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1
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Fincham REA, Yeong JPS, Kocher HM. Developing cell-based therapies for pancreatic ductal adenocarcinoma. J Clin Invest 2025; 135:e189513. [PMID: 40231460 PMCID: PMC11996857 DOI: 10.1172/jci189513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
Abstract
Prostate stem cell antigen (PSCA) is highly and preferentially expressed on the surface of pancreatic ductal adenocarcinoma (PDAC) cells, raising the promise of tumor-selective cell-based immunotherapies. In this issue of the JCI, Dai et al. harness PSCA for the development of an off-the-shelf chimeric antigen receptor (CAR) invariant natural killer T (iNKT) cell-based treatment for PDAC. Through in vitro experiments and in vivo models, the authors demonstrate selectivity and therapeutic efficacy of PSCA CAR_sIL15 iNKT cells against both gemcitabine-sensitive and -resistant PDAC cells with comparable antitumor activity for freshly produced and frozen off-the-shelf PSCA CAR_sIL15 iNKT cells. This development opens another potential therapeutic option for pancreatic cancer.
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Affiliation(s)
- Rachel Elizabeth Ann Fincham
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Joe Poh Sheng Yeong
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore
- Centre for Quantitative Medicine, Duke-National University of Singapore (NUS) Medical School, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Hemant Mahendrakumar Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
- Barts and the London Hepato-Pancreato-Biliary (HPB) Centre, The Royal London Hospital, Barts Health National Health Service Trust, London, United Kingdom
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2
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Kocher HM, Sasieni P, Corrie P, McNamara MG, Sarker D, Froeling FEM, Christie A, Gillmore R, Khan K, Propper D. Study protocol: multi-centre, randomised controlled clinical trial exploring stromal targeting in locally advanced pancreatic cancer; STARPAC2. BMC Cancer 2025; 25:106. [PMID: 39833722 PMCID: PMC11748870 DOI: 10.1186/s12885-024-13333-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 12/11/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma, the commonest form), a lethal disease, is best treated with surgical excision but is feasible in less than a fifth of patients. Around a third of patients presentlocally advanced, inoperable, non-metastatic (laPDAC), whose stadrd of care is palliative chemotherapy; a small minority are down-sized sufficiently to enable surgical excision. We propose a phase II clinical trial to test whether a combination of standard chemotherapy (gemcitabine & nab-Paclitaxel: GEM-NABP) and repurposing All Trans Retinoic Acid (ATRA) to target the stroma may extend progression-free survival and enable successful surgical resection for patients with laPDAC, since data from phase IB clinical trial demonstrate safety of GEM-NABP-ATRA combination to patients with advanced PDAC with potential therapeutic benefit. METHODS Patients with laPDAC will receive at least six cycles of GEM-NABP with 1:1 randomisation to receive this with or without ATRA to assess response, until progression or intolerance. Those with stable/responding disease may undergo surgical resection. Primary endpoint is progression free survival (PFS) defined as the time from the date of randomisation to the date of first documented tumour progression (response evaluation criteria in solid tumours [RECIST] v1.1) or death from any cause, whichever occurs first. Secondary endpoints include objective response rate (ORR), overall survival (OS), safety and tolerability, surgical resection rate, R0 surgical resection rate and patient reported outcome measures (PROMS) as measured by questionnaire EQ-5D-5L. Exploratory endpoints include a decrease or increase in CA19-9 and serum Vitamin A over time correlated with ORR, PFS, and OS. DISCUSSION STARPAC2 aims to assess the role of stromal targeting in laPDAC. TRIAL REGISTRATION EudraCT: 2019-004231-23; NCT04241276; ISRCTN11503604.
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Affiliation(s)
- Hemant M Kocher
- Barts Cancer Institute and Wolfson Institute of Public Health, Mary University of London, John Vane Science Centre, Charterhouse Square, London, Queen, EC1M 6BQ, UK.
- Barts Health NHS Trust, Whitechapel, London, E1 1BB, UK.
- Centre for Tumour Biology, Queen Mary University of LondonBarts Cancer Institute- aCRUK Centre of Excellence, Charterhouse Square, London, EC1M 6BQ, UK.
| | - Peter Sasieni
- Barts Cancer Institute and Wolfson Institute of Public Health, Mary University of London, John Vane Science Centre, Charterhouse Square, London, Queen, EC1M 6BQ, UK
| | - Pippa Corrie
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Mairéad G McNamara
- Division of Cancer Sciences, Department of Medical Oncology, University of Manchester &, The Christie NHS Foundation Trust, Manchester, UK
| | | | | | | | | | - Khurum Khan
- University College London Hospitals NHS Foundation Trust, London, UK
| | - David Propper
- Barts Cancer Institute and Wolfson Institute of Public Health, Mary University of London, John Vane Science Centre, Charterhouse Square, London, Queen, EC1M 6BQ, UK
- Barts Health NHS Trust, Whitechapel, London, E1 1BB, UK
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3
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Zou J, Jiang C, Hu Q, Jia X, Wang S, Wan S, Mao Y, Zhang D, Zhang P, Dai B, Li Y. Tumor microenvironment-responsive engineered hybrid nanomedicine for photodynamic-immunotherapy via multi-pronged amplification of reactive oxygen species. Nat Commun 2025; 16:424. [PMID: 39762214 PMCID: PMC11704041 DOI: 10.1038/s41467-024-55658-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Reactive oxygen species (ROS) is promising in cancer therapy by accelerating tumor cell death, whose therapeutic efficacy, however, is greatly limited by the hypoxia in the tumor microenvironment (TME) and the antioxidant defense. Amplification of oxidative stress has been successfully employed for tumor therapy, but the interactions between cancer cells and the other factors of TME usually lead to inadequate tumor treatments. To tackle this issue, we develop a pH/redox dual-responsive nanomedicine based on the remodeling of cancer-associated fibroblasts (CAFs) for multi-pronged amplification of ROS (ZnPP@FQOS). It is demonstrated that ROS generated by ZnPP@FQOS is endogenously/exogenously multiply amplified owing to the CAFs remodeling and down-regulation of anti-oxidative stress in cancer cells, ultimately achieving the efficient photodynamic therapy in a female tumor-bearing mouse model. More importantly, ZnPP@FQOS is verified to enable the stimulation of enhanced immune responses and systemic immunity. This strategy remarkably potentiates the efficacy of photodynamic-immunotherapy, thus providing a promising enlightenment for tumor therapy.
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Grants
- This work was financially supported by the National Key Research and Development Program of China (No. 2022YFC2403203, Y.L.), the National Natural Science Foundation of China (No. 22305081, D.Z.), Basic Research Program of Shanghai (No. 21JC1406003, Y.L.), Leading Talents in Shanghai in 2018, the Key Field Research Program (No. 2023AB054, Y.L.), Shanghai Sailing Program (23YF1408600, D.Z.) and the Innovation Program of Shanghai Municipal Education Commission (No. 2023ZKZD33, P.Z.)
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Affiliation(s)
- Jinglin Zou
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Cong Jiang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiangsheng Hu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinlin Jia
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuqi Wang
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Shiyue Wan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuanqing Mao
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dapeng Zhang
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Bin Dai
- Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, China
| | - Yongsheng Li
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China.
- Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, China.
