022-34464-6] [Citation(s) in RCA: 127] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 10/26/2022] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.
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Affiliation(s)
- Lu Han
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Yongxia Wu
- Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Kun Fang
- Division of Biostatistics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Sean Sweeney
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Ulyss K Roesner
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Melodie Parrish
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Khushbu Patel
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Tom Walter
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Julia Piermattei
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Anthony Trimboli
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Julia Lefler
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Cynthia D Timmers
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Victor X Jin
- Division of Biostatistics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Michael T Zimmermann
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Clinical and Translational Sciences Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Angela J Mathison
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Raul Urrutia
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Michael C Ostrowski
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA.
| | - Gustavo Leone
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
- Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
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Xu Y, Li Z, Shi H, Zhu M. Clinicopathological and prognostic significance of circulating immune cells in the patients with pancreatic cancer. Int Immunopharmacol 2022; 111:109157. [PMID: 35988520 DOI: 10.1016/j.intimp.2022.109157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/02/2022] [Accepted: 08/10/2022] [Indexed: 11/05/2022]
Abstract
Pancreatic cancer is characterized by immune tolerance and immunotherapeutic resistance. Circulating cells may reflect the general immune status of the patient. However, the circulating immune status of pancreatic cancer are largely uncharacterized. Here, the subset distribution was analyzed in peripheral blood samples from 101 patients with pancreatic cancer and 142 healthy volunteers by using flow cytometry. The differences of the subpopulation distribution in the two groups and the relation between clinical parameters with the subset were determined. Moreover, the clinical application of each subset as prognosis biomarker was also assessed by Kaplan-Meier analysis. The reduced proportion of total lymphocyte and upregulated CD4/CD8 ratio were observed in pancreatic cancer than those in healthy controls. Of note, increased proportions of lymphocyte and NKT cells were noticed more frequently in patients over 60 years (P = 0.043) and patients with metastasis (P = 0.027), respectively. However, our correlation analyses revealed no correlation between the proportions of T cells, B cell and NK cells with clinicopathologic features. Furthermore, the analysis displayed that proportions of CD4+T cell, B cell and CD4/CD8 ratio significantly reduced in the cohort of post-operation, while the frequency of CD8+T cell and NKT cells elevated remarkably. Finally, the Kaplan-Meier analysis indicated that patients with high lymphocyte proportion might have prolonged overall survival (P = 0.007). The altered distribution of peripheral blood immune cell subpopulation in pancreatic cancer and its relationship with clinical outcome highlight the potential use of circulating immune subsets as prognostic biomarkers in pancreatic cancer.
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Affiliation(s)
- Yijun Xu
- Department of Gastroenterology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zhaosheng Li
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Huina Shi
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Mingchen Zhu
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
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9
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Antoon R, Wang XH, Saleh AH, Warrington J, Hedley DW, Keating A. Pancreatic cancer growth promoted by bone marrow mesenchymal stromal cell-derived IL-6 is reversed predominantly by IL-6 blockade. Cytotherapy 2022; 24:699-710. [PMID: 35473998 DOI: 10.1016/j.jcyt.2021.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 11/17/2021] [Accepted: 12/06/2021] [Indexed: 12/26/2022]
Abstract
Pancreatic cancer is a highly lethal cancer characterized by local invasiveness, early metastasis, recurrence and high resistance to current therapies. Extensive stroma or desmoplasia is a key histological feature of the disease, and interactions between cancer and stromal cells are critical for pancreatic cancer development and progression. Mesenchymal stromal cells [MSCs] exhibit preferential tropism to primary and metastatic tumor sites and may either suppress or support tumor growth. Although MSCs represent a potential source of pancreatic cancer stroma, their contribution to pancreatic tumor growth remains poorly known. Here, we show that bone marrow MSCs significantly contribute to pancreatic cancer growth in vitro and in vivo. Furthermore, MSCs create a pro-carcinogenic microenvironment through the release of key factors mediating growth and angiogenesis, including interleukin (IL)-6, IL-8, vascular endothelial growth factor and activation of STAT3 signaling in tumor cells. IL-6 released by MSCs was largely responsible for the pro-tumorigenic effects of MSCs. Knockdown of IL-6 expression in MSCs by small interfering RNA (siRNA) abolished the MSC growth-promoting effect in vitro, reducing tumor cell proliferation and clonogenic potential. In addition, in a heterotopic nude mouse model of human pancreatic tumor xenografts, blockade of IL-6 with the anti-IL-6 receptor antibody, tocilizumab, or of its downstream effector STAT3 with the small molecule STAT3 inhibitor S3I-201, abrogated MSC-mediated tumor promotion and delayed tumor formation significantly. Our data demonstrate that MSCs promote pancreatic cancer growth, with IL-6 produced by MSCs playing a pivotal role.
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Affiliation(s)
- Roula Antoon
- Krembil Research Institute, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | | | - Amr H Saleh
- Krembil Research Institute, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - David W Hedley
- Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Armand Keating
- Krembil Research Institute, Toronto, ON, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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10
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Szymoński K, Milian-Ciesielska K, Lipiec E, Adamek D. Current Pathology Model of Pancreatic Cancer. Cancers (Basel) 2022; 14:2321. [PMID: 35565450 PMCID: PMC9105915 DOI: 10.3390/cancers14092321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated "cross-talk" that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients' outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis.
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Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
- Department of Pathomorphology, University Hospital, 30-688 Cracow, Poland;
| | | | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, 30-348 Cracow, Poland;
| | - Dariusz Adamek
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
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11
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Zheng K, Lan T, Li GP, Huang L, Chen YP, Su BH, Zhang S, Zheng DL. Evaluated expression of CELSR3 in oral squamous cell carcinoma is associated with perineural invasion and poor prognosis. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 133:564-573. [PMID: 35165064 DOI: 10.1016/j.oooo.2021.10.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/04/2021] [Accepted: 10/22/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE The objective of this study was to evaluate CELSR3 expression and explore its potential mechanism in oral squamous cell carcinoma. STUDY DESIGN CELSR3 mRNA expression was analyzed using The Cancer Genome Atlas (TCGA) database. CELSR3 protein expression in 135 surgical oral squamous cell carcinoma specimens was observed by immunohistochemical staining. Staining results were used to investigate the association between CELSR3 expression and clinicopathologic characteristics and prognosis. Bioinformatics analyses were used to explore the potential mechanism of CELSR3 in head and neck squamous cell carcinoma. RESULTS CELSR3 mRNA expression was upregulated in patients with head and neck squamous cell carcinoma in the TCGA head and neck squamous cell carcinoma data set. Increased CELSR3 protein expression was associated with perineural invasion and poor clinical outcomes in patients with oral squamous cell carcinoma. Bioinformatics analyses revealed that CELSR3 is involvement in axonogenesis, neuron migration, and cell-cell adhesion, all of which are involved in the process of perineural invasion. CONCLUSION CELSR3 may play a pro-oncogenic role in oral squamous cell carcinoma and can predict perineural invasion and poor survival. CELSR3 may be involved in oral squamous cell carcinoma progression by modulating perineural invasion.
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Affiliation(s)
- Ke Zheng
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University
| | - Ting Lan
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University
| | - Guo-Ping Li
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University
| | - Li Huang
- Department of Dentistry, The First Affiliated Hospital of Fujian Medical University
| | - Yu-Peng Chen
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University
| | - Bo-Hua Su
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University; Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Sheng Zhang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University.
| | - Da-Li Zheng
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University.
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12
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Han L, Seward C, Leone G, Ostrowski MC. Origin, activation and heterogeneity of fibroblasts associated with pancreas and breast cancers. Adv Cancer Res 2022; 154:169-201. [PMID: 35459469 DOI: 10.1016/bs.acr.2022.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Pancreas and breast cancers both contain abundant stromal components within the tumor tissues. A prominent cell type within the stroma is cancer-associated fibroblasts (CAFs). CAFs play critical and complex roles establishing the tumor microenvironment to either promote or prevent tumor progression. Recently, complex genetic models and single cell-based techniques have provided emerging insights on the precise functions and cellular heterogeneity of CAFs. The transformation of normal fibroblasts into CAFs is a key event during tumor initiation and progression. Such coordination between tumor cells and fibroblasts plays an important role in cancer development. Reprograming fibroblasts is currently being explored for therapeutic benefits. In this review, we will discuss recent literature shedding light on the tissues of origin, activation mechanisms, and heterogeneity of CAFs comparing pancreas and breast cancers.
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Affiliation(s)
- Lu Han
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States.
| | - Cara Seward
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Gustavo Leone
- Department of Biochemistry, Medical College of Wisconsin Cancer Center, Medical college of Wisconsin, Milwaukee, WI, United States
| | - Michael C Ostrowski
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States.
