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Turlej E, Domaradzka A, Radzka J, Drulis-Fajdasz D, Kulbacka J, Gizak A. Cross-Talk Between Cancer and Its Cellular Environment-A Role in Cancer Progression. Cells 2025; 14:403. [PMID: 40136652 PMCID: PMC11940884 DOI: 10.3390/cells14060403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/27/2025] Open
Abstract
The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.
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Affiliation(s)
- Eliza Turlej
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Aleksandra Domaradzka
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Justyna Radzka
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Dominika Drulis-Fajdasz
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Julita Kulbacka
- Departament of Molecular and Cellular Biology, Faculty of Pharmacy, Wrocław Medical University, Borowska 211A, 50-556 Wrocław, Poland;
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania
| | - Agnieszka Gizak
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
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Hernández-Hatibi S, Borau C, Martínez-Bosch N, Navarro P, García-Aznar JM, Guerrero PE. Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis. APL Bioeng 2025; 9:016116. [PMID: 40161492 PMCID: PMC11952832 DOI: 10.1063/5.0242490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/28/2025] [Indexed: 04/02/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant tumor-associated stroma composed from pancreatic stellate cells, which play a critical role in tumor progression. Developing accurate in vitro models requires understanding the complex interactions between tumor cells and their microenvironment. In this study, we present a quantitative imaging-based characterization of the three dimensional (3D) self-organization of PDAC tumour spheroids using a microfluidic platform that mimics key aspects of the tumor microenvironment. Our model incorporates collagen type I hydrogels to recreate the extracellular matrix, activated human pancreatic stellate cells (HPSCs), and various tumor cell types. Advanced imaging techniques, including Lattice Lightsheet Microscopy, allowed us to analyze the 3D growth and spatial organization of the spheroids, revealing intricate biomechanical interactions. Our results indicate that alterations in matrix properties-such as stiffness, pore size, and hydraulic permeability-due to variations in collagen concentration significantly influence the growth patterns and organization of PDAC spheroids, depending on tumor subtype and epithelial-mesenchymal phenotype. Higher collagen concentrations promoted larger spheroids in epithelial-like cell lines, while mesenchymal-type cells required increased collagen for self-organization into smaller spheroids. Furthermore, coculture with HPSCs affected spheroid formation distinctly based on each PDAC cell line's genetic and phenotypic traits. HPSCs had opposing effects on epithelial-like cell lines: one cell line exhibited enhanced spheroid growth, while another showed inhibited formation, whereas mesenchymal-like spheroids showed minimal impact. These results provide insights into tumor-stroma interactions, emphasizing the importance of the cell-specific and matrix-dependent factors for advancing our understanding of PDAC progression and informing future therapeutic strategies.
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Affiliation(s)
| | | | - Neus Martínez-Bosch
- Cancer Research Program, Hospital del Mar Research Institute (HMRI), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain
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Jin D, Khan NU, Gu W, Lei H, Goel A, Chen T. Informatics strategies for early detection and risk mitigation in pancreatic cancer patients. Neoplasia 2025; 60:101129. [PMID: 39842383 PMCID: PMC11763847 DOI: 10.1016/j.neo.2025.101129] [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: 11/07/2024] [Revised: 01/17/2025] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
This review provides a comprehensive overview of the current landscape in pancreatic cancer (PC) screening, diagnosis, and early detection. This emphasizes the need for targeted screening in high-risk groups, particularly those with familial predispositions and genetic mutations, such as BRCA1, BRCA2, and PALB2. This review highlights the sporadic nature of most PC cases and significant risk factors, including smoking, alcohol consumption, obesity, and diabetes. Advanced imaging techniques, such as Endoscopic Ultrasound (EUS) and Contrast-Enhanced Harmonic Imaging (CEH-EUS), have been discussed for their superior sensitivity in early detection. This review also explores the potential of novel biomarkers, including those found in body fluids, such as serum, plasma, urine, and bile, as well as the emerging role of liquid biopsy technologies in analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes. AI-driven approaches, such as those employed in Project Felix and CancerSEEK, have been highlighted for their potential to enhance early detection through deep learning and biomarker discovery. This review underscores the importance of universal genetic testing and the integration of AI with traditional diagnostic methods to improve outcomes in high-risk individuals. Additionally, this review points to future directions in PC diagnostics, including next-generation imaging, molecular biomarkers, and personalized medicine, aiming to overcome current diagnostic challenges and improve survival rates. Ultimately, the review advocates the adoption of informatics and AI-driven strategies to enhance early detection, reduce morbidity, and save lives in the fight against pancreatic cancer.
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Affiliation(s)
- Di Jin
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, China; Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Najeeb Ullah Khan
- Institute of Biotechnology & Genetic Engineering (Health Division), The University of Agriculture Peshawar, Peshawar, PO Box 25130, Pakistan.
| | - Wei Gu
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, China; Wenzhou Medical University, Wenzhou, 325000, China.
| | - Huijun Lei
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, China.
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California, USA; City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Tianhui Chen
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, China.
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Feng QS, Shan XF, Yau V, Cai ZG, Xie S. Facilitation of Tumor Stroma-Targeted Therapy: Model Difficulty and Co-Culture Organoid Method. Pharmaceuticals (Basel) 2025; 18:62. [PMID: 39861125 PMCID: PMC11769033 DOI: 10.3390/ph18010062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 12/28/2024] [Accepted: 01/05/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Tumors, as intricate ecosystems, comprise oncocytes and the highly dynamic tumor stroma. Tumor stroma, representing the non-cancerous and non-cellular composition of the tumor microenvironment (TME), plays a crucial role in oncogenesis and progression, through its interactions with biological, chemical, and mechanical signals. This review aims to analyze the challenges of stroma mimicry models, and highlight advanced personalized co-culture approaches for recapitulating tumor stroma using patient-derived tumor organoids (PDTOs). Methods: This review synthesizes findings from recent studies on tumor stroma composition, stromal remodeling, and the spatiotemporal heterogeneities of the TME. It explores popular stroma-related models, co-culture systems integrating PDTOs with stromal elements, and advanced techniques to improve stroma mimicry. Results: Stroma remodeling, driven by stromal cells, highlights the dynamism and heterogeneity of the TME. PDTOs, derived from tumor tissues or cancer-specific stem cells, accurately mimic the tissue-specific and genetic features of primary tumors, making them valuable for drug screening. Co-culture models combining PDTOs with stromal elements effectively recreate the dynamic TME, showing promise in personalized anti-cancer therapy. Advanced co-culture techniques and flexible combinations enhance the precision of tumor-stroma recapitulation. Conclusions: PDTO-based co-culture systems offer a promising platform for stroma mimicry and personalized anti-cancer therapy development. This review underscores the importance of refining these models to advance precision medicine and improve therapeutic outcomes.