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4
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Sun L, Zheng M, Gao Y, Brigstock DR, Gao R. Retinoic acid signaling pathway in pancreatic stellate cells: Insight into the anti-fibrotic effect and mechanism. Eur J Pharmacol 2024; 967:176374. [PMID: 38309676 DOI: 10.1016/j.ejphar.2024.176374] [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: 10/14/2023] [Revised: 01/15/2024] [Accepted: 01/30/2024] [Indexed: 02/05/2024]
Abstract
Pancreatic stellate cells (PSCs) are activated following loss of cytoplasmic vitamin A (retinol)-containing lipid droplets, which is a key event in the process of fibrogenesis of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDCA). PSCs are the major source of cancer-associated fibroblasts (CAFs) that produce stroma to induce PDAC cancer cell growth, invasion, and metastasis. As an active metabolite of retinol, retinoic acid (RA) can regulate target gene expression in PSCs through its nuclear receptor complex (RAR/RXR or RXR/RXR) or transcriptional intermediary factor. Additionally, RA also has extranuclear and non-transcriptional effects. In vitro studies have shown that RA induces PSC deactivation which reduces extracellular matrix production through multiple modes of action, such as inhibiting TβRⅡ, PDGFRβ, β-catenin and Wnt production, downregulating ERK1/2 and JNK phosphorylation and suppressing active TGF-β1 release. RA alone or in combination with other reagents have been demonstrated to have an effective anti-fibrotic effect on cerulein-induced mouse CP models in vivo studies. Clinical trial data have shown that repurposing all-trans retinoic acid (ATRA) as a stromal-targeting agent for human pancreatic cancer is safe and tolerable, suggesting the possibility of using RA for the treatment of CP and PDCA in humans. This review focuses on RA signaling pathways in PSCs and the effects and mechanisms of RA in PSC-mediated fibrogenesis as well as the anti-fibrotic and anti-tumor effects of RA targeting PSCs or CAFs in vitro and in vivo, highlighting the potential therapies of RA against CP and PDAC.
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Affiliation(s)
- Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Pathology, First Hospital of Jilin University, Changchun, China
| | - Meifang Zheng
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yanhang Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
| | - David R Brigstock
- The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
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Aguirre GA, Goulart MR, Barts Pancreas Tissue Bank, Dalli J, Kocher HM. Arachidonate 15-lipoxygenase-mediated production of Resolvin D5 n-3 DPA abrogates pancreatic stellate cell-induced cancer cell invasion. Front Immunol 2023; 14:1248547. [PMID: 38035115 PMCID: PMC10687150 DOI: 10.3389/fimmu.2023.1248547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/26/2023] [Indexed: 12/02/2023] Open
Abstract
Activation of pancreatic stellate cells (PSCs) to cancer-associated fibroblasts (CAFs) is responsible for the extensive desmoplastic reaction observed in PDAC stroma: a key driver of pancreatic ductal adenocarcinoma (PDAC) chemoresistance leading to poor prognosis. Specialized pro-resolving mediators (SPMs) are prime modulators of inflammation and its resolution, traditionally thought to be produced by immune cells. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid mediator profiling PSCs as well as primary human CAFs express enzymes and receptors to produce and respond to SPMs. Human PSC/CAF SPM secretion profile can be modulated by rendering these cells activated [transforming growth factor beta (TGF-β)] or quiescent [all-trans retinoic acid (ATRA)]. ATRA-induced nuclear translocation of arachidonate-15-lipoxygenase (ALOX15) was linked to increased production of n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA), among other SPMs. Inhibition of RvD5n-3 DPA formation increases cancer cell invasion, whereas addback of this molecule reduced activated PSC-mediated cancer cell invasion. We also observed that circulating concentrations of RvD5n-3 DPA levels were decreased in peripheral blood of metastatic PDAC patients when compared with those measured in plasma of non-metastatic PDAC patients. Together, these findings indicate that RvD5n-3 DPA may regulate cancer-stroma cross-talk and invasion.
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Affiliation(s)
- Gabriel A. Aguirre
- Centre for Tumour Biology, Barts Cancer Institute, London, United Kingdom
| | | | | | - Jesmond Dalli
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Queen Mary University of London, London, United Kingdom
| | - Hemant M. Kocher
- Centre for Tumour Biology, Barts Cancer Institute, London, United Kingdom
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Cao J, Wu J, Yang P, Qian K, Cheng Y, Xu M, Sheng D, Meng R, Wang T, Li Y, Wei Y, Zhang Q. Dual Enzyme Cascade-Activated Popcorn-Like Nanoparticles Efficiently Remodeled Stellate Cells to Alleviate Pancreatic Desmoplasia. ACS NANO 2023; 17:19793-19809. [PMID: 37805928 DOI: 10.1021/acsnano.3c03838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors.
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Affiliation(s)
- Jinxu Cao
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430081, China
| | - Jing Wu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Peng Yang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Kang Qian
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yunlong Cheng
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Minjun Xu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Dongyu Sheng
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Ran Meng
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Tianying Wang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yixian Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yan Wei
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
| | - Qizhi Zhang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
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7
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Flies DB, Langermann S, Jensen C, Karsdal MA, Willumsen N. Regulation of tumor immunity and immunotherapy by the tumor collagen extracellular matrix. Front Immunol 2023; 14:1199513. [PMID: 37662958 PMCID: PMC10470046 DOI: 10.3389/fimmu.2023.1199513] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/28/2023] [Indexed: 09/05/2023] Open
Abstract
It has been known for decades that the tumor extracellular matrix (ECM) is dysfunctional leading to loss of tissue architecture and promotion of tumor growth. The altered ECM and tumor fibrogenesis leads to tissue stiffness that act as a physical barrier to immune cell infiltration into the tumor microenvironment (TME). It is becoming increasingly clear that the ECM plays important roles in tumor immune responses. A growing body of data now indicates that ECM components also play a more active role in immune regulation when dysregulated ECM components act as ligands to interact with receptors on immune cells to inhibit immune cell subpopulations in the TME. In addition, immunotherapies such as checkpoint inhibitors that are approved to treat cancer are often hindered by ECM changes. In this review we highlight the ways by which ECM alterations affect and regulate immunity in cancer. More specifically, how collagens and major ECM components, suppress immunity in the complex TME. Finally, we will review how our increased understanding of immune and immunotherapy regulation by the ECM is leading towards novel disruptive strategies to overcome immune suppression.
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8
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Bryce AS, Dreyer SB, Froeling FEM, Chang DK. Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer. Cancers (Basel) 2022; 14:5302. [PMID: 36358721 PMCID: PMC9659154 DOI: 10.3390/cancers14215302] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 08/23/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.
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Affiliation(s)
- Adam S. Bryce
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
| | - Stephan B. Dreyer
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
| | - Fieke E. M. Froeling
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
- Beatson West of Scotland Cancer Centre, 1053 Great Western Rd, Glasgow G12 0YN, UK
| | - David K. Chang
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Switchback Road, Bearsden G61 1BD, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
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9
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Rimal R, Desai P, Daware R, Hosseinnejad A, Prakash J, Lammers T, Singh S. Cancer-associated fibroblasts: Origin, function, imaging, and therapeutic targeting. Adv Drug Deliv Rev 2022; 189:114504. [PMID: 35998825 DOI: 10.1016/j.addr.2022.114504] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 07/10/2022] [Accepted: 08/17/2022] [Indexed: 02/06/2023]
Abstract
The tumor microenvironment (TME) is emerging as one of the primary barriers in cancer therapy. Cancer-associated fibroblasts (CAF) are a common inhabitant of the TME in several tumor types and play a critical role in tumor progression and drug resistance via different mechanisms such as desmoplasia, angiogenesis, immune modulation, and cancer metabolism. Due to their abundance and significance in pro-tumorigenic mechanisms, CAF are gaining attention as a diagnostic target as well as to improve the efficacy of cancer therapy by their modulation. In this review, we highlight existing imaging techniques that are used for the visualization of CAF and CAF-induced fibrosis and provide an overview of compounds that are known to modulate CAF activity. Subsequently, we also discuss CAF-targeted and CAF-modulating nanocarriers. Finally, our review addresses ongoing challenges and provides a glimpse into the prospects that can spearhead the transition of CAF-targeted therapies from opportunity to reality.