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13
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Obaid G, Mai Z, Hasan T. Orthotopic Models of Pancreatic Cancer to Study PDT. Methods Mol Biol 2022; 2451:163-173. [PMID: 35505017 PMCID: PMC10515273 DOI: 10.1007/978-1-0716-2099-1_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its poor prognosis that stems from a marked resistance to therapy, an invasive nature, and a high metastatic potential. Photodynamic therapy (PDT) is a promising modality for effectively managing PDAC both preclinically and clinically. While clinical trials of PDT for PDAC are still in their early stages, a plethora of elegant preclinical studies are supporting the translation and clinical adoption of PDT-based treatment regimens, many of which leverage orthotopic preclinical models of PDAC. Given the aggressiveness of the disease that is largely dependent on the localization of PDAC tumors, it is imperative that preclinical models used to evaluate PDT-based treatment regimens recapitulate elements of the natural pathogenesis in order to design treatment regimens tailored to PDAC with the highest potential for clinical success. In light of the importance of clinically relevant models of PDAC, this chapter details and discusses the methodologies developed over the last three decades to leverage orthotopic PDAC models in order to evaluate PDT-based treatment regimens. The shortcomings of these are also discussed, in addition to the future directions that the field is headed to establish the most relevant orthotopic models of PDAC.
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Affiliation(s)
- Girgis Obaid
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Wellman Center for Photomedicine, Boston, MA, USA
| | - Zhiming Mai
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Wellman Center for Photomedicine, Boston, MA, USA
| | - Tayyaba Hasan
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Wellman Center for Photomedicine, Boston, MA, USA.
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14
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Cannon A, Thompson CM, Bhatia R, Armstrong KA, Solheim JC, Kumar S, Batra SK. Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma. J Gastroenterol 2021; 56:689-703. [PMID: 34279724 PMCID: PMC9052363 DOI: 10.1007/s00535-021-01800-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/15/2021] [Indexed: 02/04/2023]
Abstract
Pancreatic fibrosis (PF) is an essential component of the pathobiology of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic myofibroblasts (PMFs) are crucial for the deposition of the extracellular matrix, and fibrotic reaction in response to sustained signaling. Consequently, understanding of the molecular mechanisms of PMF activation is not only critical for understanding CP and PDAC biology but is also a fertile area of research for the development of novel therapeutic strategies for pancreatic pathologies. This review analyzes the key signaling events that drive PMF activation including, initiating signals from transforming growth factor-β1, platelet derived growth factor, as well as other microenvironmental cues, like hypoxia and extracellular matrix rigidity. Further, we discussed the intracellular signal events contributing to PMF activation, and crosstalk with different components of tumor microenvironment. Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.
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Affiliation(s)
- Andrew Cannon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Christopher Michael Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | | | - Joyce Christopher Solheim
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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15
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Park JH, Ameri AH, Dempsey KE, Conrad DN, Kem M, Mino-Kenudson M, Demehri S. Nuclear IL-33/SMAD signaling axis promotes cancer development in chronic inflammation. EMBO J 2021; 40:e106151. [PMID: 33616251 DOI: 10.15252/embj.2020106151] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 12/27/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
Interleukin (IL)-33 cytokine plays a critical role in allergic diseases and cancer. IL-33 also has a nuclear localization signal. However, the nuclear function of IL-33 and its impact on cancer is unknown. Here, we demonstrate that nuclear IL-33-mediated activation of SMAD signaling pathway in epithelial cells is essential for cancer development in chronic inflammation. Using RNA and ChIP sequencing, we found that nuclear IL-33 repressed the expression of an inhibitory SMAD, Smad6, by interacting with its transcription factor, RUNX2. IL-33 was highly expressed in the skin and pancreatic epithelial cells in chronic inflammation, leading to a markedly repressed Smad6 expression as well as dramatically upregulated p-SMAD2/3 and p-SMAD1/5 in the epithelial cells. Blocking TGF-β/SMAD signaling attenuated the IL-33-induced cell proliferation in vitro and inhibited IL-33-dependent epidermal hyperplasia and skin cancer development in vivo. IL-33 and SMAD signaling were upregulated in human skin cancer, pancreatitis, and pancreatitis-associated pancreatic cancer. Collectively, our findings reveal that nuclear IL-33/SMAD signaling is a cell-autonomous tumor-promoting axis in chronic inflammation, which can be targeted by small-molecule inhibitors for cancer treatment and prevention.
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Affiliation(s)
- Jong Ho Park
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Amir H Ameri
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kaitlin E Dempsey
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Danielle N Conrad
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marina Kem
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Shadmehr Demehri
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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16
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Wu Y, Zhang C, Jiang K, Werner J, Bazhin AV, D'Haese JG. The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives. Front Oncol 2021; 10:621937. [PMID: 33520728 PMCID: PMC7841014 DOI: 10.3389/fonc.2020.621937] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.
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Affiliation(s)
- Yang Wu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Chun Zhang
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Kuirong Jiang
- Pancreas Center and Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Jan G D'Haese
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
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17
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Gİrgİn B, KaradaĞ-Alpaslan M, KocabaŞ F. Oncogenic and tumor suppressor function of MEIS and associated factors. ACTA ACUST UNITED AC 2021; 44:328-355. [PMID: 33402862 PMCID: PMC7759197 DOI: 10.3906/biy-2006-25] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022]
Abstract
MEIS proteins are historically associated with tumorigenesis, metastasis, and invasion in cancer. MEIS and associated PBX-HOX proteins may act as tumor suppressors or oncogenes in different cellular settings. Their expressions tend to be misregulated in various cancers. Bioinformatic analyses have suggested their upregulation in leukemia/lymphoma, thymoma, pancreas, glioma, and glioblastoma, and downregulation in cervical, uterine, rectum, and colon cancers. However, every cancer type includes, at least, a subtype with high MEIS expression. In addition, studies have highlighted that MEIS proteins and associated factors may function as diagnostic or therapeutic biomarkers for various diseases. Herein, MEIS proteins and associated factors in tumorigenesis are discussed with recent discoveries in addition to how they could be modulated by noncoding RNAs or newly developed small-molecule MEIS inhibitors.
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Affiliation(s)
- Birkan Gİrgİn
- Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul Turkey.,Graduate School of Natural and Applied Sciences, Yeditepe University, İstanbul Turkey.,Meinox Pharma Technologies, İstanbul Turkey
| | - Medine KaradaĞ-Alpaslan
- Department of Medical Genetics, Faculty of Medicine, Ondokuz Mayıs University, Samsun Turkey
| | - Fatih KocabaŞ
- Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul Turkey.,Graduate School of Natural and Applied Sciences, Yeditepe University, İstanbul Turkey.,Meinox Pharma Technologies, İstanbul Turkey
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18
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Garcia PE, Scales MK, Allen BL, Pasca di Magliano M. Pancreatic Fibroblast Heterogeneity: From Development to Cancer. Cells 2020; 9:E2464. [PMID: 33198201 PMCID: PMC7698149 DOI: 10.3390/cells9112464] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/10/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression. Cancer-associated fibroblasts (CAFs) are a prominent cellular component of the stroma, but their role during carcinogenesis remains controversial, with both tumor-supporting and tumor-restraining functions reported in different studies. One explanation for these contradictory findings is the heterogeneous nature of the fibroblast populations, and the different roles each subset might play in carcinogenesis. Here, we review the current literature on the origin and function of pancreatic fibroblasts, from the developing organ to the healthy adult pancreas, and throughout the initiation and progression of PDA. We also discuss clinical approaches to targeting fibroblasts in PDA.
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Affiliation(s)
- Paloma E. Garcia
- Program in Molecular and Cellular Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Michael K. Scales
- Department of Cell and Developmental Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA; (M.K.S.); (B.L.A.)
| | - Benjamin L. Allen
- Department of Cell and Developmental Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA; (M.K.S.); (B.L.A.)
- Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Pasca di Magliano
- Department of Cell and Developmental Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA; (M.K.S.); (B.L.A.)
- Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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19
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Sperb N, Tsesmelis M, Wirth T. Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2020; 21:E5486. [PMID: 32752017 PMCID: PMC7432853 DOI: 10.3390/ijms21155486] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/22/2020] [Accepted: 07/29/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer. The poor prognosis calls for a more detailed understanding of disease biology in order to pave the way for the development of effective therapies. Typically, the pancreatic tumor is composed of a minority of malignant cells within an excessive tumor microenvironment (TME) consisting of extracellular matrix (ECM), fibroblasts, immune cells, and endothelial cells. Research conducted in recent years has particularly focused on cancer-associated fibroblasts (CAFs) which represent the most prominent cellular component of the desmoplastic stroma. Here, we review the complex crosstalk between CAFs, tumor cells, and other components of the TME, and illustrate how these interactions drive disease progression. We also discuss the emerging field of CAF heterogeneity, their tumor-supportive versus tumor-suppressive capacity, and the consequences for designing stroma-targeted therapies in the future.