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Affiliation(s)
- Qiu-Shi Feng
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Xiao-Feng Shan
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Vicky Yau
- Division of Oral and Maxillofacial Surgery, Columbia Irving Medical Center, New York City, NY 10027, USA;
| | - Zhi-Gang Cai
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Shang Xie
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
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Lencioni G, Gregori A, Toledo B, Rebelo R, Immordino B, Amrutkar M, Xavier CPR, Kocijančič A, Pandey DP, Perán M, Castaño JP, Walsh N, Giovannetti E. Unravelling the complexities of resistance mechanism in pancreatic cancer: Insights from in vitro and ex-vivo model systems. Semin Cancer Biol 2024; 106-107:217-233. [PMID: 39299411 DOI: 10.1016/j.semcancer.2024.09.002] [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: 07/19/2024] [Revised: 09/07/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis and rising global deaths. Late diagnosis, due to absent early symptoms and biomarkers, limits treatment mainly to chemotherapy, which soon encounters resistance. PDAC treatment innovation is hampered by its complex and heterogeneous resistant nature, including mutations in key genes and a stromal-rich, immunosuppressive tumour microenvironment. Recent studies on PDAC resistance stress the need for suitable in vitro and ex vivo models to replicate its complex molecular and microenvironmental landscape. This review summarises advances in these models, which can aid in combating chemoresistance and serve as platforms for discovering new therapeutics. Immortalised cell lines offer homogeneity, unlimited proliferation, and reproducibility, but while many gemcitabine-resistant PDAC cell lines exist, fewer models are available for resistance to other drugs. Organoids from PDAC patients show promise in mimicking tumour heterogeneity and chemosensitivity. Bioreactors, co-culture systems and organotypic slices, incorporating stromal and immune cells, are being developed to understand tumour-stroma interactions and the tumour microenvironment's role in drug resistance. Lastly, another innovative approach is three-dimensional bioprinting, which creates tissue-like structures resembling PDAC architecture, allowing for drug screening. These advanced models can guide researchers in selecting optimal in vitro tests, potentially improving therapeutic strategies and patient outcomes.
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Affiliation(s)
- Giulia Lencioni
- Fondazione Pisana per La Scienza, San Giuliano Terme, Italy; Department of Biology, University of Pisa, Pisa, Italy
| | - Alessandro Gregori
- Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Medical Oncology, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Belén Toledo
- Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Health Sciences, University of Jaén, Campus Lagunillas, Jaén E-23071, Spain
| | - Rita Rebelo
- Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, the Netherlands; Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto 4200-135, Portugal; Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, Porto 4200-135, Portugal; Department of Biological Sciences, Faculty of Pharmacy of the University of Porto (FFUP), Porto, Portugal
| | - Benoît Immordino
- Fondazione Pisana per La Scienza, San Giuliano Terme, Italy; Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Manoj Amrutkar
- Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Cristina P R Xavier
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto 4200-135, Portugal; Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, Porto 4200-135, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), Gandra, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy, University Institute of Health Sciences - CESPU, Gandra, Portugal
| | - Anja Kocijančič
- Centre for Embryology and Healthy Development, Department of Microbiology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
| | - Deo Prakash Pandey
- Centre for Embryology and Healthy Development, Department of Microbiology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Campus Lagunillas, Jaén E-23071, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Justo P Castaño
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain
| | - Naomi Walsh
- Life Sciences Institute, School of Biotechnology, Dublin City University, Dublin, Ireland
| | - Elisa Giovannetti
- Fondazione Pisana per La Scienza, San Giuliano Terme, Italy; Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Medical Oncology, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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Qin T, Hu S, Kong D, Lakey JR, de Vos P. Pancreatic stellate cells support human pancreatic β-cell viability in vitro and enhance survival of immunoisolated human islets exposed to cytokines. Mater Today Bio 2024; 27:101129. [PMID: 39022526 PMCID: PMC11253154 DOI: 10.1016/j.mtbio.2024.101129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/06/2024] [Accepted: 06/16/2024] [Indexed: 07/20/2024] Open
Abstract
Pancreatic islet transplantation is proposed as a cure for type 1 diabetes mellitus (T1D). Despite its success in optimal regulation of glucose levels, limitations in longevity of islet grafts still require innovative solutions. Inflammatory stress post-transplantation and loss of extracellular matrix attribute to the limited β-cell survival. Pancreatic stellate cells (PSCs), identified as pancreatic-specific stromal cells, have the potential to play a crucial role in preserving islet survival. Our study aimed to determine the effects of PSCs co-cultured with human CM β-cells and human islets under inflammatory stress induced by a cytokine cocktail of IFN-γ, TNF-α and IL-1β. Transwell culture inserts were utilized to assess the paracrine impact of PSCs on β-cells, alongside co-cultures enabling direct interaction between PSCs and human islets. We found that co-culturing PSCs with human CM β-cells and human cadaveric islets had rescuing effects on cytokine-induced stress. Effects were different under normoglycemic and hyperglycemic conditions. PSCs were associated with upregulation of β-cell mitochondrial activity and suppression of inflammatory gene expression. The rescuing effects exist both in indirect and direct co-culture methods. Furthermore, we tested whether PSCs have rescuing effects on human islets in conventional alginate-based microcapsules and in composite microcapsules composed of alginate-pectin collagen type IV, laminin sequence RGD, Nec-1, and amino acid. PSCs partially prevented cytokine-induced stress in both systems, but beneficial effects were stronger in composite capsules. Our findings show novel effects of PSCs on islet health. Islets and PSCs coculturing or co-transplantation might mitigate the inflammation stress and improve islet transplantation outcomes.