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Affiliation(s)
- Rahul Rimal
- Max Planck Institute for Medical Research (MPImF), Jahnstrasse 29, 69120 Heidelberg, Germany
| | - Prachi Desai
- DWI-Leibniz Institute for Interactive Materials, RWTH Aachen University, Forkenbeckstrasse 50, 52074 Aachen, Germany
| | - Rasika Daware
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Aisa Hosseinnejad
- DWI-Leibniz Institute for Interactive Materials, RWTH Aachen University, Forkenbeckstrasse 50, 52074 Aachen, Germany
| | - Jai Prakash
- Department of Advanced Organ Bioengineering and Therapeutics, Section: Engineered Therapeutics, Technical Medical Centre, University of Twente, 7500AE Enschede, the Netherlands.
| | - Twan Lammers
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
| | - Smriti Singh
- Max Planck Institute for Medical Research (MPImF), Jahnstrasse 29, 69120 Heidelberg, Germany.
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10
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Menezes S, Okail MH, Jalil SMA, Kocher HM, Cameron AJM. Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets. J Pathol 2022; 257:526-544. [PMID: 35533046 PMCID: PMC9327514 DOI: 10.1002/path.5926] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/03/2022] [Accepted: 05/05/2022] [Indexed: 11/29/2022]
Abstract
Cancer-associated fibroblasts (CAFs) have conflicting roles in the suppression and promotion of cancer. Current research focuses on targeting the undesirable properties of CAFs, while attempting to maintain tumour-suppressive roles. CAFs have been widely associated with primary or secondary therapeutic resistance, and strategies to modify CAF function have therefore largely focussed on their combination with existing therapies. Despite significant progress in preclinical studies, clinical translation of CAF targeted therapies has achieved limited success. Here we will review our emerging understanding of heterogeneous CAF populations in tumour biology and use examples from pancreatic ductal adenocarcinoma to explore why successful clinical targeting of protumourigenic CAF functions remains elusive. Single-cell technologies have allowed the identification of CAF subtypes with a differential impact on prognosis and response to therapy, but currently without clear consensus. Identification and pharmacological targeting of CAF subtypes associated with immunotherapy response offers new hope to expand clinical options for pancreatic cancer. Various CAF subtype markers may represent biomarkers for patient stratification, to obtain enhanced response with existing and emerging combinatorial therapeutic strategies. Thus, CAF subtyping is the next frontier in understanding and exploiting the tumour microenvironment for therapeutic benefit. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Shinelle Menezes
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Mohamed Hazem Okail
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Siti Munira Abd Jalil
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Hemant M Kocher
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
- Barts and the London HPB Centre, The Royal London HospitalBarts Health NHS TrustLondonUK
| | - Angus J M Cameron
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
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11
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Nano-delivery of salvianolic acid B induces the quiescence of tumor-associated fibroblasts via interfering with TGF-β1/Smad signaling to facilitate chemo- and immunotherapy in desmoplastic tumor. Int J Pharm 2022; 623:121953. [PMID: 35753535 DOI: 10.1016/j.ijpharm.2022.121953] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/01/2022] [Accepted: 06/21/2022] [Indexed: 02/06/2023]
Abstract
As the key stromal cells that mediate the desmoplastic reaction, tumor-associated fibroblasts (TAFs) play a critical role in the limited nanoparticle penetration and suppressive immune tumor microenvironment. Herein, we found that salvianolic acid B-loaded PEGylated liposomes (PEG-SAB-Lip) can interfere with the activation of TAFs by inhibiting the secretion of TGF-β1. After inhibiting the activation of TAFs, collagen deposition in tumors was reduced, and the penetration of nanoparticles in tumors was enhanced. The results of RT-qPCR and immunofluorescence staining showed the high expression of Th1 cytokines and chemokines (CXCL9 and CXCL10) and the recruitment of CD4+, CD8+ T cells, and M1 macrophages in the tumor area. At the same time, the low expression of Th2 cytokine and chemokine CXCL13, as well as the decrease of MDSCs, Tregs, and M2 macrophages were also observed in the tumor area. These results were related to the inactivation of TAFs. The combined treatment of PEG-SAB-Lip and docetaxel-loaded PEG-modified liposomes (PEG-DTX-Lip) can significantly inhibit tumor growth. Moreover, PEG-SAB-Lip further inhibited tumor metastasis to the lung. Therefore, our results showed that PEG-SAB-Lip can remodel the tumor microenvironment and improve the efficacy of nanoparticles.
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12
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Chen Q, Wang Q, Wang Y, Chu Y, Luo Y, You H, Su B, Li C, Guo Q, Sun T, Jiang C. Penetrating Micelle for Reversing Immunosuppression and Drug Resistance in Pancreatic Cancer Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2107712. [PMID: 35285149 DOI: 10.1002/smll.202107712] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/11/2022] [Indexed: 06/14/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is on of the most lethal malignant tumors with relatively poor prognosis, characterized with insufficient drug penetration, low immune response and obvious drug resistances. The therapeutic inefficiency is multifactorially related to its specific tumor microenvironment (TME), which is representatively featured as rich stroma and immunosuppression. In this work, a versatile drug delivery system is developed that can coencapsulate two prodrugs modified from gemcitabine (GEM) and a signal transducer and activator of transcription 3 (STAT3) inhibitor (HJC0152), and the gradient pH variation is further sensed in the TME of PDAC to achieve a higher penetration by reversing its surficial charges. The escorted prodrugs can release GEM intracellularly, and respond to the hypoxic condition to yield the parental STAT3 inhibitor HJC0152, respectively. By inhibiting STAT3, the tumor immunosuppression microenvironment can be re-educated through the reversion of M2-like tumor associated macrophages (M2-TAMs), recruitment of cytotoxic T lymphocytes and downregulation of regulatory T cells (Treg s). Furthermore, cytidine deaminase (CDA) and α-smooth muscle actin (α-SMA) expression can be downregulated, plus the lipid modification of GEM, the drug resistance of GEM can be greatly relieved. Based on the above design, a synergetic therapeutic efficacy in PDAC treatment can be achieved to provide more opportunity for clinical applications.
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Affiliation(s)
- Qinjun Chen
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Qingbing Wang
- Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Yu Wang
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Yongchao Chu
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Yifan Luo
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Haoyu You
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Boyu Su
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Chao Li
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Qin Guo
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Tao Sun
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Chen Jiang
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
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13
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Willumsen N, Jensen C, Green G, Nissen NI, Neely J, Nelson DM, Pedersen RS, Frederiksen P, Chen IM, Boisen MK, Johansen AZ, Madsen DH, Svane IM, Lipton A, Leitzel K, Ali SM, Erler JT, Hurkmans DP, Mathijssen RHJ, Aerts J, Eslam M, George J, Christiansen C, Bissel MJ, Karsdal MA. Fibrotic activity quantified in serum by measurements of type III collagen pro-peptides can be used for prognosis across different solid tumor types. Cell Mol Life Sci 2022; 79:204. [PMID: 35332383 PMCID: PMC8948122 DOI: 10.1007/s00018-022-04226-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/15/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022]
Abstract
Due to activation of fibroblast into cancer-associated fibroblasts, there is often an increased deposition of extracellular matrix and fibrillar collagens, e.g. type III collagen, in the tumor microenvironment (TME) that leads to tumor fibrosis (desmoplasia). Tumor fibrosis is closely associated with treatment response and poor prognosis for patients with solid tumors. To assure that the best possible treatment option is provided for patients, there is medical need for identifying patients with high (or low) fibrotic activity in the TME. Measuring unique collagen fragments such as the pro-peptides released into the bloodstream during fibrillar collagen deposition in the TME can provide a non-invasive measure of the fibrotic activity. Based on data from 8 previously published cohorts, this review provides insight into the prognostic value of quantifying tumor fibrosis by measuring the pro-peptide of type III collagen in serum of a total of 1692 patients with different solid tumor types and discusses the importance of tumor fibrosis for understanding prognosis and for potentially guiding future drug development efforts that aim at overcoming the poor outcome associated with a fibrotic TME.