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Affiliation(s)
| | | | - Thomas Wirth
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (N.S.); (M.T.)
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20
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Mundry CS, Eberle KC, Singh PK, Hollingsworth MA, Mehla K. Local and systemic immunosuppression in pancreatic cancer: Targeting the stalwarts in tumor's arsenal. Biochim Biophys Acta Rev Cancer 2020; 1874:188387. [PMID: 32579889 DOI: 10.1016/j.bbcan.2020.188387] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/13/2020] [Accepted: 06/15/2020] [Indexed: 02/06/2023]
Abstract
Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3rd leading cause of cancer-related deaths in the United States. Cooperation between the tumor cells and the immune system leads to the immune escape and eventual establishment of the tumor. For more than 20 years, sincere efforts have been made to intercept the tumor-immune crosstalk and identify the probable therapeutic targets for breaking self-tolerance toward tumor antigens. However, the success of these studies depends on detailed examination and understanding of tumor-immune cell interactions, not only in the primary tumor but also at distant systemic niches. Innate and adaptive arms of the immune system sculpt tumor immunogenicity, where they not only aid in providing an amenable environment for their survival but also act as a driver for tumor relapse at primary or distant organ sites. This review article highlights the key events associated with tumor-immune communication and associated immunosuppression at both local and systemic microenvironments in PDAC. Furthermore, we discuss the approaches and benefits of targeting both local and systemic immunosuppression for PDAC patients. The present articles integrate data from clinical and genetic mouse model studies to provide a widespread consensus on the role of local and systemic immunosuppression in undermining the anti-tumor immune responses against PDAC.
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MESH Headings
- Adaptive Immunity/drug effects
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Bone Marrow/drug effects
- Bone Marrow/immunology
- Bone Marrow/pathology
- Cancer Vaccines/administration & dosage
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/therapy
- Chemotherapy, Adjuvant/methods
- Clinical Trials as Topic
- Combined Modality Therapy/methods
- Disease Models, Animal
- Disease-Free Survival
- Fluorouracil/pharmacology
- Fluorouracil/therapeutic use
- Humans
- Immunity, Innate/drug effects
- Immunotherapy/methods
- Irinotecan/pharmacology
- Irinotecan/therapeutic use
- Leucovorin/pharmacology
- Leucovorin/therapeutic use
- Lymph Node Excision
- Lymph Nodes/immunology
- Lymph Nodes/pathology
- Lymph Nodes/surgery
- Mice
- Mice, Transgenic
- Neoadjuvant Therapy/methods
- Oxaliplatin/pharmacology
- Oxaliplatin/therapeutic use
- Pancreas/immunology
- Pancreas/pathology
- Pancreas/surgery
- Pancreatectomy
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/therapy
- Spleen/immunology
- Spleen/pathology
- Spleen/surgery
- Splenectomy
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Transplantation, Autologous/methods
- Tumor Escape/drug effects
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/immunology
- United States/epidemiology
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Affiliation(s)
- Clara S Mundry
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
| | - Kirsten C Eberle
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
| | - Pankaj K Singh
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
| | - Michael A Hollingsworth
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
| | - Kamiya Mehla
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
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21
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Lin Y, Cao Y, Kim HJ, Salim A, Speed TP, Lin DM, Yang P, Yang JYH. scClassify: sample size estimation and multiscale classification of cells using single and multiple reference. Mol Syst Biol 2020; 16:e9389. [PMID: 32567229 PMCID: PMC7306901 DOI: 10.15252/msb.20199389] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 12/26/2022] Open
Abstract
Automated cell type identification is a key computational challenge in single-cell RNA-sequencing (scRNA-seq) data. To capitalise on the large collection of well-annotated scRNA-seq datasets, we developed scClassify, a multiscale classification framework based on ensemble learning and cell type hierarchies constructed from single or multiple annotated datasets as references. scClassify enables the estimation of sample size required for accurate classification of cell types in a cell type hierarchy and allows joint classification of cells when multiple references are available. We show that scClassify consistently performs better than other supervised cell type classification methods across 114 pairs of reference and testing data, representing a diverse combination of sizes, technologies and levels of complexity, and further demonstrate the unique components of scClassify through simulations and compendia of experimental datasets. Finally, we demonstrate the scalability of scClassify on large single-cell atlases and highlight a novel application of identifying subpopulations of cells from the Tabula Muris data that were unidentified in the original publication. Together, scClassify represents state-of-the-art methodology in automated cell type identification from scRNA-seq data.
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Affiliation(s)
- Yingxin Lin
- School of Mathematics and StatisticsUniversity of SydneySydneyNSWAustralia
- Charles Perkins CentreUniversity of SydneySydneyNSWAustralia
| | - Yue Cao
- School of Mathematics and StatisticsUniversity of SydneySydneyNSWAustralia
- Charles Perkins CentreUniversity of SydneySydneyNSWAustralia
| | - Hani Jieun Kim
- School of Mathematics and StatisticsUniversity of SydneySydneyNSWAustralia
- Charles Perkins CentreUniversity of SydneySydneyNSWAustralia
- Computational Systems Biology GroupChildren's Medical Research InstituteUniversity of SydneyWestmeadNSWAustralia
| | - Agus Salim
- Department of Mathematics and StatisticsLa Trobe UniversityBundooraVICAustralia
- Baker Heart and Diabetes InstituteMelbourneVICAustralia
- Bioinformatics DivisionWalter and Eliza Hall Institute of Medical ResearchParkvilleVICAustralia
| | - Terence P Speed
- Bioinformatics DivisionWalter and Eliza Hall Institute of Medical ResearchParkvilleVICAustralia
| | - David M Lin
- Department of Biomedical SciencesCornell UniversityIthacaNYUSA
| | - Pengyi Yang
- School of Mathematics and StatisticsUniversity of SydneySydneyNSWAustralia
- Charles Perkins CentreUniversity of SydneySydneyNSWAustralia
- Computational Systems Biology GroupChildren's Medical Research InstituteUniversity of SydneyWestmeadNSWAustralia
| | - Jean Yee Hwa Yang
- School of Mathematics and StatisticsUniversity of SydneySydneyNSWAustralia
- Charles Perkins CentreUniversity of SydneySydneyNSWAustralia
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22
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Gu X, Li H, Sha L, Mao Y, Shi C, Zhao W. CELSR3 mRNA expression is increased in hepatocellular carcinoma and indicates poor prognosis. PeerJ 2019; 7:e7816. [PMID: 31608178 PMCID: PMC6786253 DOI: 10.7717/peerj.7816] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 09/02/2019] [Indexed: 12/20/2022] Open
Abstract
Objective Hepatocellular carcinoma (HCC) is a disease that is associated with high mortality; currently, there is no curative and reliable treatment. Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) is the key signaling molecule in the wingless and INT-1/planar cell polarity (WNT/PCP) pathway. This study aimed to elucidate the prognostic significance of CELSR3 in HCC patients. Methods The Cancer Genome Atlas (TCGA) database, the Cancer Cell Line Encyclopedia (CCLE) database and the Gene Expression Omnibus (GEO) database were used to analyze the expression of CELSR3 mRNA in HCC samples and cells. The relationship between CELSR3 mRNA and clinical features was assessed by the chi-square test. the diagnostic and predictive value of CELSR3 mRNA expression were analyzed using the receiver operating characteristic (ROC) curve. Kaplan–Meier curve and Cox regression analyses were performed to assess the prognostic value of CELSR3 mRNA in HCC patients. Finally, all three cohorts database was used for gene set enrichment analysis(GSEA) and the identification of CELSR3-related signal transduction pathways. Results The expression of CELSR3 mRNA was upregulated in HCC, and its expression was correlated with age (P = 0.025), tumor status (P = 0.022), clinical stage (P = 0.003), T classification (P = 0.010), vital status (P = 0.001), and relapse (P = 0.005). The ROC curve assessment indicated that CELSR3 mRNA expression has high diagnostic value in HCC and in the subgroup analysis of stage. In addition, the Kaplan-Meier curve and Cox analyses suggested that patients with high CELSR3 mRNA expression have a poor prognosis, indicating that CELSR3 mRNA is an independent prognostic factor for the overall survival of HCC patients. GSEA showed that GO somatic diversification of immune receptors, GO endonuclease activity, GO DNA repair complex and GO somatic cell DNA recombination, were differentially enriched in the meta-GEO cohort, the HCC cell line cohort and the TCGA cohort of the high CELSR3 mRNA expression phenotype. Conclusion Our results indicate that CELSR3 mRNA is involved in the progression of cancer and can be used as a biomarker for the prognosis of HCC patients.