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Affiliation(s)
- Tian Qin
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, the Netherlands
| | - Shuxian Hu
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, the Netherlands
- Biological and Environmental Engineering, Cornell University, Ithaca, NY, 14853, USA
| | - Defu Kong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jonathan R.T. Lakey
- Department of Surgery, University of California Irvine, Irvine, CA, 92868, USA
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, 92697, USA
| | - Paul de Vos
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, the Netherlands
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Mottini C, Auciello FR, Manni I, Pilarsky C, Caputo D, Caracciolo G, Rossetta A, Di Gennaro E, Budillon A, Blandino G, Roca MS, Piaggio G. The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers. J Exp Clin Cancer Res 2024; 43:198. [PMID: 39020414 PMCID: PMC11256648 DOI: 10.1186/s13046-024-03117-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 07/06/2024] [Indexed: 07/19/2024] Open
Abstract
Pancreatic cancer (PC) is a clinically challenging tumor to combat due to its advanced stage at diagnosis as well as its resistance to currently available therapies. The absence of early symptoms and known detectable biomarkers renders this disease incredibly difficult to detect/manage. Recent advances in the understanding of PC biology have highlighted the importance of cancer-immune cell interactions, not only in the tumor micro-environment but also in distant systemic sites, like the bone marrow, spleen and circulating immune cells, the so-called macro-environment. The response of the macro-environment is emerging as a determining factor in tumor development by contributing to the formation of an increasingly immunogenic micro-environment promoting tumor homeostasis and progression. We will summarize the key events associated with the feedback loop between the tumor immune micro-environment (TIME) and the tumor immune macroenvironment (TIMaE) in pancreatic precancerous lesions along with how it regulates disease development and progression. In addition, liquid biopsy biomarkers capable of diagnosing PC at an early stage of onset will also be discussed. A clearer understanding of the early crosstalk between micro-environment and macro-environment could contribute to identifying new molecular therapeutic targets and biomarkers, consequently improving early PC diagnosis and treatment.
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Affiliation(s)
- Carla Mottini
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Francesca Romana Auciello
- UOC Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Isabella Manni
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | | | | | - Giulio Caracciolo
- Dipartimento Di Medicina Molecolare Sapienza, Università Di Roma, Rome, Italy
| | | | - Elena Di Gennaro
- Experimental Pharmacology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via M. Semmola, 80131, Naples, Italy
| | - Alfredo Budillon
- Scientific Directorate, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy
| | - Giovanni Blandino
- UOC Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Maria Serena Roca
- Experimental Pharmacology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via M. Semmola, 80131, Naples, Italy.
| | - Giulia Piaggio
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
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Ni JS, Fu SY, Wang ZY, Ding WB, Huang J, Guo XG, Gu FM. Interleukin-17A educated hepatic stellate cells promote hepatocellular carcinoma occurrence through fibroblast activation protein expression. J Gene Med 2024; 26:e3693. [PMID: 38860366 DOI: 10.1002/jgm.3693] [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: 03/18/2024] [Revised: 04/10/2024] [Accepted: 05/06/2024] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC. METHODS An HCC model was established in male Sprague-Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses. RESULTS The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs. CONCLUSIONS The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.
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Affiliation(s)
- Jun-Sheng Ni
- The Third Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Si-Yuan Fu
- The Third Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Zong-Yan Wang
- The Third Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Wen-Bin Ding
- The Third Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jian Huang
- The Third Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xing-Gang Guo
- The Third Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fang-Ming Gu
- The Third Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
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Li Y, Zheng Y, Xu S, Hu H, Peng L, Zhu J, Wu M. The nanobody targeting PD-L1 and CXCR4 counteracts pancreatic stellate cell-mediated tumour progression by disrupting tumour microenvironment. Int Immunopharmacol 2024; 132:111944. [PMID: 38581990 DOI: 10.1016/j.intimp.2024.111944] [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: 11/28/2023] [Revised: 03/11/2024] [Accepted: 03/25/2024] [Indexed: 04/08/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy worldwide owing to its complex tumour microenvironment and dense physical barriers. Stromal-derived factor-1 (SDF-1), which is abundantly secreted by tumour stromal cells, plays a pivotal role in promoting PDAC growth and metastasis. In this study, we investigated the impact and molecular mechanisms of the anti-PD-L1&CXCR4 bispecific nanobody on the TME and their consequent interference with PDAC progression. We found that blocking the SDF-1/CXCR4 signalling pathway delayed the epithelial-mesenchymal transition in pancreatic cancer cells. Anti-PD-L1&CXCR4 bispecific nanobody effectively suppress the secretion of SDF-1 by pancreatic stellate cells and downregulate the expression of smooth muscle actin alpha(α-SMA), thereby preventing the activation of cancer-associated fibroblasts by downregulating the PI3K/AKT signaling pathway. This improves the pancreatic tumour microenvironment, favouring the infiltration of T cells into the tumour tissue. In conclusion, our results suggest that the anti-PD-L1&CXCR4 bispecific nanobody exerts an antitumor immune response by changing the pancreatic tumour microenvironment. Hence, the anti-PD-L1&CXCR4 bispecific nanobody is a potential candidate for pancreatic cancer treatment.
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Affiliation(s)
- Yaxian Li
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
| | - Yuejiang Zheng
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Shuyi Xu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
| | - Hai Hu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Liyun Peng
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Jianwei Zhu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Mingyuan Wu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
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10
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Silva LGDO, Lemos FFB, Luz MS, Rocha Pinheiro SL, Calmon MDS, Correa Santos GL, Rocha GR, de Melo FF. New avenues for the treatment of immunotherapy-resistant pancreatic cancer. World J Gastrointest Oncol 2024; 16:1134-1153. [PMID: 38660642 PMCID: PMC11037047 DOI: 10.4251/wjgo.v16.i4.1134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Affiliation(s)
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana dos Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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11
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Natu J, Nagaraju GP. Gemcitabine effects on tumor microenvironment of pancreatic ductal adenocarcinoma: Special focus on resistance mechanisms and metronomic therapies. Cancer Lett 2023; 573:216382. [PMID: 37666293 DOI: 10.1016/j.canlet.2023.216382] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/26/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest malignancies, with dismal survival rates and extremely prevalent chemoresistance. Gemcitabine is one of the primary treatments used in treating PDACs, but its benefits are limited due to chemoresistance, which could be attributed to interactions between the tumor microenvironment (TME) and intracellular processes. In preclinical models, certain schedules of administration of gemcitabine modulate the TME in a manner that does not promote resistance. Metronomic therapy constitutes a promising strategy to overcome some barriers associated with current PDAC treatments. This review will focus on gemcitabine's mechanism in treating PDAC, combination therapies, gemcitabine's interactions with the TME, and gemcitabine in metronomic therapies.
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Affiliation(s)
- Jay Natu
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL, 35233, USA
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL, 35233, USA.