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Affiliation(s)
| | - Christina Jensen
- Nordic Bioscience, Herlev Hovedgade 205-207, 2730, Herlev, Denmark
| | | | - Neel I Nissen
- Nordic Bioscience, Herlev Hovedgade 205-207, 2730, Herlev, Denmark
| | | | | | | | | | - Inna M Chen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Mogens K Boisen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Astrid Z Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Daniel H Madsen
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Inge Marie Svane
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Allan Lipton
- Penn State Hershey Medical Center, Hershey, PA, USA
| | - Kim Leitzel
- Penn State Hershey Medical Center, Hershey, PA, USA
| | | | - Janine T Erler
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Daan P Hurkmans
- Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Joachim Aerts
- Department of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | | | - Mina J Bissel
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Morten A Karsdal
- Nordic Bioscience, Herlev Hovedgade 205-207, 2730, Herlev, Denmark
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14
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Delvecchio FR, Goulart MR, Fincham REA, Bombadieri M, Kocher HM. B cells in pancreatic cancer stroma. World J Gastroenterol 2022; 28:1088-1101. [PMID: 35431504 PMCID: PMC8985484 DOI: 10.3748/wjg.v28.i11.1088] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/18/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a disease with high unmet clinical need. Pancreatic cancer is also characterised by an intense fibrotic stroma, which harbours many immune cells. Studies in both human and animal models have demonstrated that the immune system plays a crucial role in modulating tumour onset and progression. In human pancreatic ductal adenocarcinoma, high B-cell infiltration correlates with better patient survival. Hence, B cells have received recent interest in pancreatic cancer as potential therapeutic targets. However, the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to study. Nevertheless, it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells (DCs), surrounded by T cells and DCs to form tertiary lymphoid structures (TLS). TLS are increasingly recognised as sites for antigen presentation, T-cell activation, B-cell maturation and differentiation in plasma cells. In this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.
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Affiliation(s)
- Francesca Romana Delvecchio
- William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Michelle R Goulart
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | | | - Michele Bombadieri
- William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Hemant M Kocher
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
- Barts and the London HPB Centre, Barts Health NHS Trust, London E1 1BB, United Kingdom
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15
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Nissen NI, Johansen AZ, Chen I, Johansen JS, Pedersen RS, Hansen CP, Karsdal MA, Willumsen N. Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:819. [PMID: 35159087 PMCID: PMC8833921 DOI: 10.3390/cancers14030819] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 01/30/2022] [Accepted: 02/02/2022] [Indexed: 11/24/2022] Open
Abstract
The use of novel tools to understand tumour-fibrosis in pancreatic ductal adenocarcinoma (PDAC) and novel anti-fibrotic treatments are highly needed. We established a pseudo-3D in vitro model including humane pancreatic fibroblasts (PFs) and pancreatic cancer-associated fibroblasts (CAFs) in combination with clinical collagen biomarkers, as a translational anti-fibrotic drug screening tool. Furthermore, we investigated the prognostic potential of serum collagen biomarkers in 810 patients with PDAC. PFs and CAFs were cultured in Ficoll-media. Cells were treated w/wo TGF-ß1 and the anti-fibrotic compound ALK5i. Biomarkers measuring the formation of type III (PRO-C3) and VI (PRO-C6) collagens were measured by ELISA in supernatant at days 3, 6, 9, and 12. PRO-C3 and PRO-C6, and their association with overall survival (OS), were evaluated in serum with PDAC (n = 810). PRO-C3 and PRO-C6 were upregulated in CAFs compared to PFs (p < 0.0001.). TGF-ß1 increased PRO-C3 in both PFs and CAFs (p < 0.0001). The anti-fibrotic compound ALK5i inhibited both PRO-C3 and PRO-C6 (p < 0.0001). High serum levels of PRO-C3 and PRO-C6 in patients with PDAC were associated with short OS (PRO-C3: HR = 1.48, 95%CI: 1.29-1.71, p < 0.0001 and PRO-C6: HR = 1.31, 95%CI: 1.14-1.50, p = 0.0002). PRO-C3 and PRO-C6 have the potential to be used both pre-clinically and clinically as a measure of tumor fibrosis and CAF activity.
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Affiliation(s)
- Neel I. Nissen
- Biotech Research & Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark
- Biomarkers & Research, Nordic Bioscience, 2730 Herlev, Denmark; (R.S.P.); (M.A.K.); (N.W.)
| | - Astrid Z. Johansen
- Department of Oncology, Copenhagen University Hospital—Herlev and Gentofte, 2730 Herlev, Denmark; (A.Z.J.); (I.C.); (J.S.J.)
| | - Inna Chen
- Department of Oncology, Copenhagen University Hospital—Herlev and Gentofte, 2730 Herlev, Denmark; (A.Z.J.); (I.C.); (J.S.J.)
| | - Julia S. Johansen
- Department of Oncology, Copenhagen University Hospital—Herlev and Gentofte, 2730 Herlev, Denmark; (A.Z.J.); (I.C.); (J.S.J.)
- Department of Medicine, Copenhagen University Hospital—Herlev and Gentofte, 2730 Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Rasmus S. Pedersen
- Biomarkers & Research, Nordic Bioscience, 2730 Herlev, Denmark; (R.S.P.); (M.A.K.); (N.W.)
- Department of Biomedical Science, University of Copenhagen (UCPH), 2200 Copenhagen, Denmark
| | - Carsten P. Hansen
- Department of Surgery, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark;
| | - Morten A. Karsdal
- Biomarkers & Research, Nordic Bioscience, 2730 Herlev, Denmark; (R.S.P.); (M.A.K.); (N.W.)
| | - Nicholas Willumsen
- Biomarkers & Research, Nordic Bioscience, 2730 Herlev, Denmark; (R.S.P.); (M.A.K.); (N.W.)
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16
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Murray ER, Menezes S, Henry JC, Williams JL, Alba-Castellón L, Baskaran P, Quétier I, Desai A, Marshall JJT, Rosewell I, Tatari M, Rajeeve V, Khan F, Wang J, Kotantaki P, Tyler EJ, Singh N, Reader CS, Carter EP, Hodivala-Dilke K, Grose RP, Kocher HM, Gavara N, Pearce O, Cutillas P, Marshall JF, Cameron AJM. Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion. Cell Rep 2022; 38:110227. [PMID: 35081338 PMCID: PMC8810397 DOI: 10.1016/j.celrep.2021.110227] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 10/18/2021] [Accepted: 12/15/2021] [Indexed: 12/13/2022] Open
Abstract
In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.