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Affiliation(s)
- Xuefeng Gu
- Medical School, Southeast University, Nanjing, Jiangsu, China.,The Second Hospital of Nanjing, Medical School, Southeast University, Nanjing, Jiangsu, China
| | - Hongbo Li
- Department of Hepatology, Infectious diseases Hospital Affliated to Soochow University, Suzhou, Jiangsu, China
| | - Ling Sha
- Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yuan Mao
- Department of Hematology and Oncology, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, Nanjing, Jiangsu, China
| | - Chuanbing Shi
- Department of Pathology, Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Zhao
- Medical School, Southeast University, Nanjing, Jiangsu, China.,The Second Hospital of Nanjing, Medical School, Southeast University, Nanjing, Jiangsu, China
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23
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Farran B, Nagaraju GP. The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets. Cytokine Growth Factor Rev 2019; 48:11-23. [PMID: 31331827 DOI: 10.1016/j.cytogfr.2019.07.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023]
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24
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Pandey V, Storz P. Targeting the tumor microenvironment in pancreatic ductal adenocarcinoma. Expert Rev Anticancer Ther 2019; 19:473-482. [PMID: 31148495 PMCID: PMC6548630 DOI: 10.1080/14737140.2019.1622417] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/20/2019] [Indexed: 12/18/2022]
Abstract
Introduction: The dismally slow improvement in patient survival over the years for pancreatic cancer patients is mainly due to two factors: the late diagnosis, at which point the disease is spread to distant organs; and the fact that tumor cells are surrounded by a dense, highly immunosuppressive microenvironment. The tumor microenvironment not only shields pancreatic cancer cells from chemotherapy but also leaves it unsusceptible to various immunotherapeutic strategies that have been proven successful in other types of cancer. Areas covered: This review highlights the main components of the pancreatic tumor microenvironment, how they cross-talk with each other to generate stroma and promote tumor growth. Additionally, we discuss the most promising treatment targets in the microenvironment whose modulation can be robustly tested in combination with standard of care chemotherapy. Currently, active clinical trials for pancreatic cancer involving components of the microenvironment are also listed. Expert opinion: Although immunotherapeutic approaches involving checkpoint inhibition are being pursued enthusiastically, there is still more work to be done with several other emerging immune targets that could provide therapeutic benefit.
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Affiliation(s)
- Veethika Pandey
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
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25
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Saini F, Argent RH, Grabowska AM. Sonic Hedgehog Ligand: A Role in Formation of a Mesenchymal Niche in Human Pancreatic Ductal Adenocarcinoma. Cells 2019; 8:E424. [PMID: 31072042 PMCID: PMC6563044 DOI: 10.3390/cells8050424] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/05/2019] [Accepted: 05/07/2019] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterised by desmoplasia, thought to support progression and chemotherapeutic resistance. The Hedgehog pathway is known to play an important role in this cancer. While the upregulation of Sonic hedgehog (Shh) in the epithelium of PDAC is known, we investigated its expression in the tumour microenvironment in order to find new targets for new chemotherapeutical approaches. Immunohistochemistry was used for the investigation of Shh and Vimentin in primary human pancreatic tissues. Gene (qRT-PCR) and protein (immunofluorescence) expression of Shh, αSMA (a marker of the mesenchymal phenotype) and periostin (a marker of mesenchymal cells within a mixed population) were investigated in in vitro cell models. Shh expression was significantly upregulated in the stromal and epithelial compartments of poorly-differentiated PDAC samples, with a strong correlation with the amount of stroma present. Characterisation of stromal cells showed that there was expression of Shh ligand in a mixed population comprising αSMA+ myofibroblasts and αSMA- mesenchymal stem cells. Moreover, we demonstrated the interaction between these cell lines by showing a higher rate of mesenchymal cell proliferation and the upregulation of periostin. Therefore, targeting stromal Shh could affect the equilibrium of the tumour microenvironment and its contribution to tumour growth.
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Affiliation(s)
- Francesca Saini
- Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
| | - Richard H Argent
- Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
| | - Anna M Grabowska
- Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
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26
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Neuzillet C, Tijeras‐Raballand A, Ragulan C, Cros J, Patil Y, Martinet M, Erkan M, Kleeff J, Wilson J, Apte M, Tosolini M, Wilson AS, Delvecchio FR, Bousquet C, Paradis V, Hammel P, Sadanandam A, Kocher HM. Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J Pathol 2019; 248:51-65. [PMID: 30575030 PMCID: PMC6492001 DOI: 10.1002/path.5224] [Citation(s) in RCA: 221] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 11/18/2018] [Accepted: 12/18/2018] [Indexed: 12/13/2022]
Abstract
Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- versus anti-tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Cindy Neuzillet
- Centre for Tumour Biology, Barts Cancer Institute ‐ a CRUK Centre of ExcellenceQueen Mary University of LondonLondonUK
- Barts and The London HPB CentreThe Royal London HospitalBarts Health NHS Trust, LondonUK
- INSERM UMR1149Beaujon University Hospital, Paris 7 Diderot UniversityParisFrance
- Department of Medical OncologyCurie Institute, Versailles Saint‐Quentin UniversityParisFrance
| | | | - Chanthirika Ragulan
- Division of Molecular PathologyThe Institute of Cancer ResearchLondonUK
- Centre for Molecular PathologyThe Royal Marsden Hospital NHS Foundation TrustLondonUK
| | - Jérôme Cros
- INSERM UMR1149Beaujon University Hospital, Paris 7 Diderot UniversityParisFrance
- Department of PathologyBeaujon University Hospital, Paris 7 Diderot UniversityParisFrance
| | - Yatish Patil
- Division of Molecular PathologyThe Institute of Cancer ResearchLondonUK
- Centre for Molecular PathologyThe Royal Marsden Hospital NHS Foundation TrustLondonUK
| | | | - Mert Erkan
- Department of SurgeryKoc University School of MedicineIstanbulTurkey
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine SurgeryMartin‐Luther‐University Halle‐WittenbergHalle (Saale)Germany
| | - Jeremy Wilson
- Pancreatic Research Group, South Western Sydney Clinical SchoolUniversity of New South Wales and Ingham Institute for Applied Medical ResearchSydneyAustralia
| | - Minoti Apte
- Pancreatic Research Group, South Western Sydney Clinical SchoolUniversity of New South Wales and Ingham Institute for Applied Medical ResearchSydneyAustralia
| | - Marie Tosolini
- INSERM UMR 1037, Technological Pole and Bioinformatic PlatformCancer Research Center of ToulouseToulouseFrance
| | - Abigail S Wilson
- Centre for Tumour Biology, Barts Cancer Institute ‐ a CRUK Centre of ExcellenceQueen Mary University of LondonLondonUK
| | - Francesca R Delvecchio
- Centre for Tumour Biology, Barts Cancer Institute ‐ a CRUK Centre of ExcellenceQueen Mary University of LondonLondonUK
| | - Corinne Bousquet
- INSERM UMR 1037, Team 6 Protein Synthesis and Secretion in CarcinogenesisCancer Research Center of ToulouseToulouseFrance
| | - Valérie Paradis
- INSERM UMR1149Beaujon University Hospital, Paris 7 Diderot UniversityParisFrance
- Department of PathologyBeaujon University Hospital, Paris 7 Diderot UniversityParisFrance
| | - Pascal Hammel
- INSERM UMR1149Beaujon University Hospital, Paris 7 Diderot UniversityParisFrance
- Digestive Oncology UnitBeaujon University Hospital, Paris 7 Diderot UniversityParisFrance
| | - Anguraj Sadanandam
- Division of Molecular PathologyThe Institute of Cancer ResearchLondonUK
- Centre for Molecular PathologyThe Royal Marsden Hospital NHS Foundation TrustLondonUK
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute ‐ a CRUK Centre of ExcellenceQueen Mary University of LondonLondonUK
- Barts and The London HPB CentreThe Royal London HospitalBarts Health NHS Trust, LondonUK
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27
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Parente P, Parcesepe P, Covelli C, Olivieri N, Remo A, Pancione M, Latiano TP, Graziano P, Maiello E, Giordano G. Crosstalk between the Tumor Microenvironment and Immune System in Pancreatic Ductal Adenocarcinoma: Potential Targets for New Therapeutic Approaches. Gastroenterol Res Pract 2018; 2018:7530619. [PMID: 30662458 PMCID: PMC6312626 DOI: 10.1155/2018/7530619] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/04/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is a lethal disease for which radical surgery and chemotherapy represent the only curative options for a small proportion of patients. Recently, FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of metastatic patients but prognosis remains poor. A pancreatic tumor microenvironment is a dynamic milieu of cellular and acellular elements, and it represents one of the major limitations to chemotherapy efficacy. The continued crosstalk between cancer cells and the surrounding microenvironment causes immunosuppression within pancreatic immune infiltrate increasing tumor aggressiveness. Several potential targets have been identified among tumor microenvironment components, and different therapeutic approaches are under investigation. In this article, we provide a qualitative literature review about the crosstalk between the tumor microenvironment components and immune system in pancreatic cancer. Finally, we discuss potential therapeutic strategies targeting the tumor microenvironment and we show the ongoing trials.