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12
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Wang Z, He R, Dong S, Zhou W. Pancreatic stellate cells in pancreatic cancer: as potential targets for future therapy. Front Oncol 2023; 13:1185093. [PMID: 37409257 PMCID: PMC10318188 DOI: 10.3389/fonc.2023.1185093] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 06/05/2023] [Indexed: 07/07/2023] Open
Abstract
Pancreatic cancer is a strongly malignant gastrointestinal carcinoma characterized by late detection, high mortality rates, poor patient prognosis and lack of effective treatments. Consequently, there is an urgent need to identify novel therapeutic strategies for this disease. Pancreatic stellate cells, which constitute a significant component of the mesenchymal cellular layer within the pancreatic tumor microenvironment, play a pivotal role in modulating this environment through their interactions with pancreatic cancer cells. This paper reviews the mechanisms by which pancreatic stellate cells inhibit antitumor immune responses and promote cancer progression. We also discuss preclinical studies focusing on these cells, with the goal of providing some theoretical references for the development of new therapeutic approaches for pancreatic cancer.
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Affiliation(s)
- Zhengfeng Wang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ru He
- The Second School of Clinical Medicine, Lanzhou University Medical College, Lanzhou, China
| | - Shi Dong
- The Second School of Clinical Medicine, Lanzhou University Medical College, Lanzhou, China
| | - Wence Zhou
- The Second School of Clinical Medicine, Lanzhou University Medical College, Lanzhou, China
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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13
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Li Y, Xiang S, Pan W, Wang J, Zhan H, Liu S. Targeting tumor immunosuppressive microenvironment for pancreatic cancer immunotherapy: Current research and future perspective. Front Oncol 2023; 13:1166860. [PMID: 37064113 PMCID: PMC10090519 DOI: 10.3389/fonc.2023.1166860] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/20/2023] [Indexed: 03/31/2023] Open
Abstract
Pancreatic cancer is one of the most malignant tumors with increased incidence rate. The effect of surgery combined with chemoradiotherapy on survival of patients is unsatisfactory. New treatment strategy such as immunotherapy need to be investigated. The accumulation of desmoplastic stroma, infiltration of immunosuppressive cells including myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), cancer‐associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as tumor associated cytokine such as TGF-β, IL-10, IL-35, CCL5 and CXCL12 construct an immunosuppressive microenvironment of pancreatic cancer, which presents challenges for immunotherapy. In this review article, we explore the roles and mechanism of immunosuppressive cells and lymphocytes in establishing an immunosuppressive tumor microenvironment in pancreatic cancer. In addition, immunotherapy strategies for pancreatic cancer based on tumor microenvironment including immune checkpoint inhibitors, targeting extracellular matrix (ECM), interfering with stromal cells or cytokines in TME, cancer vaccines and extracellular vesicles (EVs) are also discussed. It is necessary to identify an approach of immunotherapy in combination with other modalities to produce a synergistic effect with increased response rates in pancreatic cancer therapy.
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Affiliation(s)
- Ying Li
- Department of Blood Transfusion, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shuai Xiang
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenjun Pan
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Wang
- Department of Operating Room, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hanxiang Zhan
- Department of General Surgery, Qilu hospital, Shandong University, Jinan, Shandong, China
- *Correspondence: Shanglong Liu, ; Hanxiang Zhan,
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Shanglong Liu, ; Hanxiang Zhan,
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14
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Wang T, Yang J, Mao J, Zhu L, Luo X, Cheng C, Zhang L. ITGA5 inhibition in pancreatic stellate cells re-educates the in vitro tumor-stromal crosstalk. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:39. [PMID: 36469173 DOI: 10.1007/s12032-022-01902-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/16/2022] [Indexed: 12/07/2022]
Abstract
The interaction between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) promotes aggressive progression of pancreatic cancer, and disrupting the tumor-stromal crosstalk is a promising therapeutic strategy. Integrin α5 (ITGA5) is specifically overexpressed in pancreatic cancer stroma and activated PSCs. ITGA5 acts as a mediator in PCCs-PSCs interaction, but its role in regulating biological behaviors of PSCs and PCCs is still not quite clear. In this study, ITGA5 in PSCs was inhibited using its specific inhibitor AV3 peptide or siRNA knockdown technique. Pancreatic cancer SW1990 cells conditioned medium (SW1990-CM) and an indirect co-culture system were used to mimic the environment of the in vitro tumor-stromal crosstalk. Our results showed that ITGA5 inhibition impaired the proliferation and migration of PSCs, but enhanced autophagy. After co-culture with PSCs, SW1990 cells gained some cancer stem cells (CSCs)-like characteristics, such as increased drug resistance, migration and invasion ability, but PSCs with ITGA5 knockdown were incapable of producing these effects. The present results suggested that ITGA5 was involved in the development of the malignant biological behaviors of PSCs and PCCs, and ITGA5 inhibition in PSCs might benefit the treatment of pancreatic cancer by re-educating PCCs-PSCs interaction.
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Affiliation(s)
- Tao Wang
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
| | - Jian Yang
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Juanli Mao
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Lizhi Zhu
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Xiu Luo
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Chao Cheng
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
| | - Lu Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
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15
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Zhu Z, Li W, Gong M, Wang L, Yue Y, Qian W, Zhou C, Duan W, Han L, Li L, Wu Z, Ma Q, Lin M, Wang S, Wang Z. Piezo1 act as a potential oncogene in pancreatic cancer progression. Life Sci 2022; 310:121035. [DOI: 10.1016/j.lfs.2022.121035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/26/2022] [Accepted: 09/30/2022] [Indexed: 11/06/2022]
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16
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Recent developments of nanomedicine delivery systems for the treatment of pancreatic cancer. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.104042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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17
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Girish BP, Dariya B, Mannarapu M, Nagaraju GP, Raju GSR. Targeting the tumor microenvironment of pancreatic ductal adenocarcinoma using nano-phytomedicines. Semin Cancer Biol 2022; 86:1155-1162. [PMID: 34147639 DOI: 10.1016/j.semcancer.2021.06.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/05/2021] [Accepted: 06/14/2021] [Indexed: 01/09/2023]
Abstract
Despite advanced therapeutic strategies, the mortality and morbidity of pancreatic cancer (PC) have been increasing. This is due to the anomalous proliferation activity of stromal cells, like cancer-associated fibroblasts (CAFs), in the tumor microenvironment (TME). These cells develop resistance in the tumor cells, blocking the drug from entering the target tumor site, ultimately resulting in tumor metastasis. Additionally, the current conventional adjuvant techniques, including chemo and radiotherapy, carry higher risk due to their excess toxicity against normal healthy cells. Phytochemicals including curcumin, irinotecan and paclitaxel are anti-oxidants, less toxic, and have anti-cancerous properties; however, the use of phytochemicals is limited due to their less solubility and bioavailability. Nanotechnology offers the resources to directly target the drug to the tumor site, thereby enhancing the therapeutic efficacy of the current treatment modalities. This review focuses on the importance of nanotechnology for pancreatic ductal adenocarcinoma (PDAC) therapy and on delivering the nano-formulated phytochemicals to the target site.