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Affiliation(s)
- Elizabeth R Murray
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Shinelle Menezes
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Jack C Henry
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Josie L Williams
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Lorena Alba-Castellón
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Priththivika Baskaran
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Ivan Quétier
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Ami Desai
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Jacqueline J T Marshall
- Protein Phosphorylation Laboratory, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Ian Rosewell
- Transgenic Services, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Marianthi Tatari
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Vinothini Rajeeve
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Faraz Khan
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Jun Wang
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Panoraia Kotantaki
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Eleanor J Tyler
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Namrata Singh
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Claire S Reader
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Edward P Carter
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Kairbaan Hodivala-Dilke
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Richard P Grose
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Hemant M Kocher
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London E1 1BB, UK
| | - Nuria Gavara
- Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
| | - Oliver Pearce
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Pedro Cutillas
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - John F Marshall
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Angus J M Cameron
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
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17
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Goulart MR, Stasinos K, Fincham REA, Delvecchio FR, Kocher HM. T cells in pancreatic cancer stroma. World J Gastroenterol 2021; 27:7956-7968. [PMID: 35046623 PMCID: PMC8678814 DOI: 10.3748/wjg.v27.i46.7956] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/18/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a dismal 5-year survival rate. PDAC has a complex tumour microenvironment; characterised by a robust desmoplastic stroma, extensive infiltration of immunesuppressive cells such as immature myeloid cells, tumour-associated macrophages, neutrophils and regulatory T cells, and the presence of exhausted and senescent T cells. The cross-talk between cells in this fibrotic tumour establishes an immune-privileged microenvironment that supports tumour cell escape from immune-surveillance, disease progression and spread to distant organs. PDAC tumours, considered to be non-immunogenic or cold, express low mutation burden, low infiltration of CD8+ cytotoxic lymphocytes that are localised along the invasive margin of the tumour border in the surrounding fibrotic tissue, and often display an exhausted phenotype. Here, we review the role of T cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of T cells as therapy.
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Affiliation(s)
- Michelle R Goulart
- Centre for Tumour Biology Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Konstantinos Stasinos
- Centre for Tumour Biology Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, United Kingdom
| | - Rachel Elizabeth Ann Fincham
- Centre for Tumour Biology Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Francesca R Delvecchio
- Centre for Tumour Biology Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Hemant M Kocher
- Centre for Tumour Biology Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, United Kingdom
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18
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Goulart MR, Watt J, Siddiqui I, Lawlor RT, Imrali A, Hughes C, Saad A, ChinAleong J, Hurt C, Cox C, Salvia R, Mantovani A, Crnogorac-Jurcevic T, Mukherjee S, Scarpa A, Allavena P, Kocher HM. Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma. NPJ Precis Oncol 2021; 5:61. [PMID: 34188166 PMCID: PMC8242009 DOI: 10.1038/s41698-021-00192-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 05/25/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65-97%) and specificity (86%, 95% CI: 79-91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.
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Affiliation(s)
- Michelle R Goulart
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK
| | - Jennifer Watt
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Imran Siddiqui
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, Rozzano, Italy
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Rita T Lawlor
- ARC-NET Research Center for Applied Research on Cancer, and Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Ahmet Imrali
- Barts Pancreas Tissue Bank, Barts Cancer Institute- a CRUK Centre of Excellence, Queen Mary University London, London, UK
| | - Christine Hughes
- Barts Pancreas Tissue Bank, Barts Cancer Institute- a CRUK Centre of Excellence, Queen Mary University London, London, UK
| | - Amina Saad
- Barts Pancreas Tissue Bank, Barts Cancer Institute- a CRUK Centre of Excellence, Queen Mary University London, London, UK
| | - Joanne ChinAleong
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Chris Hurt
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Catrin Cox
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Roberto Salvia
- The Pancreas Institute and Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Alberto Mantovani
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, Rozzano, Italy
- The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK
| | - Tatjana Crnogorac-Jurcevic
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK
| | - Somnath Mukherjee
- Oxford Institute for Radiation Oncology, Churchill Hospital - Oxford Cancer Centre, University of Oxford, Oxford, UK
| | - Aldo Scarpa
- ARC-NET Research Center for Applied Research on Cancer, and Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Paola Allavena
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, Rozzano, Italy
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK.
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK.
- Barts Pancreas Tissue Bank, Barts Cancer Institute- a CRUK Centre of Excellence, Queen Mary University London, London, UK.
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19
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Fincham REA, Delvecchio FR, Goulart MR, Yeong JPS, Kocher HM. Natural killer cells in pancreatic cancer stroma. World J Gastroenterol 2021; 27:3483-3501. [PMID: 34239264 PMCID: PMC8240050 DOI: 10.3748/wjg.v27.i24.3483] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/06/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer remains one of medicine's largest areas of unmet need. With five-year survival rates of < 8%, little improvement has been made in the last 50 years. Typically presenting with advance stage disease, treatment options are limited. To date, surgery remains the only potentially curative option, however, with such late disease presentation, the majority of patients are unresectable. Thus, new therapeutic options and a greater understanding of the complex stromal interactions within the tumour microenvironment are sorely needed to revise the dismal outlook for pancreatic cancer patients. Natural killer (NK) cells are crucial effector units in cancer immunosurveillance. Often used as a prognostic biomarker in a range of malignancies, NK cells have received much attention as an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. Despite this interest, the role of NK cells in pancreatic cancer remains poorly defined. Nevertheless, increasing evidence of the importance of NK cells in this dismal prognosis disease is beginning to come to light. Here, we review the role of NK cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of NK cells as therapy.
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Affiliation(s)
- Rachel Elizabeth Ann Fincham
- Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Francesca Romana Delvecchio
- Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Michelle R Goulart
- Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Joe Poe Sheng Yeong
- Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
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20
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Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer. Cells 2021; 10:cells10040847. [PMID: 33918004 PMCID: PMC8068358 DOI: 10.3390/cells10040847] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/25/2021] [Accepted: 04/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease.
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21
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Li Y, Zhao Z, Lin CY, Liu Y, Staveley-OCarroll KF, Li G, Cheng K. Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer. Am J Cancer Res 2021; 11:2182-2200. [PMID: 33500719 PMCID: PMC7797682 DOI: 10.7150/thno.53102] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
Rationale: Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass. Type I collagen is the major component of the extracellular matrix (ECM), which acts as a barrier to impede the delivery of drugs into the tumor microenvironment. While the strategy to deplete PDAC stroma has failed in clinical trials, normalization of the stroma to allow chemotherapy to kill the tumor cells in the “nest” could be a promising strategy for PDAC therapy. We hypothesize that silencing the poly(rC)-binding protein 2 (αCP2, encoded by the PCBP2 gene) leads to the destabilization and normalization of type I collagen in the PDAC stroma. Methods: We develop a micro-flow mixing method to fabricate a peptide-based core-stabilized PCBP2 siRNA nanocomplex to reverse the accumulation of type I collagen in PDAC tumor stroma. Various in vitro studies were performed to evaluate the silencing activity, cellular uptake, serum stability, and tumor penetration of the PCBP2 siRNA nanocomplex. We also investigated the penetration of small molecules in stroma-rich pancreatic cancer spheroids after the treatment with the PCBP2 siRNA nanocomplex. The anti-tumor activity of the PCBP2 siRNA nanocomplex and its combination with gemcitabine was evaluated in an orthotopic stroma-rich pancreatic cancer mouse model. Results: Silencing the PCBP2 gene using siRNA reverses the accumulation of type I collagen in human pancreatic stellate cells (PSCs) and mouse NIH 3T3 fibroblast cells. The siRNA nanocomplex significantly reduces ECM production and enhances drug penetration through desmoplastic tumor stroma. The combination of gemcitabine with the PCBP2 siRNA nanocomplex markedly suppresses the tumor progression in a desmoplastic PDAC orthotopic mouse model. Conclusion: This approach provides a new therapeutic avenue to improve the antitumor efficacy of PDAC therapies by normalizing tumor stroma using the PCBP2 siRNA nanocomplex.