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Affiliation(s)
- Paola Parente
- Fondazione IRCCS Casa Sollievo della Sofferenza, UO di Anatomia Patologica, Viale Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy
| | - Pietro Parcesepe
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, P.le L.A. Scuro 10, 37134 Verona, Italy
| | - Claudia Covelli
- Fondazione IRCCS Casa Sollievo della Sofferenza, UO di Anatomia Patologica, Viale Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy
| | - Nunzio Olivieri
- Biology Department, University of Naples Federico II, Via Mezzocannone 8, 80134 Naples, Italy
| | - Andrea Remo
- “Mater Salutis” Hospital, ULSS 9, Via C. Gianella 1, 37045 Legnago, Verona, Italy
| | - Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
| | - Tiziana Pia Latiano
- Fondazione IRCCS Casa Sollievo della Sofferenza, UO di Oncologia Medica, Viale Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy
| | - Paolo Graziano
- Fondazione IRCCS Casa Sollievo della Sofferenza, UO di Anatomia Patologica, Viale Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy
| | - Evaristo Maiello
- Fondazione IRCCS Casa Sollievo della Sofferenza, UO di Oncologia Medica, Viale Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy
| | - Guido Giordano
- Fondazione IRCCS Casa Sollievo della Sofferenza, UO di Oncologia Medica, Viale Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy
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Abstract
Stellate cells are resident lipid-storing cells of the pancreas and liver that transdifferentiate to a myofibroblastic state in the context of tissue injury. Beyond having roles in tissue homeostasis, stellate cells are increasingly implicated in pathological fibrogenic and inflammatory programs that contribute to tissue fibrosis and that constitute a growth-permissive tumor microenvironment. Although the capacity of stellate cells for extracellular matrix production and remodeling has long been appreciated, recent research efforts have demonstrated diverse roles for stellate cells in regulation of epithelial cell fate, immune modulation, and tissue health. Our present understanding of stellate cell biology in health and disease is discussed here, as are emerging means to target these multifaceted cells for therapeutic benefit.
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Affiliation(s)
- Mara H Sherman
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon 97201, USA;
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29
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Xue R, Jia K, Wang J, Yang L, Wang Y, Gao L, Hao J. A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front Physiol 2018; 9:754. [PMID: 29967585 PMCID: PMC6015921 DOI: 10.3389/fphys.2018.00754] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/29/2018] [Indexed: 12/17/2022] Open
Abstract
Pancreatic stellate cell (PSC) is a type of pluripotent cell located between pancreatic lobules and the surrounding area of acinars. When activated, PSC can be transformed into myofibroblast-like cell. A number of evidences suggest that activated PSC is the main source of the accumulation of extracellular matrix (ECM) protein under the pathological conditions, which lead to pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. Recent studies have found that PSC also plays an important role in the endocrine cell function, islet fibrosis and diabetes. In order to provide new strategies for the treatment of pancreatic diseases, this paper systematically summarizes the recent researches about the biological behaviors of PSC, including its stem/progenitor cell characteristics, secreted exosomes, cellular senescence, epithelial mesenchymal transformation (EMT), energy metabolism and direct mechanical reprogramming.
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Affiliation(s)
- Ran Xue
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Kai Jia
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jianxin Wang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lixin Yang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yanbin Wang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lingyun Gao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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30
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Experimental models of pancreatic cancer desmoplasia. J Transl Med 2018; 98:27-40. [PMID: 29155423 DOI: 10.1038/labinvest.2017.127] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 10/12/2017] [Accepted: 10/12/2017] [Indexed: 01/18/2023] Open
Abstract
Desmoplasia is a fibro-inflammatory process and a well-established feature of pancreatic cancer. A key contributor to pancreatic cancer desmoplasia is the pancreatic stellate cell. Various in vitro and in vivo methods have emerged for the isolation, characterization, and use of pancreatic stellate cells in models of cancer-associated fibrosis. In addition to cell culture models, genetically engineered animal models have been established that spontaneously develop pancreatic cancer with desmoplasia. These animal models are currently being used for the study of pancreatic cancer pathogenesis and for evaluating therapeutics against pancreatic cancer. Here, we review various in vitro and in vivo models that are being used or have the potential to be used to study desmoplasia in pancreatic cancer.
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31
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Liang C, Shi S, Meng Q, Liang D, Ji S, Zhang B, Qin Y, Xu J, Ni Q, Yu X. Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going. Exp Mol Med 2017; 49:e406. [PMID: 29611542 PMCID: PMC5750480 DOI: 10.1038/emm.2017.255] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 07/23/2017] [Accepted: 08/07/2017] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.
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Affiliation(s)
- Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Dingkong Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Ferdek PE, Jakubowska MA. Biology of pancreatic stellate cells-more than just pancreatic cancer. Pflugers Arch 2017; 469:1039-1050. [PMID: 28382480 PMCID: PMC5554282 DOI: 10.1007/s00424-017-1968-0] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 03/13/2017] [Accepted: 03/16/2017] [Indexed: 01/18/2023]
Abstract
Pancreatic stellate cells, normally quiescent, are capable of remarkable transition into their activated myofibroblast-like phenotype. It is now commonly accepted that these cells play a pivotal role in the desmoplastic reaction present in severe pancreatic disorders. In recent years, enormous scientific effort has been devoted to understanding their roles in pancreatic cancer, which continues to remain one of the most deadly diseases. Therefore, it is not surprising that considerably less attention has been given to studying physiological functions of pancreatic stellate cells. Here, we review recent advances not only in the field of pancreatic stellate cell pathophysiology but also emphasise their roles in physiological processes.
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Affiliation(s)
- Pawel E Ferdek
- Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, CF10 3AX, UK.
| | - Monika A Jakubowska
- Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, CF10 3AX, UK
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von Ahrens D, Bhagat TD, Nagrath D, Maitra A, Verma A. The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol 2017; 10:76. [PMID: 28351381 PMCID: PMC5371211 DOI: 10.1186/s13045-017-0448-5] [Citation(s) in RCA: 287] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/23/2017] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer generally refractory to conventional treatments. Cancer-associated fibroblasts (CAFs) are cellular components of the desmoplastic stroma characteristic to the tumor that contributes to this treatment resistance. Various markers for CAFs have been explored including palladin and CD146 that have prognostic and functional roles in the pathobiology of PDAC. Mechanisms of CAF-tumor cell interaction have been described including exosomal transfer and paracrine signaling mediated by cytokines such as GM-CSF and IL-6. The role of downstream signaling pathways including JAK/STAT, mTOR, sonic hedge hog (SHH), and NFkB have also been shown to play an important function in PDAC-CAF cross talk. The role of autophagy and other metabolic effects on each cell type within the tumor have also been proposed to play roles in facilitating CAF secretory function and enhancing tumor growth in a low-glucose microenvironment. Targeting the stroma has gained interest with multiple preclinical and clinical trials targeting SHH, JAK2, and methods of either exploiting the secretory capability of CAFs to enhance drug delivery or inhibiting it to prevent its influence on cancer cell chemoresistance. This review summarizes the most recent progress made in understanding stromal formation; its contribution to tumor proliferation, invasion, and metastasis; its role in chemoresistance; and potential therapeutic strategies on the horizon.
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Affiliation(s)
- Dagny von Ahrens
- Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA
| | - Tushar D Bhagat
- Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA
| | - Deepak Nagrath
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Anirban Maitra
- The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Amit Verma
- Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.
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Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology. Cancer Lett 2017; 392:83-93. [PMID: 28189533 DOI: 10.1016/j.canlet.2017.01.041] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 01/28/2017] [Accepted: 01/31/2017] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a "passive bystander", stroma may play a role as a "partner in crime" in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease.
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Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV, Reddy DN, Talukdar R. Pancreatic stellate cell: Pandora's box for pancreatic disease biology. World J Gastroenterol 2017; 23:382-405. [PMID: 28210075 PMCID: PMC5291844 DOI: 10.3748/wjg.v23.i3.382] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 11/09/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.
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Nielsen MFB, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016; 22:2678-2700. [PMID: 26973408 PMCID: PMC4777992 DOI: 10.3748/wjg.v22.i9.2678] [Citation(s) in RCA: 170] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/19/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and non-cellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a context-dependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.