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Affiliation(s)
- Bala Prabhakar Girish
- Nanotechnology Laboratory, Institute of Frontier Technology, Regional Agricultural Research Station, Acharya N.G. Ranga Agricultural University, Tirupati, 517502, India
| | - Begum Dariya
- Department of Biosciences and Biotechnology, Banasthali University, Banasthali, 304022, Rajasthan, India
| | - Mastan Mannarapu
- Department of Biotechnology, Dravidian University, Kuppam, Chittoor, Andra Pradesh, 517 426, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | - Ganji Seeta Rama Raju
- Department of Energy and Materials Engineering, Dongguk University-Seoul, Seoul, 04620, Republic of Korea.
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18
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Wu CWK, Reid M, Leedham S, Lui RN. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol 2022; 37:1411-1425. [PMID: 35815339 PMCID: PMC7617119 DOI: 10.1111/jgh.15937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.
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Affiliation(s)
- Claudia WK Wu
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
| | - Madeleine Reid
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Simon Leedham
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rashid N Lui
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
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19
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Mitochondria oxidative stress mediated nicotine-promoted activation of pancreatic stellate cells by regulating mitochondrial dynamics. Toxicol In Vitro 2022; 84:105436. [PMID: 35842057 DOI: 10.1016/j.tiv.2022.105436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 06/09/2022] [Accepted: 07/10/2022] [Indexed: 11/21/2022]
Abstract
Nicotine, one of the main ingredients of cigarettes, promotes activation of pancreatic stellate cells(PSCs) and exacerbates pancreatic fibrosis in previous studies. Here we focus on the inner relationship between mitochondrial oxidative stress and mitochondrial dynamics to explore the possible mechanism. Primary human PSCs were stimulated by nicotine. The effect of nicotine on oxidative stress and mitochondrial dynamics was analyzed by reactive oxygen species (ROS) assay, quantitative real-time PCR, and western blotting. Mitochondrial morphology was observed. Antioxidant and small interfering RNA transfection were applied to explore the interrelationship between oxidative stress and mitochondrial dynamics, as well as its effect on PSCs activation. Nicotine exposure significantly increased Intracellular and mitochondrial ROS of hPSCs and promoted mitochondrial fission by upregulating dynamin-related protein 1(DRP1). Knockdown Drp1 reversed mitochondrial fragmentation and hPSCs activation that promoted by nicotine, but fail to alleviate oxidative stress. A mitochondrial-targeted antioxidant could reverse all the above changes. Our finding suggests that mitochondria oxidative stress mediated nicotine-promoted activation of PSCs by inducing Drp1-mediated mitochondrial fission, provides a new perspective on the possible mechanism by which nicotine affects PSCs, and reveals a potential therapeutic strategy.
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20
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Zhou T, Liu J, Xie Y, Yuan S, Guo Y, Bai W, Zhao K, Jiang W, Wang H, Wang H, Zhao T, Huang C, Gao S, Wang X, Yang S, Hao J. ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4. Gut 2022; 71:357-371. [PMID: 33674341 PMCID: PMC9422994 DOI: 10.1136/gutjnl-2020-321952] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 02/02/2021] [Accepted: 02/20/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS The crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs' niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF. DESIGN We used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study. RESULTS CXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy. CONCLUSIONS EHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.
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Affiliation(s)
- Tianxing Zhou
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Jing Liu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China.,Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, China
| | - Yongjie Xie
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Shuai Yuan
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Yu Guo
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, 38 Tongyan Road, Tianjin, 300071, China
| | - Weiwei Bai
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Kaili Zhao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Wenna Jiang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Hongwei Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Haotian Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Tiansuo Zhao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Chongbiao Huang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Song Gao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Xiuchao Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, PR China
| | - Shengyu Yang
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA
| | - Jihui Hao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China
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21
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Zhang W, Xing J, Liu T, Zhang J, Dai Z, Zhang H, Wang D, Tang D. Small extracellular vesicles: from mediating cancer cell metastasis to therapeutic value in pancreatic cancer. Cell Commun Signal 2022; 20:1. [PMID: 34980146 PMCID: PMC8722298 DOI: 10.1186/s12964-021-00806-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 11/20/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a highly malignant tumor and, is extremely difficult to diagnose and treat. Metastasis is one of the critical steps in the development of cancer and uses cell to cell communication to mediate changes in the microenvironment. Small extracellular vesicles (sEVs)-carry proteins, nucleic acids and other bioactive substances, and are important medium for communication between cells. There are two primary steps in sVEs-mediated metastasis: communication between pancreatic cancer cells and their surrounding microenvironment; and the communication between primary tumor cells and distant organ cells in distant organs that promotes angiogenesis, reshaping extracellular matrix, forming immunosuppressive environment and other ways to form appropriate pre-metastasis niche. Here, we explore the mechanism of localization and metastasis of pancreatic cancer and use sEVs as early biomarkers for the detection and treatment of pancreatic cancer. Video Abstract.
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Affiliation(s)
- Wenjie Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Juan Xing
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Tian Liu
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Jie Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Zhujiang Dai
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Huan Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Northern Jiangsu Province Hospital, Yangzhou University, Yangzhou, 225001 China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Northern Jiangsu Province Hospital, Yangzhou University, Yangzhou, 225001 China
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22
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Hrabák P, Kalousová M, Krechler T, Zima T. Pancreatic stellate cells - rising stars in pancreatic pathologies. Physiol Res 2021. [DOI: 10.33549//physiolres.934783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Pluripotent pancreatic stellate cells (PSCs) receive growing interest in past decades. Two types of PSCs are recognized –vitamin A accumulating quiescent PSCs and activated PSCs- the main producents of extracellular matrix in pancreatic tissue. PSCs plays important role in pathogenesis of pancreatic fibrosis in pancreatic cancer and chronic pancreatitis. PSCs are intensively studied as potential therapeutical target because of their important role in developing desmoplastic stroma in pancreatic cancer. There also exists evidence that PSC are involved in other pathologies like type-2 diabetes mellitus. This article brings brief characteristics of PSCs and recent advances in research of these cells.
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Affiliation(s)
| | - M Kalousová
- 2Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.