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22
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Kocher HM, Basu B, Froeling FEM, Sarker D, Slater S, Carlin D, deSouza NM, De Paepe KN, Goulart MR, Hughes C, Imrali A, Roberts R, Pawula M, Houghton R, Lawrence C, Yogeswaran Y, Mousa K, Coetzee C, Sasieni P, Prendergast A, Propper DJ. Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. Nat Commun 2020; 11:4841. [PMID: 32973176 PMCID: PMC7518421 DOI: 10.1038/s41467-020-18636-w] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/02/2020] [Indexed: 12/20/2022] Open
Abstract
Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.
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Affiliation(s)
- Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK.
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK.
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London, E1 1FR, UK.
- Barts Pancreas Tissue Bank, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK.
| | - Bristi Basu
- Department of Oncology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust-Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Fieke E M Froeling
- Department of Surgery and Cancer, Imperial College London-Hammersmith Hospital, London, W12 0HS, UK
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA
| | - Debashis Sarker
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital Campus, London, SE1 9RT, UK
| | - Sarah Slater
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London, E1 1FR, UK
| | - Dominic Carlin
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Nandita M deSouza
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Katja N De Paepe
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Michelle R Goulart
- Centre for Tumour Biology, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Christine Hughes
- Centre for Tumour Biology, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Ahmet Imrali
- Barts Pancreas Tissue Bank, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Rhiannon Roberts
- Barts Pancreas Tissue Bank, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Maria Pawula
- PK/Bioanalytics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
| | - Richard Houghton
- PK/Bioanalytics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
| | - Cheryl Lawrence
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Yathushan Yogeswaran
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Kelly Mousa
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Carike Coetzee
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Peter Sasieni
- Cancer Prevention Trials Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, EC1M 6BQ, UK
- School of Cancer & Pharmaceutical Sciences, and King's Clinical Trials Unit, King's College London, London, SE1 9RT, UK
| | - Aaron Prendergast
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - David J Propper
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London, E1 1FR, UK
- Centre for Cancer and Inflammation, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
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23
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Hughes CS, ChinAleong JA, Kocher HM. CRABP2 and FABP5 expression levels in diseased and normal pancreas. Ann Diagn Pathol 2020; 47:151557. [PMID: 32593808 DOI: 10.1016/j.anndiagpath.2020.151557] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 06/18/2020] [Indexed: 12/30/2022]
Abstract
Recently, stromal targeting, by agents such as All trans retinoic acid (ATRA), has been regarded as a promising avenue for the treatment of pancreatic ductal adenocarcinoma (PDAC). The intra-cellular transportation of ATRA to the nuclear receptors is performed by either: fatty acid binding protein 5 (FABP5) or cellular retinoic acid binding protein 2 (CRABP2), dictating the transcription of downstream genes and, thus, eventual cell phenotype. Here, we explored the levels of each protein, in pancreatic tissues of patients presenting with a range of pancreatic diseases (pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), cholangiocarcinoma (CC)). We demonstrate that there is a significantly lower CRABP2 and FABP5 expression in activated fibroblasts or pancreatic stellate cells (PSC) in PDAC, as well as other diseased pancreas as in CC and CP, versus quiescent fibroblasts. The quiescent fibroblasts consistently show a pattern of high FABP5:CRABP2 ratio, whereas PSC in all non-PDAC tissues showed a low FABP5:CRABP2 ratio. PSC in PDAC patients had a range of FABP5:CRABP2 ratios (high, even and low). There was a lower CRABP2 expression in cancerous epithelial cells (PDAC) versus normal epithelial cells. This is also present in other disease states (CP, CC). Contrasting to the patterns seen for fibroblasts, the FABP5 expression in PDAC epithelial cells matched that of the normal epithelial cells. However, the normal epithelial cells had a high FABP5:CRABP2 ratio, compared to the PDAC epithelial cells. These ratios may have correlation with tumor progression, and overall survival. These findings could be confirmed in in vitro cell lysates. CRABP2 and FABP5 levels and ratios could serve as valuable biomarkers.
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Affiliation(s)
- Christine S Hughes
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
| | - Jo-Anne ChinAleong
- Barts and the London HPB Centre, Department of Surgery and Pathology, Barts Health NHS Trust, The Royal London Hospital, London E1 1BB, UK
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK; Barts and the London HPB Centre, Department of Surgery and Pathology, Barts Health NHS Trust, The Royal London Hospital, London E1 1BB, UK.
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24
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Steins A, van Mackelenbergh MG, van der Zalm AP, Klaassen R, Serrels B, Goris SG, Kocher HM, Waasdorp C, de Jong JH, Tekin C, Besselink MG, Busch OR, van de Vijver MJ, Verheij J, Dijk F, van Tienhoven G, Wilmink JW, Medema JP, van Laarhoven HWM, Bijlsma MF. High-grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF-1. EMBO Rep 2020; 21:e48780. [PMID: 32173982 PMCID: PMC7202203 DOI: 10.15252/embr.201948780] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 02/11/2020] [Accepted: 02/18/2020] [Indexed: 01/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high-grade PDAC had reduced collagen deposition compared to low-grade PDAC. Xenografts and organotypic co-cultures established from mesenchymal-like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal-like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony-stimulating factor 1 as the mesenchymal PDAC-derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high-grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor-restricting microenvironment.
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Affiliation(s)
- Anne Steins
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Madelaine G van Mackelenbergh
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Amber P van der Zalm
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Remy Klaassen
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Bryan Serrels
- Wolfson Wohl Cancer Research CentreGlasgow Precision Oncology LaboratoryUniversity of GlasgowGlasgowUK
| | - Sandrine G Goris
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Hemant M Kocher
- Centre for Tumor BiologyBarts Cancer InstituteQueen Mary University of LondonLondonUK
| | - Cynthia Waasdorp
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Joan H de Jong
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Cansu Tekin
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Marc G Besselink
- Department of SurgeryCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Olivier R Busch
- Department of SurgeryCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Marc J van de Vijver
- Department of PathologyAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Joanne Verheij
- Department of PathologyAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Frederike Dijk
- Department of PathologyAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Geertjan van Tienhoven
- Department of Radiation OncologyAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Johanna W Wilmink
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Hanneke WM van Laarhoven
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Maarten F Bijlsma
- Laboratory for Experimental Oncology and RadiobiologyCenter for Experimental and Molecular MedicineCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
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25
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Yoneda A, Sakai-Sawada K, Minomi K, Tamura Y. Heat Shock Protein 47 Maintains Cancer Cell Growth by Inhibiting the Unfolded Protein Response Transducer IRE1α. Mol Cancer Res 2020; 18:847-858. [PMID: 32102897 DOI: 10.1158/1541-7786.mcr-19-0673] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 10/06/2019] [Accepted: 02/21/2020] [Indexed: 11/16/2022]
Abstract
HSP47 is a collagen-specific protein chaperone expressed in fibroblasts, myofibroblasts, and stromal cells. HSP47 is also expressed in and involved in growth of cancer cells in which collagen levels are extremely low. However, its role in cancer remains largely unclear. Here, we showed that HSP47 maintains cancer cell growth via the unfolded protein response (UPR), the activation of which is well known to be induced by endoplasmic reticulum (ER) stress. We observed that HSP47 forms a complex with both the UPR transducer inositol-requiring enzyme 1α (IRE1α) and ER chaperone BiP in cancer cells. Moreover, HSP47 silencing triggered dissociation of BiP from IRE1α and IRE1α activation, followed by an increase in the intracellular level of reactive oxygen species (ROS). Increase in ROS induced accumulation of 4-hydroxy-2-nonenal-protein adducts and activated two UPR transducers, PKR-like ER kinase (PERK) and activating transcription factor 6α (ATF6α), resulting in impaired cancer cell growth. Our work indicates that HSP47 expressed in cancer cells relieves the ER stress arising from protein synthesis overload within these cells and tumor environments, such as stress induced by hypoxia, low glucose, and pH. We also propose that HSP47 has a biological role that is distinct from its normal function as a collagen-specific chaperone. IMPLICATIONS: HSP47 maintains cancer cell growth by inhibiting IRE1α.