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Bijlsma MF, van Laarhoven HWM. The conflicting roles of tumor stroma in pancreatic cancer and their contribution to the failure of clinical trials: a systematic review and critical appraisal. Cancer Metastasis Rev 2016; 34:97-114. [PMID: 25566685 DOI: 10.1007/s10555-014-9541-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
A nearly universal feature of pancreatic ductal adenocarcinoma (PDAC) is an extensive presence of activated stroma. This stroma is thought to aid in various tumor-promoting processes and hampers response to therapy. Here, we aim to evaluate the evidence that supports this role of the stroma in PDAC with functional experiments in relevant models, discuss the clinical trials that have aimed to target the stroma in this disease, and examine recent work that explains why these clinical trials based on stroma-targeting strategies have thus far not achieved the expected success. We systematically searched PubMed through August 2014 with no restrictions to identify published peer-reviewed research articles assessing the effect of targeting the stroma on tumor growth or metastases in preclinical animal models. Five hundred and thirty articles were extracted of which 31 were included in the analysis. Unfortunately, due to the large variety in models and outcome measures, we could not perform a meta-analysis of our data. We find that despite an abundance of positive outcomes reported in previous studies on stroma targeting, a strong discrepancy exists with the outcomes of clinical trials and the more recent preclinical work that is in line with these trials. We explain the incongruities by the duration of stroma targeting and propose that chronic stroma targeting treatment is possibly detrimental in the treatment of this disease.
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Affiliation(s)
- Maarten F Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
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Ali S, Suresh R, Banerjee S, Bao B, Xu Z, Wilson J, Philip PA, Apte M, Sarkar FH. Contribution of microRNAs in understanding the pancreatic tumor microenvironment involving cancer associated stellate and fibroblast cells. Am J Cancer Res 2015; 5:1251-1264. [PMID: 26046003 PMCID: PMC4449452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/15/2015] [Indexed: 06/04/2023] Open
Abstract
Understanding of molecular events associated with tumor microenvironment in pancreatic cancer (PC) is an active area of research especially because of the rich desmoplasia seen in human PC. Desmoplasia is contributed by several cell types including cancer-associated fibroblast (CAF) and stellate cells (PSCs), which are believed to play critical roles in conferring aggressiveness to PC. The aberrant expression of microRNAs (miRNAs) in PSCs and CAF cells appears to play a pivotal role in the development and progression of PC. In this study, expression analysis of miR-21/miR-221 in conditioned media derived from PSCs/CAF cells, and from PSCs/CAF cells showed up-regulation of both miRNAs compared to MIAPaCa-2 PC cells. In addition, miR-21 expression in stellate cells derived from normal pancreas was substantially lower when compared to PSCs or CAF cells. COLO-357 PC cells cultured in the presence of conditioned media derived from PSC/CAF cells led to a significant increase in clonogenicity and pancreatosphere formation. Furthermore, inhibition of miR-21 with antisense oligonucleotide (ASO) transfection resulted in decreased migration/invasive capacity of PSCs. Similarly, the effect of ASO-miR-221 transfection in CAF cells reduced the expression of NF-κB and K-Ras (target of miR-221) along with inhibition of migration/invasion. Moreover, miRNA expression profiling of PSCs, MIAPaCa-2, and COLO-357 cells, and further validation by real-time PCR, showed several differentially expressed miRNAs, among which four was significantly up-regulated. Collectively, these results suggest a crosstalk between PSCs/CAF cells and PC cells, resulting in the up-regulation of miR-21/miR-221 expression which in part may confer aggressiveness to PC. We conclude that targeting these miRNAs could be useful for developing precision medicine for the prevention of tumor progression and/or for the treatment of PC.
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Affiliation(s)
- Shadan Ali
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, Michigan
| | - Raagini Suresh
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, Michigan
| | - Sanjeev Banerjee
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, Michigan
| | - Bin Bao
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, Michigan
| | - Zhihong Xu
- Pancreatic Research Group, University of New South Wales, and Ingham Institute for Applied Medical ResearchSydney, Australia
| | - Jeremy Wilson
- Pancreatic Research Group, University of New South Wales, and Ingham Institute for Applied Medical ResearchSydney, Australia
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, Michigan
| | - Minoti Apte
- Pancreatic Research Group, University of New South Wales, and Ingham Institute for Applied Medical ResearchSydney, Australia
| | - Fazlul H Sarkar
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, Michigan
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, Michigan
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Fokas E, O'Neill E, Gordon-Weeks A, Mukherjee S, McKenna WG, Muschel RJ. Pancreatic ductal adenocarcinoma: From genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1855:61-82. [PMID: 25489989 DOI: 10.1016/j.bbcan.2014.12.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Revised: 12/01/2014] [Accepted: 12/03/2014] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Despite improvements in the clinical management, the prognosis of PDAC remains dismal. In the present comprehensive review, we will examine the knowledge of PDAC genetics and the new insights into human genome sequencing and clonal evolution. Additionally, the biology and the role of the stroma in tumour progression and response to treatment will be presented. Furthermore, we will describe the evidence on tumour chemoresistance and radioresistance and will provide an overview on the recent advances in PDAC metabolism and circulating tumour cells. Next, we will explore the characteristics and merits of the different mouse models of PDAC. The inflammatory milieu and the immunosuppressive microenvironment mediate tumour initiation and treatment failure. Hence, we will also review the inflammatory and immune escaping mechanisms and the new immunotherapies tested in PDAC. A better understanding of the different mechanisms of tumour formation and progression will help us to identify the best targets for testing in future clinical studies of PDAC.
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MESH Headings
- Animals
- Cancer Vaccines/therapeutic use
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/therapy
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Disease Models, Animal
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/immunology
- Humans
- Immunotherapy/methods
- Inflammation/pathology
- Mice
- Neoplastic Cells, Circulating/immunology
- Neoplastic Cells, Circulating/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/therapy
- Radiation Tolerance/genetics
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Affiliation(s)
- Emmanouil Fokas
- Department of Oncology, Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK.
| | - Eric O'Neill
- Department of Oncology, Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK
| | - Alex Gordon-Weeks
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Somnath Mukherjee
- Department of Oncology, Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK
| | - W Gillies McKenna
- Department of Oncology, Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK
| | - Ruth J Muschel
- Department of Oncology, Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK
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Lin WR, Yen TH, Lim SN, Perng MD, Lin CY, Su MY, Yeh CT, Chiu CT. Granulocyte colony-stimulating factor reduces fibrosis in a mouse model of chronic pancreatitis. PLoS One 2014; 9:e116229. [PMID: 25551560 PMCID: PMC4281240 DOI: 10.1371/journal.pone.0116229] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Accepted: 12/05/2014] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Chronic pancreatitis (CP) is a necroinflammatory process resulting in extensive pancreatic fibrosis. Granulocyte colony-stimulating factor (G-CSF), a hematopoietic stem cell mobilizer, has been shown to exert an anti-fibrotic effect partly through the enrichment of bone marrow (BM) cells in fibrotic organ. We aimed to test the effect of G-CSF on fibrosis in a mouse model of CP. METHODS CP was induced in C57Bl/6J mice by consecutive cerulein injection (50 µg/kg/day, 2 days a week) for 6 weeks. Mice were then treated with G-CSF (200 µg/kg/day, 5 day a week) or normal saline for 1 week, and sacrificed at week 7 or week 9 after first cerulein injection. Pancreatic histology, pancreatic matrix metallopeptidase 9 (MMP-9), MMP-13 and collagen expression were examined. Pancreatic myofibroblasts were isolated and cultured with G-CSF. Collagen, MMP-9 and MMP-13 expression by myofibroblasts was examined. The BM-mismatched mice model was used to examine the change of BM-derived myofibroblasts and non-myofibroblastic BM cells by G-CSF in the pancreas. RESULTS The pancreatic collagen expression were significantly decreased in the G-CSF-treated group sacrificed at week 9. While collagen produced from myofibroblasts was not affected by G-CSF, the increase of MMP13 expression was observed in vitro. There were no effect of G-CSF in the number of myofibroblasts and BM-derived myofibroblasts. However, the number of non-myofibroblastic BM cells and macrophages were significantly increased in the pancreata of cerulein- and G-CSF-treated mice, suggesting a potential anti-fibrotic role of non-myofibroblastic BM cells and macrophages stimulated by G-CSF. CONCLUSIONS Our data indicated that G-CSF contributed to the regression of pancreatic fibrosis. The anti-fibrotic effects were possibly through the stimulation of MMP-13 from myofibroblasts, and the enhanced accumulation of non-myofibroblastic BM cells and macrophages in the pancreas.