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23
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Zhao X, Wu J, Zhang K, Guo D, Hong L, Chen X, Wang B, Song Y. The synthesis of a nanodrug using metal-based nanozymes conjugated with ginsenoside Rg3 for pancreatic cancer therapy. NANOSCALE ADVANCES 2021; 4:190-199. [PMID: 36132964 PMCID: PMC9419118 DOI: 10.1039/d1na00697e] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 10/20/2021] [Indexed: 05/10/2023]
Abstract
Nanozymes have limited applications in clinical practice due to issues relating to their safety, stability, biocompatibility, and relatively low catalytic activity in the tumor microenvironment (TME) in vivo. Herein, we report a synergistic enhancement strategy involving the conjugation of metal-based nanozymes (Fe@Fe3O4) with natural bioactive organic molecules (ginsenoside Rg3) to establish a new nanodrug. Importantly, this metal-organic nanocomposite drug ensured the stability and biosafety of the nanozyme cores and the cellular uptake efficiency of the whole nanodrug entity. This nanodrug is based on integrating the biological characteristics and intrinsic physicochemical properties of bionics. The glycoside chain of Rg3 forms a hydrophilic layer on the outermost layer of the nanodrug to improve the biocompatibility and pharmacokinetics. Additionally, Rg3 can activate apoptosis and optimize the activity and status of normal cells. Internal nanozymes enter the TME and release Fe3+ and Fe2+, and the central metal Fe(0) continuously generates highly active Fe2+ under the conditions of the TME and in the presence of Fe3+, maintaining the catalytic activity. Therefore, these nanozymes can effectively produce reactive oxygen species and oxygen in the TME, thereby promoting the apoptosis of cancer cells. Thus, we propose the use of a new type of metal-organic nanocomposite material as a synergistic strategy against cancer.
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Affiliation(s)
- Xiaoxiong Zhao
- Center for Modern Physics Technology, School of Mathematics and Physics, University of Science and Technology Beijing Beijing 100083 China
- Zhejiang Key Laboratory for Pulsed Power Technology Translational Medicine Hangzhou 310000 China
| | - Jicheng Wu
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310009 China
- Institute of Translational Medicine, Zhejiang University Hangzhou 310029 China
| | - Kaixin Zhang
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310009 China
- Institute of Translational Medicine, Zhejiang University Hangzhou 310029 China
| | - Danjing Guo
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310003 China
| | - Liangjie Hong
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310003 China
| | - Xinhua Chen
- Zhejiang Key Laboratory for Pulsed Power Technology Translational Medicine Hangzhou 310000 China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310003 China
| | - Ben Wang
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310009 China
- Institute of Translational Medicine, Zhejiang University Hangzhou 310029 China
| | - Yujun Song
- Center for Modern Physics Technology, School of Mathematics and Physics, University of Science and Technology Beijing Beijing 100083 China
- Zhejiang Key Laboratory for Pulsed Power Technology Translational Medicine Hangzhou 310000 China
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Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics. Cells 2021; 10:cells10071596. [PMID: 34202136 PMCID: PMC8305303 DOI: 10.3390/cells10071596] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is the unrelenting deposition of excessively large amounts of insoluble interstitial collagen due to profound matrigenic activities of wound-associated myofibroblasts during chronic injury in diverse tissues and organs. It is a highly debilitating pathology that affects millions of people globally and leads to decreased function of vital organs and increased risk of cancer and end-stage organ disease. Extracellular vesicles (EVs) produced within the chronic wound environment have emerged as important vehicles for conveying pro-fibrotic signals between many of the cell types involved in driving the fibrotic response. On the other hand, EVs from sources such as stem cells, uninjured parenchymal cells, and circulation have in vitro and in vivo anti-fibrotic activities that have provided novel and much-needed therapeutic options. Finally, EVs in body fluids of fibrotic individuals contain cargo components that may have utility as fibrosis biomarkers, which could circumvent current obstacles to fibrosis measurement in the clinic, allowing fibrosis stage, progression, or regression to be determined in a manner that is accurate, safe, minimally-invasive, and conducive to repetitive testing. This review highlights the rapid and recent progress in our understanding of EV-mediated fibrotic pathogenesis, anti-fibrotic therapy, and fibrosis staging in the lung, kidney, heart, liver, pancreas, and skin.
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25
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Role of stromal activin A in human pancreatic cancer and metastasis in mice. Sci Rep 2021; 11:7986. [PMID: 33846512 PMCID: PMC8042028 DOI: 10.1038/s41598-021-87213-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 03/22/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the cancers with the highest mortality rates. Activin A has been implicated in colon cancer and its stroma but its role in the stroma of PDAC has not been elucidated. Activin A expression in cancer and stroma was assessed in human PDAC tissue microarrays (TMA). Activin A expression in human TMA is significantly higher in cancer samples, with expression in stroma correlated with shorter survival. Cultured pancreatic stellate cells (PSC) were found to secrete high levels of activin A resulting in PDAC cell migration that is abolished by anti-activin A neutralizing antibody. KPC mice treated with anti-activin A neutralizing antibody were evaluated for tumors, lesions and metastases quantified by immunohistochemistry. KPC mice with increased tumor burden express high plasma activin A. Treating KPC mice with an activin A neutralizing antibody does not reduce primary tumor size but decreases tumor metastases. From these data we conclude that PDAC patients with high activin A expression in stroma have a worse prognosis. PSCs secrete activin A, promoting increased PDAC migration. Inhibition of activin A in mice decreased metastases. Hence, stroma-rich PDAC patients might benefit from activin A inhibition.
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26
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Zeng Z, Lei S, He Z, Chen T, Jiang J. YEATS2 is a target of HIF1α and promotes pancreatic cancer cell proliferation and migration. J Cell Physiol 2021; 236:2087-2098. [PMID: 32749678 DOI: 10.1002/jcp.29995] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 07/17/2020] [Accepted: 07/24/2020] [Indexed: 12/22/2022]
Abstract
Hypoxia is involved in the development of pancreatic cancer (PC). The responses of hypoxia-associated genes and their regulated mechanisms are largely unknown. In this study, through bioinformatic analysis and quantitative real-time polymerase chain reaction, the YEATS domain containing 2 (YEATS2) was determined to be a key hypoxia-associated gene. It was increased in PC cells under hypoxia, upregulated in PC tissues, and predicted poor outcome. YEATS2 inhibition decreased the proliferation and migration of PC cells under both normoxia and hypoxia in vitro as well as proliferation and metastasis in vivo. We found that hypoxia-inducible factor 1α (HIF1α) regulated the expression of YEATS2 via binding to the hypoxia response element (HRE) of YEATS2 and coexpressed with YEATS2 in PC tissues. Overexpression of YEATS2 blocked the inhibitory effects of HIF1α silence on PC cell proliferation and migration under hypoxia. Collectively, our study revealed that YEATS2 is a target gene of HIF1α and promotes PC development under hypoxia.