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Affiliation(s)
- Akihiro Yoneda
- Department of Molecular Therapeutics, Center for Food and Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, Sapporo, Japan.
| | - Kaori Sakai-Sawada
- Department of Molecular Therapeutics, Center for Food and Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, Sapporo, Japan
| | - Kenjiro Minomi
- Department of Molecular Therapeutics, Center for Food and Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, Sapporo, Japan.,Research & Development Department, Nucleic Acid Medicine Business Division, Nitto Denko Corporation, Osaka, Japan
| | - Yasuaki Tamura
- Department of Molecular Therapeutics, Center for Food and Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, Sapporo, Japan
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26
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Han X, Xu Y, Geranpayehvaghei M, Anderson GJ, Li Y, Nie G. Emerging nanomedicines for anti-stromal therapy against desmoplastic tumors. Biomaterials 2020; 232:119745. [DOI: 10.1016/j.biomaterials.2019.119745] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 11/29/2019] [Accepted: 12/25/2019] [Indexed: 02/09/2023]
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27
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North B, Kocher HM, Sasieni P. A new pragmatic design for dose escalation in phase 1 clinical trials using an adaptive continual reassessment method. BMC Cancer 2019; 19:632. [PMID: 31242873 PMCID: PMC6595589 DOI: 10.1186/s12885-019-5801-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 06/06/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible. METHODS The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD. RESULTS The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric. CONCLUSION When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario. TRIAL REGISTRATION Clinical Trials NCT03307148 (11 October 2017).
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Affiliation(s)
- Bernard North
- Cancer Prevention Trials Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
- Current addresses: Exploristics Ltd, Belfast, UK
| | - Hemant Mahendrakumar Kocher
- Centre for Tumour Biology and Experimental Cancer Medicine, Barts Cancer Institute- a CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ UK
| | - Peter Sasieni
- Cancer Prevention Trials Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
- Current addresses: School of Cancer & Pharmaceutical Sciences, and King’s Clinical Trials Unit, King’s College London, London, UK
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Fabris L, Perugorria MJ, Mertens J, Björkström NK, Cramer T, Lleo A, Solinas A, Sänger H, Lukacs-Kornek V, Moncsek A, Siebenhüner A, Strazzabosco M. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:63-78. [PMID: 30907492 PMCID: PMC10878127 DOI: 10.1111/liv.14098] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 12/11/2022]
Abstract
Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padova, Italy
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - María Jesús Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- ESCAM – European Surgery Center Aachen Maastricht, Germany and The Netherlands
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Antonio Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Hanna Sänger
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Veronika Lukacs-Kornek
- Institute of Experimental Immunology, University Hospital, Friedrich-Wilhelms-Universität Bonn, Germany
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Alexander Siebenhüner
- Department of Hematology and Medical Oncology, University Hospital Zürich, Zürich, Switzerland
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
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29
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Cao J, Pickup S, Clendenin C, Blouw B, Choi H, Kang D, Rosen M, O'Dwyer PJ, Zhou R. Dynamic Contrast-enhanced MRI Detects Responses to Stroma-directed Therapy in Mouse Models of Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2019; 25:2314-2322. [PMID: 30587546 PMCID: PMC6445712 DOI: 10.1158/1078-0432.ccr-18-2276] [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: 07/16/2018] [Revised: 11/20/2018] [Accepted: 12/19/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE The dense stroma underlies the drug resistance of pancreatic ductal adenocarcinoma (PDA) and has motivated the development of stroma-directed drugs. Our objective is to test the concept that dynamic contrast-enhanced (DCE) MRI using FDA-approved contrast media, an imaging method sensitive to the tumor microenvironment, can detect early responses to stroma-directed drug. EXPERIMENTAL DESIGN Imaging studies were performed in three mouse models exhibiting high desmoplastic reactions: the autochthonous PDA in genetically engineered mice (KPC), an orthotopic model in syngeneic mice, and a xenograft model of human PDA in athymic mice. An investigational drug, PEGPH20 (pegvorhyaluronidase alfa), which degrades hyaluronan (HA) in the stroma of PDA, was injected alone or in combination with gemcitabine. RESULTS At 24 hours after a single injection of PEGPH20, Ktrans , a DCE-MRI-derived marker that measures how fast a unit volume of contrast media is transferred from capillaries to interstitial space, increased 56% and 50% from baseline in the orthotopic and xenograft tumors, respectively, compared with a 4% and 6% decrease in vehicle groups (both P < 0.05). Similarly, after three combined treatments, Ktrans in KPC mice increased 54%, whereas it decreased 4% in controls treated with gemcitabine alone (P < 0.05). Consistently, after a single injection of PEGPH20, tumor HA content assessed by IHC was reduced substantially in all three models while drug delivery (measured by paclitaxel accumulation in tumor) was increased by 2.6-fold. CONCLUSIONS These data demonstrated a DCE-MRI marker, Ktrans , can detect early responses to stroma-directed drug and reveal the sustained effect of combination treatment (PEGPH20+ gemcitabine).
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Affiliation(s)
- Jianbo Cao
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Medical College, Xiamen University, Xiamen, Fujian, P.R. China
| | - Stephen Pickup
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Cynthia Clendenin
- Pancreatic Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Hoon Choi
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David Kang
- Halozyme Therapeutics, San Diego, California
| | - Mark Rosen
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Peter J O'Dwyer
- Pancreatic Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rong Zhou
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
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30
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Nissen NI, Karsdal M, Willumsen N. Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology. J Exp Clin Cancer Res 2019; 38:115. [PMID: 30841909 PMCID: PMC6404286 DOI: 10.1186/s13046-019-1110-6] [Citation(s) in RCA: 331] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 02/15/2019] [Indexed: 12/18/2022] Open
Abstract
The extracellular matrix (ECM) plays an important role in cancer progression. It can be divided into the basement membrane (BM) that supports epithelial/endothelial cell behavior and the interstitial matrix (IM) that supports the underlying stromal compartment. The major components of the ECM are the collagens. While breaching of the BM and turnover of e.g. type IV collagen, is a well described part of tumorigenesis, less is known regarding the impact on tumorigenesis from the collagens residing in the stroma. Here we give an introduction and overview to the link between tumorigenesis and stromal collagens, with focus on the fibrillar collagens type I, II, III, V, XI, XXIV and XXVII as well as type VI collagen. Moreover, we discuss the impact of the cells responsible for this altered stromal collagen remodeling, the cancer associated fibroblasts (CAFs), and how these cells are key players in orchestrating the tumor microenvironment composition and tissue microarchitecture, hence also driving tumorigenesis and affecting response to treatment. Lastly, we discuss how specific collagen-derived biomarkers reflecting the turnover of stromal collagens and CAF activity may be used as tools to non-invasively interrogate stromal reactivity in the tumor microenvironment and predict response to treatment.