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Affiliation(s)
- Wey-Ran Lin
- Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Liver Research Unit, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tzung-Hai Yen
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Der Perng
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chun-Yen Lin
- Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Yo Su
- Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Unit, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Tang Chiu
- Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Very small embryonic-like stem cells are involved in regeneration of mouse pancreas post-pancreatectomy. Stem Cell Res Ther 2014; 5:106. [PMID: 25182166 PMCID: PMC4355147 DOI: 10.1186/scrt494] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 08/21/2014] [Indexed: 12/12/2022] Open
Abstract
Introduction Despite numerous research efforts, mechanisms underlying regeneration of pancreas remains controversial. Views are divided whether stem cells are involved during pancreatic regeneration or it involves duplication of pre-existing islets or ductal cells or whether pancreatic islet numbers are fixed by birth or they renew throughout life. Pluripotent embryonic stem (ES) and induced pluripotent stem (iPS) cells have been used by several groups to regenerate diabetic mouse pancreas but the beneficial effects are short-lived. It has been suggested that cells obtained after directed differentiation of ES/iPS cells resemble fetal and not their adult counterparts; thus are functionally different and may be of little use to regenerate adult pancreas. A novel population of pluripotent very small embryonic-like stem cells (VSELs) exists in several adult body tissues in both mice and humans. VSELs have been reported in the mouse pancreas, and nuclear octamer-binding transcription factor 4 (OCT-4) positive, small-sized cells have also been detected in human pancreas. VSELs are mobilized into peripheral blood in streptozotocin treated diabetic mice and also in patients with pancreatic cancer. This study aimed to evaluate whether VSELs are involved during regeneration of adult mouse pancreas after partial pancreatectomy. Methods Mice were subjected to partial pancreatectomy wherein almost 70% of pancreas was surgically removed and residual pancreas was studied on Days 1, 3 and 5 post-surgery. Results VSELs were detected in Hematoxylin and Eosin stained smears of pancreatic tissue as spherical, small sized cells with a large nucleus surrounded by a thin rim of cytoplasm and could be sorted as LIN-/CD45-/SCA-1+ cells by flow cytometry. Results reveal that although neutrophils with multi-lobed nuclei are mobilized into the pancreas on day 1 after pancreatectomy, by day 5 VSELs with spherical nuclei, high nucleo-cytoplasmic ratio and nuclear OCT-4 are mobilized into the residual pancreas. VSELs undergo differentiation and give rise to PDX-1 and OCT-4 positive progenitors which possibly regenerate both acinar cells and islets. Conclusions Results provide direct evidence supporting the presence of VSELs in adult mouse pancreas and their role during regeneration. VSELs are an interesting alternative to ES/iPS cells to regenerate a diabetic pancreas in future.
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Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014; 25:719-734. [PMID: 24856586 PMCID: PMC4180632 DOI: 10.1016/j.ccr.2014.04.005] [Citation(s) in RCA: 1878] [Impact Index Per Article: 170.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 02/08/2014] [Accepted: 04/10/2014] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
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Affiliation(s)
- Berna C Özdemir
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | | | - Julienne L Carstens
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Xiaofeng Zheng
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Chia-Chin Wu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Tyler R Simpson
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Hanane Laklai
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Hikaru Sugimoto
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | - Christoph Kahlert
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | - Sergey V Novitskiy
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Ana De Jesus-Acosta
- Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
| | - Padmanee Sharma
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Pedram Heidari
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Umar Mahmood
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Lynda Chin
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Harold L Moses
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Valerie M Weaver
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Anirban Maitra
- Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - James P Allison
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Valerie S LeBleu
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
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Ino K, Masuya M, Tawara I, Miyata E, Oda K, Nakamori Y, Suzuki K, Ohishi K, Katayama N. Monocytes infiltrate the pancreas via the MCP-1/CCR2 pathway and differentiate into stellate cells. PLoS One 2014; 9:e84889. [PMID: 24416305 PMCID: PMC3885670 DOI: 10.1371/journal.pone.0084889] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 11/24/2013] [Indexed: 01/11/2023] Open
Abstract
Recent studies have shown that monocytes possess pluripotent plasticity. We previously reported that monocytes could differentiate into hepatic stellate cells. Although stellate cells are also present in the pancreas, their origin remains unclear. An accumulation of enhanced green fluorescent protein (EGFP)+CD45– cells was observed in the pancreases and livers of chimeric mice, which were transplanted with a single hematopoietic stem cell isolated from EGFP-transgenic mice and treated with carbon tetrachloride (CCl4). Because the vast majority of EGFP+CD45– cells in the pancreas expressed stellate cell-associated antigens such as vimentin, desmin, glial fibrillary acidic protein, procollagen-I, and α-smooth muscle actin, they were characterized as pancreatic stellate cells (PaSCs). EGFP+ PaSCs were also observed in CCl4-treated mice adoptively transferred with monocytes but not with other cell lineages isolated from EGFP-transgenic mice. The expression of monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) increased in the pancreas of CCl4-treated mice and their respective receptors, C-C chemokine receptor 2 (CCR2) and Ang II type 1 receptor (AT1R), were expressed on Ly6Chigh monocytes isolated from EGFP-transgenic mice. We examined the effect of an AT1R antagonist, irbesartan, which is also a CCR2 antagonist, on the migration of monocytes into the pancreas. Monocytes migrated toward MCP-1 but not Ang II in vitro. Irbesartan inhibited not only their in vitro chemotaxis but also in vivo migration of adoptively transferred monocytes from peripheral blood into the pancreas. Irbesartan treatment significantly reduced the numbers of EGFP+F4/80+CCR2+ monocytic cells and EGFP+ PaSCs in the pancreas of CCl4-treated chimeric mice receiving EGFP+ bone marrow cells. A specific CCR2 antagonist RS504393 inhibited the occurrence of EGFP+ PaSCs in injured mice. We propose that CCR2+ monocytes migrate into the pancreas possibly via the MCP-1/CCR2 pathway and give rise to PaSCs.
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Affiliation(s)
- Kazuko Ino
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Masahiro Masuya
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
- * E-mail: (MM); (NK)
| | - Isao Tawara
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Eri Miyata
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Keiko Oda
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Yoshiki Nakamori
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kei Suzuki
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kohshi Ohishi
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Naoyuki Katayama
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
- * E-mail: (MM); (NK)
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Kano Y, Ishii H, Konno M, Yamasaki M, Miyata H, Nishikawa S, Hamabe A, Ogawa H, Takahashi H, Ohta K, Hasegawa S, Tanaka K, Fukusumi T, Otsuka M, Kawamoto K, Haraguchi N, Fujimoto R, Isobe M, Tomita Y, Matsuura N, Takiguchi S, Mori M, Doki Y. Cells of origin of squamous epithelium, dysplasia and cancer in the head and neck region after bone marrow transplantation. Int J Oncol 2013; 44:443-50. [PMID: 24317739 DOI: 10.3892/ijo.2013.2206] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 08/26/2013] [Indexed: 11/06/2022] Open
Abstract
Secondary solid tumors that occur after hematopoietic stem cell transplantation (HSCT) are late complications of HSCT. Previously, secondary solid tumors were considered to be recipient-derived cells because transplanted cells do not contain epithelial cells. Recently, however, not only donor‑derived epithelial cells but also donor-derived secondary solid tumors have also been reported in mice and humans. It means that circulating bone marrow-derived stem cells (BMDCs) including hematopoietic stem cells include the stem cells of many tissue types and the precancerous cells of many solid tumors. In most reports of donor-derived secondary solid tumors, however, tumors contained a low proportion of BMDC-derived epithelial cells in mixed solid tumor tissues. To our knowledge, there are only five known cases of completely donor-derived tumor tissues, i.e., four oral SCCs and a pharyngeal SCC. In this study, we analyzed five human clinical samples of solid tumors, i.e., two esophageal squamous cell carcinomas (SCCs), two oral SCCs and a tongue carcinoma. In the oral and tongue, completely donor-derived tissues were not observed, but in esophagus a completely donor-derived esophageal epidermis and SCC were observed for the first time. In addition, in another esophageal SCC patient, a completely donor-derived dysplasia region of esophageal epidermis was observed near recipient-derived SCC. This study suggests that BMDC-derived cells include the stem cells of esophageal epidermis and the precancerous cells of esophageal SCC and can differentiate into esophageal epithelium and esophageal SCC.