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Affiliation(s)
- Zhirui Zeng
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Key Laboratory of Tissue Engineering and Stem Cell of Guizhou Province, Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, China
| | - Shan Lei
- Key Laboratory of Tissue Engineering and Stem Cell of Guizhou Province, Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, China
| | - Zhiwei He
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Tengxiang Chen
- Key Laboratory of Tissue Engineering and Stem Cell of Guizhou Province, Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, China
| | - Jianxin Jiang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive System Disease of Wuhan University, Wuhan, China
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27
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Wu Y, Zhang C, Jiang K, Werner J, Bazhin AV, D'Haese JG. The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives. Front Oncol 2021; 10:621937. [PMID: 33520728 PMCID: PMC7841014 DOI: 10.3389/fonc.2020.621937] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.
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Affiliation(s)
- Yang Wu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Chun Zhang
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Kuirong Jiang
- Pancreas Center and Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Jan G D'Haese
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
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28
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Garcia PE, Scales MK, Allen BL, Pasca di Magliano M. Pancreatic Fibroblast Heterogeneity: From Development to Cancer. Cells 2020; 9:E2464. [PMID: 33198201 PMCID: PMC7698149 DOI: 10.3390/cells9112464] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/10/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression. Cancer-associated fibroblasts (CAFs) are a prominent cellular component of the stroma, but their role during carcinogenesis remains controversial, with both tumor-supporting and tumor-restraining functions reported in different studies. One explanation for these contradictory findings is the heterogeneous nature of the fibroblast populations, and the different roles each subset might play in carcinogenesis. Here, we review the current literature on the origin and function of pancreatic fibroblasts, from the developing organ to the healthy adult pancreas, and throughout the initiation and progression of PDA. We also discuss clinical approaches to targeting fibroblasts in PDA.
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Affiliation(s)
- Paloma E. Garcia
- Program in Molecular and Cellular Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Michael K. Scales
- Department of Cell and Developmental Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA; (M.K.S.); (B.L.A.)
| | - Benjamin L. Allen
- Department of Cell and Developmental Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA; (M.K.S.); (B.L.A.)
- Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Pasca di Magliano
- Department of Cell and Developmental Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA; (M.K.S.); (B.L.A.)
- Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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29
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Xu J, Liu S, Yang X, Cao S, Zhou Y. Paracrine HGF promotes EMT and mediates the effects of PSC on chemoresistance by activating c-Met/PI3K/Akt signaling in pancreatic cancer in vitro. Life Sci 2020; 263:118523. [PMID: 33039386 DOI: 10.1016/j.lfs.2020.118523] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/19/2020] [Accepted: 09/27/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Pancreatic stellate cells (PSCs) play key roles in the pancreatic tumor microenvironment and are considered to contribute to chemoresistance. PSCs can participate in malignant behaviors of pancreatic carcinoma (PC) by secreting hepatocyte growth factor (HGF). The objective of this research was to explore the potential molecular mechanism of HGF on gemcitabine (GEM) chemoresistance of PC. MATERIALS AND METHODS HGF, c-Met, E-Cadherin and Vimentin levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The changes of HGF level were detected by ELISA. The half maximal inhibitory concentration, the growth inhibitions and apoptosis of pancreatic cancer cells (PCCs) were respectively assayed using CCK-8 and flow cytometry. Associated proteins were measured using western blot and cell immunofluorescence assay. KEY FINDINGS PSCs strongly expressed HGF, and its receptor c-Met was expressed in PCCs. PCCs exerted a positive regulative effect on HGF production. HGF neutralizing antibody AMG102 could effectively reduce the HGF level in PSC-conditioned medium (PSC-CM). PSC-CM promoted chemoresistance in PCCs. When exposed to PSC-CM, PCCs underwent epithelial-to-mesenchymal transition (EMT), and c-Met was also activated. Recombinant human HGF had the same protective effect. Blocking the HGF/c-Met axis with a c-Met inhibitor PHA665752 and AMG102 reduced the phosphorylation level of c-Met (p-c-Met) and attenuated EMT and chemoresistance. P-c-Met overexpression resulted in activation of the PI3K/Akt pathway, and inhibition of PI3K/Akt signaling with LY294002 reversed chemoresistance and EMT. SIGNIFICANCE PSCs can activate the c-Met/PI3K/Akt pathway in PCCs via paracrine HGF, induce EMT of PCCs and inhibit cancer cell apoptosis, thus enhance chemoresistance to Gem in PCCs.
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Affiliation(s)
- Jianfei Xu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaopeng Yang
- Department of Gastrointestinal Surgery, Yidu Central Hospital, Weifang, China
| | - Shougen Cao
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanbing Zhou
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China.
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30
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Srivani G, Behera SK, Dariya B, Chalikonda G, Alam A, Nagaraju GP. HIF-1α and RKIP: a computational approach for pancreatic cancer therapy. Mol Cell Biochem 2020; 472:95-103. [PMID: 32562168 DOI: 10.1007/s11010-020-03788-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 06/11/2020] [Indexed: 12/18/2022]
Abstract
Protein-protein interactions (PPIs) are important biochemical processes that represent a major challenge in modern biology. Current approaches, which include high-throughput screening and computer aided ligand design, have limitations regarding the identification of hit matter. This current investigation focuses on computational study for protein-protein docking of hypoxia inducible factor-1α (HIF-1α), a tumor inducible factor, and Raf-1 kinase inhibitory protein (RKIP), a tumor metastasis suppressor. These are individually crystallized structures of interacting proteins, which interact to generate a conformational space. HIF activity in pancreatic tumors is determined by hypoxia and HIF-1α subunit availability. RKIP can be used as a prognostic indicator in a number of tumors. The interaction of RKIP with HIF-1α protects against pancreatic cancer (PC) metastasis by inhibiting its hypoxia function. We have explored the binding affinity between both the proteins with the HADDOCK (high ambiguity driven protein-protein docking) server, which determined that 158 structures in 11 clusters represent 79.0% of water-refined models. Of the best 10 clusters, the structures of cluster 2 were found to be better, as they had the lowest Z-score. Further supporting HIF-1α-RKIP interaction, pulldown assay has shown dissociation of RKIP from HIF-1α after CoCl2 treatment in both PC cell lines.