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Affiliation(s)
- Neel I. Nissen
- Biomarkers and Research, Nordic Bioscience A/S, Herlev Hovedgade 205-207, 2730 Herlev, Denmark
- Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes vej 5, 2200 Copenhagen N, Denmark
| | - Morten Karsdal
- Biomarkers and Research, Nordic Bioscience A/S, Herlev Hovedgade 205-207, 2730 Herlev, Denmark
| | - Nicholas Willumsen
- Biomarkers and Research, Nordic Bioscience A/S, Herlev Hovedgade 205-207, 2730 Herlev, Denmark
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31
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Procacci P, Moscheni C, Sartori P, Sommariva M, Gagliano N. Tumor⁻Stroma Cross-Talk in Human Pancreatic Ductal Adenocarcinoma: A Focus on the Effect of the Extracellular Matrix on Tumor Cell Phenotype and Invasive Potential. Cells 2018; 7:cells7100158. [PMID: 30301152 PMCID: PMC6209911 DOI: 10.3390/cells7100158] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/27/2018] [Accepted: 10/03/2018] [Indexed: 02/07/2023] Open
Abstract
The extracellular matrix (ECM) in the tumor microenvironment modulates the cancer cell phenotype, especially in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by an intense desmoplastic reaction. Because the epithelial-to-mesenchymal transition (EMT), a process that provides cancer cells with a metastatic phenotype, plays an important role in PDAC progression, the authors aimed to explore in vitro the interactions between human PDAC cells and ECM components of the PDAC microenvironment, focusing on the expression of EMT markers and matrix metalloproteinases (MMPs) that are able to digest the basement membrane during tumor invasion. EMT markers and the invasive potential of HPAF-II, HPAC, and PL45 cells grown on different ECM substrates (fibronectin, laminin, and collagen) were analyzed. While N-cadherin, αSMA, and type I collagen were not significantly affected by ECM components, the E-cadherin/β-catenin complex was highly expressed in all the experimental conditions, and E-cadherin was upregulated by collagen in PL45 cells. Cell migration was unaffected by fibronectin and delayed by laminin. In contrast, collagen significantly stimulated cell migration and the secretion of MMPs. This study's results showed that ECM components impacted cell migration and invasive potential differently. Collagen exerted a more evident effect, providing new insights into the understanding of the intricate interplay between ECM molecules and cancer cells, in order to find novel therapeutic targets for PDAC treatment.
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Affiliation(s)
- Patrizia Procacci
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
| | - Claudia Moscheni
- Department of Biomedical and Clinical Sciences "L. Sacco", Università degli Studi di Milano, via G.B. Grassi 74, 20157 Milan, Italy.
| | - Patrizia Sartori
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
| | - Michele Sommariva
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
| | - Nicoletta Gagliano
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, via L. Mangiagalli 31, 20133 Milan, Italy.
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32
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Han X, Li Y, Xu Y, Zhao X, Zhang Y, Yang X, Wang Y, Zhao R, Anderson GJ, Zhao Y, Nie G. Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem. Nat Commun 2018; 9:3390. [PMID: 30139933 PMCID: PMC6107580 DOI: 10.1038/s41467-018-05906-x] [Citation(s) in RCA: 249] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 07/26/2018] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.
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Affiliation(s)
- Xuexiang Han
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
- Department of Chemistry, Tsinghua University, Beijing, 100084, P.R. China
| | - Yiye Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
| | - Ying Xu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Yinlong Zhang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Xiao Yang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Yongwei Wang
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P.R. China
| | - Ruifang Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Gregory J Anderson
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia
| | - Yuliang Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
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33
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Di Maggio F, Arumugam P, Delvecchio FR, Batista S, Lechertier T, Hodivala-Dilke K, Kocher HM. Pancreatic stellate cells regulate blood vessel density in the stroma of pancreatic ductal adenocarcinoma. Pancreatology 2016; 16:995-1004. [PMID: 27288147 PMCID: PMC5123629 DOI: 10.1016/j.pan.2016.05.393] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 05/03/2016] [Accepted: 05/23/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES The vascular heterogeneity of pancreatic ductal adenocarcinoma (PDAC) has never been characterised. We analysed the heterogeneous vascular density of human PDAC along with its prognostic correlation. METHODS Tissue Microarrays of 87 patients with different pancreatico-biliary pathologies were analysed in an automated manner (Ariol™) after CD31 staining to assess vascular density in juxta-tumoral and panstromal compartments. In vitro and ex vivo assays were carried out to assess the role of PSC. RESULTS PDAC has a distinct vascular density and distribution of vessels compared to cholangiocarcinoma. The PDAC juxta-tumoral stroma was hypovascular and the normal adjacent rim was hypervascular compared to the panstromal compartment. These features adversely affected patient prognosis, suggesting a model for spatio-temporal PDAC evolution. Mice aortic rings and 3D organotypic cultures demonstrated pro- and anti-angiogenic signalling from activated PSC and cancer cells respectively. ATRA-induced quiescence suppressed the pro-angiogenic activity of PSC. CONCLUSION Human PDAC has variable vascularity at microscopic level suggesting that novel stromal directed therapies would need to be determined by pathological characteristics.
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Affiliation(s)
- Francesco Di Maggio
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Prabhu Arumugam
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Francesca R Delvecchio
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK
| | - Silvia Batista
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK
| | - Tanguy Lechertier
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK
| | - Kairbaan Hodivala-Dilke
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK.
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34
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Sarper M, Cortes E, Lieberthal TJ, del Río Hernández A. ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells. Sci Rep 2016; 6:27639. [PMID: 27375161 PMCID: PMC4931506 DOI: 10.1038/srep27639] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 05/20/2016] [Indexed: 02/07/2023] Open
Abstract
The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.
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Affiliation(s)
- Muge Sarper
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Ernesto Cortes
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Tyler J. Lieberthal
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Armando del Río Hernández
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
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35
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Carapuça EF, Gemenetzidis E, Feig C, Bapiro TE, Williams MD, Wilson AS, Delvecchio FR, Arumugam P, Grose RP, Lemoine NR, Richards FM, Kocher HM. Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma. J Pathol 2016; 239:286-96. [PMID: 27061193 PMCID: PMC5025731 DOI: 10.1002/path.4727] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 03/01/2016] [Accepted: 04/04/2016] [Indexed: 12/18/2022]
Abstract
Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to the lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti-tumour efficacy of chemotherapy. Gemcitabine and all-trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSCs) respectively, in 3D organotypic culture models and genetically engineered mice (LSL-Kras(G12D) (/+) ;LSL-Trp53(R172H) (/+) ;Pdx-1-Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extracellular matrix proteins such as collagen and fibronectin) and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid, and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial-mesenchymal transition, cellular polarity, and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co-targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour-stroma cross-talk, rather than ablating stroma or targeting a single pathway. © 2016 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)
- Elisabete F Carapuça
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Emilios Gemenetzidis
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Christine Feig
- The University of Cambridge Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Tashinga E Bapiro
- The University of Cambridge Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Michael D Williams
- The University of Cambridge Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Abigail S Wilson
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Francesca R Delvecchio
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Prabhu Arumugam
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Richard P Grose
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Nicholas R Lemoine
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Frances M Richards
- The University of Cambridge Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
- Barts and The London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK
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