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Affiliation(s)
- Yoshihiro Kano
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Hiroshi Miyata
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Shimpei Nishikawa
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hamabe
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Hisataka Ogawa
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Katsuya Ohta
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Shinichiro Hasegawa
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Kouji Tanaka
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Takahito Fukusumi
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Masahisa Otsuka
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Rika Fujimoto
- Laboratory of Molecular and Cellular Biology, Department of Materials and Biosystem Engineering, Faculty of Engineering, Toyama University, Toyama, Japan
| | - Masaharu Isobe
- Laboratory of Molecular and Cellular Biology, Department of Materials and Biosystem Engineering, Faculty of Engineering, Toyama University, Toyama, Japan
| | - Yasuhiko Tomita
- Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Nariaki Matsuura
- Department of Functional Diagnostic Science, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan
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Yang C, Gu L, Deng D. Bone marrow-derived cells may not be the original cells for carcinogen-induced mouse gastrointestinal carcinomas. PLoS One 2013; 8:e79615. [PMID: 24260263 PMCID: PMC3834118 DOI: 10.1371/journal.pone.0079615] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 10/03/2013] [Indexed: 12/14/2022] Open
Abstract
AIM It has been reported that bone marrow-derived cells (BMDC) can be original cells of mouse gastric cancers induced by Helicobacter felis (H. felis) infection. However, it is unknown whether BMDCs are also the original cells of mouse gastrointestinal cancers induced by gastric carcinogens N-nitroso-N-methylurea (NMU) and H. felis infection. METHODS C57BL/6 recipient mice were initially irradiated with 10Gy X-ray, reconstituted with bone marrow cells from the C57BL/6-Tg (CAG-EGFP) donor mice to label BMDCs with green fluorescence protein (GFP). After 4 weeks of recovery, the bone marrow-transplanted mice were given NMU in drinking water (240 ppm) and subsequently infected with H. felis by gavage. Eighty weeks later, all mice were euthanized for pathological examination. The BMDCs expressing GFP were detected in tissues using direct GFP fluorescence confocal microscopy analysis and immunohistochemistry staining (IHC) assays. RESULTS Neoplastic lesions were induced by NMU treatment and/or H. felis infection at the antrum of the glandular stomach and small intestine. In the direct GFP fluorescence confocal assay, GFP(+) epithelial cell cluster or glands were not observed in these gastrointestinal tumors, however, most GFP(+) BMDCs sporadically located in the tumor stromal tissues. Some of these GFP(+) stromal BMDCs co-expressed the hematopoietic marker CD45 or myofibroblasts markers αSMA and SRF. In the indirect GFP IHC assay, similar results were observed among 11 gastric intraepithelial neoplasia lesions and 2 small intestine tumors. CONCLUSION These results demonstrated that BMDCs might not be the source of gastrointestinal tumor cells induced by NMU and/or H. felis infection.
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Affiliation(s)
- Chen Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital & Institute, Haidian District, Beijing, China
| | - Liankun Gu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital & Institute, Haidian District, Beijing, China
| | - Dajun Deng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital & Institute, Haidian District, Beijing, China
- * E-mail:
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Hamada S, Masamune A, Shimosegawa T. Alteration of pancreatic cancer cell functions by tumor-stromal cell interaction. Front Physiol 2013; 4:318. [PMID: 24198790 PMCID: PMC3814547 DOI: 10.3389/fphys.2013.00318] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 10/14/2013] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer shows a characteristic tissue structure called desmoplasia, which consists of dense fibrotic stroma surrounding cancer cells. Interactions between pancreatic cancer cells and stromal cells promote invasive growth of cancer cells and establish a specific microenvironment such as hypoxia which further aggravates the malignant behavior of cancer cells. Pancreatic stellate cells (PSCs) play a pivotal role in the development of fibrosis within the pancreatic cancer tissue, and also affect cancer cell function. PSCs induce epithelial-mesenchymal transition and cancer stem cell (CSC)-related phenotypes in pancreatic cancer cells by activating multiple signaling pathways. In addition, pancreatic cancer cells and PSCs recruit myeloid-derived suppressor cells which attenuate the immune reaction against pancreatic cancer cells. As a result, pancreatic cancer cells become refractory against conventional therapies. The formation of the CSC-niche by stromal cells facilitates postoperative recurrence, re-growth of therapy-resistant tumors and distant metastasis. Conventional therapies targeting cancer cells alone have failed to conquer pancreatic cancer, but targeting the stromal cells and immune cells in animal experiments has provided evidence of improved therapeutic responses. A combination of novel strategies altering stromal cell functions could contribute to improving the pancreatic cancer prognosis.
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Affiliation(s)
- Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine Sendai, Japan
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Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 2013; 144:1210-1219. [PMID: 23622130 PMCID: PMC3729446 DOI: 10.1053/j.gastro.2012.11.037] [Citation(s) in RCA: 363] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Revised: 11/27/2012] [Accepted: 11/28/2012] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. Treatments that target tumor cells have largely failed. This could be because research has focused on cancer cells and the influence of the stroma on tumor progression has been largely ignored. The focus of pancreatic cancer research began to change with the identification of pancreatic stellate cells, which produce the pancreatic tumor stroma. There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. We review the background and recent advances in these areas, along with important areas of future research that could improve therapy.
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Affiliation(s)
- Minoti V. Apte
- Pancreatic Research Groups
- Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales Sydney, New South Wales, Australia
| | - Jeremy S. Wilson
- Pancreatic Research Groups
- Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales Sydney, New South Wales, Australia
| | - Aurelia Lugea
- Pancreatic Research Groups
- Department of Veterans Affairs and University of California, Los Angeles, California
| | - Stephen J. Pandol
- Pancreatic Research Groups
- Department of Veterans Affairs and University of California, Los Angeles, California
- Cedars-Sinai Medical Center, Los Angeles, California
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48
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Starzyńska T, Dąbkowski K, Błogowski W, Zuba-Surma E, Budkowska M, Sałata D, Dołęgowska B, Marlicz W, Lubikowski J, Ratajczak MZ. An intensified systemic trafficking of bone marrow-derived stem/progenitor cells in patients with pancreatic cancer. J Cell Mol Med 2013; 17:792-9. [PMID: 23672538 PMCID: PMC3823183 DOI: 10.1111/jcmm.12065] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Accepted: 03/19/2013] [Indexed: 12/20/2022] Open
Abstract
Various experimental studies indicate potential involvement of bone marrow (BM)-derived stem cells (SCs) in malignancy development and progression. In this study, we comprehensively analysed systemic trafficking of various populations of BM-derived SCs (BMSCs), i.e., mesenchymal, haematopoietic, endothelial stem/progenitor cells (MSCs, HSCs, EPCs respectively), and of recently discovered population of very small embryonic/epiblast-like SCs (VSELs) in pancreatic cancer patients. Circulating CD133+/Lin−/CD45−/CD34+ cells enriched for HSCs, CD105+/STRO-1+/CD45− cells enriched for MSCs, CD34+/KDR+/CD31+/CD45− cells enriched for EPCs and small CXCR4+CD34+CD133+ subsets of Lin−CD45− cells that correspond to VSELs were enumerated and sorted from blood samples derived from 29 patients with pancreatic cancer, and 19 healthy controls. In addition, plasma levels of stromal-derived factor-1 (SDF-1), growth/inhibitory factors and sphingosine-1-phosphate (S1P; chemoattractants for SCs), as well as, of complement cascade (CC) molecules (C3a, C5a and C5b-9/membrane attack complex – MAC) were measured. Higher numbers of circulating VSELs and MSCs were detected in pancreatic cancer patients (P < 0.05 and 0.01 respectively). This trafficking of BMSCs was associated with significantly elevated C5a (P < 0.05) and C5b-9/MAC (P < 0.005) levels together with S1P concentrations detected in plasma of cancer patients, and seemed to be executed in a SDF-1 independent manner. In conclusion, we demonstrated that in patients with pancreatic cancer, intensified peripheral trafficking of selected populations of BMSCs occurs. This phenomenon seems to correlate with systemic activation of the CC, hepatocyte growth factor and S1P levels. In contrast to previous studies, we demonstrate herein that systemic SDF-1 levels do not seem to be linked with increased mobilization of stem cells in patients with pancreatic cancer.
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Affiliation(s)
- Teresa Starzyńska
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
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Demicheli R. Tumours and tissues: similar homeostatic systems? Target Oncol 2013; 8:97-105. [PMID: 23636780 DOI: 10.1007/s11523-013-0277-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 04/03/2013] [Indexed: 12/26/2022]
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50
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Scarlett CJ. Contribution of bone marrow derived cells to the pancreatic tumor microenvironment. Front Physiol 2013; 4:56. [PMID: 23531764 PMCID: PMC3607802 DOI: 10.3389/fphys.2013.00056] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 03/08/2013] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer is a complex, aggressive, and heterogeneous malignancy driven by the multifaceted interactions within the tumor microenvironment. While it is known that the tumor microenvironment accommodates many cell types, each playing a key role in tumorigenesis, the major source of these stromal cells is not well-understood. This review examines the contribution of bone marrow-derived cells (BMDC) to pancreatic carcinogenesis, with respect to their role in constituting the tumor microenvironment. In particular, their role in supporting fibrosis, immunosuppression, and neovascularization will be discussed.
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Affiliation(s)
- Christopher J Scarlett
- Food Bioactives and Pancreatic Cancer Biology Group, School of Environmental and Life Sciences, University of Newcastle Ourimbah, NSW, Australia ; Cancer Research Program, Garvan Institute of Medical Research Darlinghurst, Sydney, NSW, Australia
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