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Affiliation(s)
- Gowru Srivani
- Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India
| | - Santosh Kumar Behera
- Biomedical Informatics Centre, ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, 751 023, India
| | - Begum Dariya
- Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India
| | - Gayathri Chalikonda
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | - Afroz Alam
- Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
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31
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Dey S, Liu S, Factora TD, Taleb S, Riverahernandez P, Udari L, Zhong X, Wan J, Kota J. Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment. BMC Cancer 2020; 20:651. [PMID: 32660466 PMCID: PMC7359459 DOI: 10.1186/s12885-020-07135-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 07/02/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. METHODS In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing and control human PSCs (hPSCs). Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top miR-29a candidate targets in hPSCs transfected with miR-29a mimic or scramble control. RESULTS RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. CONCLUSIONS Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-cancer cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.
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Affiliation(s)
- Shatovisha Dey
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tricia D Factora
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Solaema Taleb
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Primavera Riverahernandez
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lata Udari
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xiaoling Zhong
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Janaiah Kota
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
- The Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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32
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Nanoparticle mediated cancer immunotherapy. Semin Cancer Biol 2020; 69:307-324. [PMID: 32259643 DOI: 10.1016/j.semcancer.2020.03.015] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 03/09/2020] [Accepted: 03/23/2020] [Indexed: 12/18/2022]
Abstract
The versatility and nanoscale size have helped nanoparticles (NPs) improve the efficacy of conventional cancer immunotherapy and opened up exciting approaches to combat cancer. This review first outlines the tumor immune evasion and the defensive tumor microenvironment (TME) that hinders the activity of host immune system against tumor. Then, a detailed description on how the NP based strategies have helped improve the efficacy of conventional cancer vaccines and overcome the obstacles led by TME. Sustained and controlled drug delivery, enhanced cross presentation by immune cells, co-encapsulation of adjuvants, inhibition of immune checkpoints and intrinsic adjuvant like properties have aided NPs to improve the therapeutic efficacy of cancer vaccines. Also, NPs have been efficient modulators of TME. In this context, NPs facilitate better penetration of the chemotherapeutic drug by dissolution of the inhibitory meshwork formed by tumor associated cells, blood vessels, soluble mediators and extra cellular matrix in TME. NPs achieve this by suppression, modulation, or reprogramming of the immune cells and other mediators localised in TME. This review further summarizes the applications of NPs used to enhance the efficacy of cancer vaccines and modulate the TME to improve cancer immunotherapy. Finally, the hurdles faced in commercialization and translation to clinic have been discussed and intriguingly, NPs owe great potential to emerge as clinical formulations for cancer immunotherapy in near future.
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Amrutkar M, Larsen EK, Aasrum M, Finstadsveen AV, Andresen PA, Verbeke CS, Gladhaug IP. Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor. Cells 2020; 9:cells9010227. [PMID: 31963309 PMCID: PMC7016771 DOI: 10.3390/cells9010227] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/10/2020] [Accepted: 01/14/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method. Characterization of cell morphology, cytostructural, and functional profiles and proteomics-based secretome analysis were performed. All PCCs harbored KRAS and TP53 mutations, and expressed cytokeratin 19, ki-67, and p53, while the expression of EpCAM and vimentin was variable. All PSCs expressed α-smooth muscle actin (α-SMA) and vimentin. PCCs showed a significantly higher growth rate and proliferation than PSCs. Secretome analysis confirmed the distinct nature of PCCs as compared to PSCs and allowed identification of potential molecular regulators of PSC-conditioned medium (PSC-CM)-induced migration of PCCs. Paired primary cultures of PCCs and PSCs derived from the same tumor specimen represent a novel experimental model for basic research in PDAC tumor biology.
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Affiliation(s)
- Manoj Amrutkar
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway; (E.K.L.); (M.A.)
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Blindern, 0318 Oslo, Norway;
- Correspondence: ; Tel.: +47-409-94-132
| | - Emma Kristine Larsen
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway; (E.K.L.); (M.A.)
| | - Monica Aasrum
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway; (E.K.L.); (M.A.)
| | - Anette Vefferstad Finstadsveen
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway; (A.V.F.); (P.A.A.); (C.S.V.)
| | - Per Arne Andresen
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway; (A.V.F.); (P.A.A.); (C.S.V.)
| | - Caroline S. Verbeke
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway; (A.V.F.); (P.A.A.); (C.S.V.)
- Department of Pathology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway
| | - Ivar P. Gladhaug
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Blindern, 0318 Oslo, Norway;
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway
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Li Z, Zhang X, Jin T, Hao J. Nicotine promotes activation of human pancreatic stellate cells through inducing autophagy via α7nAChR-mediated JAK2/STAT3 signaling pathway. Life Sci 2020; 243:117301. [PMID: 31953160 DOI: 10.1016/j.lfs.2020.117301] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/03/2020] [Accepted: 01/12/2020] [Indexed: 12/11/2022]
Abstract
AIM Pancreatic stellate cells (PSCs) are the main functional cells leading to pancreatic fibrosis. Nicotine is widely considered as an independent risk factor of pancreatic fibrosis, but the mechanism is still unclear. Our study was aimed to explore the effects of nicotine on human pancreatic stellate cells (hPSCs) and involved pathways. MATERIALS AND METHODS Primary human PSCs were cultured and treated with nicotine (0.1 μM and 1 μM). The proliferation, apoptosis, α-SMA expression, extracellular matrix metabolism and autophagy of hPSCs were detected by CCK-8 assay, flow cytometry, real-time PCR and Western blotting analysis. The α7nAChR-mediated JAK2/STAT3 signaling pathway was also examined, and an α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. KEY FINDINGS The proliferation, α-SMA expression and autophagy of hPSCs were significantly promoted by 1 μM nicotine. Meanwhile, the apoptosis of hPSCs was significantly reduced. The extracellular matrix metabolism of hPSCs was also regulated by nicotine. Moreover, the α7nAChR-mediated JAK2/STAT3 signaling pathway was activated by nicotine, this pathway and effects of nicotine can be blocked by α-BTX. SIGNIFICANCE Our finding suggests that nicotine can promote activation of human pancreatic stellate cells (hPSCs) through inducing autophagy via α7nAChR-mediated JAK2/STAT3 signaling pathway, providing a new insight into the mechanisms by which nicotine affects pancreatic fibrosis.
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Affiliation(s)
- Zhiren Li
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xiaoyun Zhang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Tong Jin
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
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