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Pratticò F, Garajová I. Focus on Pancreatic Cancer Microenvironment. Curr Oncol 2024; 31:4241-4260. [PMID: 39195299 PMCID: PMC11352508 DOI: 10.3390/curroncol31080316] [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: 06/16/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Pancreatic ductal adenocarcinoma remains one of the most lethal solid tumors due to its local aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. A robust connection between pancreatic cancer microenvironment and tumor progression exists, as well as resistance to current anticancer treatments. Pancreatic cancer has a complex tumor microenvironment, characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts and immune cells. The complex composition of the tumor microenvironment is also reflected in the diversity of its acellular components, such as the extracellular matrix, cytokines, growth factors and secreted ligands involved in signaling pathways. Desmoplasia, the hallmark of the pancreatic cancer microenvironment, contributes by creating a dense and hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance and suppresses anti-tumor immune invasion. We discuss the complex crosstalk among tumor microenvironment components and explore therapeutic strategies and opportunities in pancreatic cancer research. Better understanding of the tumor microenvironment and its influence on pancreatic cancer progression could lead to potential novel therapeutic options, such as integration of immunotherapy and cytokine-targeted treatments.
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Affiliation(s)
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy;
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2
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Lee MJ, Cho JY, Bae S, Jung HS, Kang CM, Kim SH, Choi HJ, Lee CK, Kim H, Jo D, Paik YK. Inhibition of the Alternative Complement Pathway May Cause Secretion of Factor B, Enabling an Early Detection of Pancreatic Cancer. J Proteome Res 2024; 23:985-998. [PMID: 38306169 DOI: 10.1021/acs.jproteome.3c00695] [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] [Indexed: 02/03/2024]
Abstract
This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent ∼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activity was observed in CP and other benign conditions compared with that in HD and PDAC patients, suggesting a functional link between ACP and PDAC. Protein-protein interaction analyses involving key complement proteins and their regulatory factors were conducted using blood samples from PDAC patients and cultured cell lines. Our findings revealed a complex control system governing the ACP and its regulatory factors, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, adrenomedullin (AM), and complement factor H (CFH). Particularly, AM emerged as a crucial player in CFB secretion, activating CFH and promoting its predominant binding to C3b over CFB. Mechanistically, our data suggest that the KRAS mutation stimulates AM expression, enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction conferred greater affinity for C3b over CFB, potentially suppressing the ACP cascade. This sequence of events likely culminated in the preferential release of ductal CFB into plasma during the early stages of PDAC. (Data set ID PXD047043.).
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Affiliation(s)
- Min Jung Lee
- Yonsei Proteome Research Center, Yonsei University, Seoul 03722, South Korea
| | - Jin-Young Cho
- Yonsei Proteome Research Center, Yonsei University, Seoul 03722, South Korea
| | - Sumi Bae
- JW BioScience Corp., 38 Gwacheon-daero, Gwacheon-si, Gyeonggi-do 13840, South Korea
| | - Hye Soo Jung
- JW BioScience Corp., 38 Gwacheon-daero, Gwacheon-si, Gyeonggi-do 13840, South Korea
| | - Chang Moo Kang
- Department of Surgery, Division of HBP Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Sung Hyun Kim
- Department of Surgery, Division of HBP Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Hye Jin Choi
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Choong-Kun Lee
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Hoguen Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Daewoong Jo
- Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea
| | - Young-Ki Paik
- Yonsei Proteome Research Center, Yonsei University, Seoul 03722, South Korea
- Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea
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Van den Eynde A, Gehrcken L, Verhezen T, Lau HW, Hermans C, Lambrechts H, Flieswasser T, Quatannens D, Roex G, Zwaenepoel K, Marcq E, Joye P, Cardenas De La Hoz E, Deben C, Gasparini A, Montay-Gruel P, Le Compte M, Lion E, Lardon F, Van Laere S, Siozopoulou V, Campillo-Davo D, De Waele J, Pauwels P, Jacobs J, Smits E, Van Audenaerde JRM. IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts. J Hematol Oncol 2024; 17:8. [PMID: 38331849 PMCID: PMC10854128 DOI: 10.1186/s13045-024-01525-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 01/11/2024] [Indexed: 02/10/2024] Open
Abstract
BACKGROUND It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma. METHODS RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70+ tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs. RESULTS In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70+ tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70+ tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner. CONCLUSIONS We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70+ cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.
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Affiliation(s)
- Astrid Van den Eynde
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
| | - Laura Gehrcken
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Tias Verhezen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Ho Wa Lau
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Christophe Hermans
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Hilde Lambrechts
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Tal Flieswasser
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Delphine Quatannens
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Gils Roex
- Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Edegem, Belgium
| | - Karen Zwaenepoel
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
- Department of Pathology, Antwerp University Hospital, Edegem, Belgium
| | - Elly Marcq
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
- Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Philippe Joye
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Wilrijk, Belgium
| | | | - Christophe Deben
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Alessia Gasparini
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
- Iridium Netwerk, Radiation Oncology, Antwerp, Belgium
| | - Pierre Montay-Gruel
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
- Iridium Netwerk, Radiation Oncology, Antwerp, Belgium
| | - Maxim Le Compte
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Eva Lion
- Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Edegem, Belgium
- Center for Cell Therapy and Regenerative Medicine (CCRG), Antwerp University Hospital, Edegem, Belgium
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Steven Van Laere
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
- Department of Pathology, Antwerp University Hospital, Edegem, Belgium
| | - Vasiliki Siozopoulou
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
- University Hospital Saint-Luc, University of Louvain, Brussels, Belgium
| | - Diana Campillo-Davo
- Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Edegem, Belgium
| | - Jorrit De Waele
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Patrick Pauwels
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
- Department of Pathology, Antwerp University Hospital, Edegem, Belgium
| | - Julie Jacobs
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Evelien Smits
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Jonas R M Van Audenaerde
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
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Histone Modifications Represent a Key Epigenetic Feature of Epithelial-to-Mesenchyme Transition in Pancreatic Cancer. Int J Mol Sci 2023; 24:ijms24054820. [PMID: 36902253 PMCID: PMC10003015 DOI: 10.3390/ijms24054820] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Pancreatic cancer is one of the most lethal malignant diseases due to its high invasiveness, early metastatic properties, rapid disease progression, and typically late diagnosis. Notably, the capacity for pancreatic cancer cells to undergo epithelial-mesenchymal transition (EMT) is key to their tumorigenic and metastatic potential, and is a feature that can explain the therapeutic resistance of such cancers to treatment. Epigenetic modifications are a central molecular feature of EMT, for which histone modifications are most prevalent. The modification of histones is a dynamic process typically carried out by pairs of reverse catalytic enzymes, and the functions of these enzymes are increasingly relevant to our improved understanding of cancer. In this review, we discuss the mechanisms through which histone-modifying enzymes regulate EMT in pancreatic cancer.
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Cai ZW, Li JL, Liu M, Wang HW, Jiang CY. Low preoperative skeletal muscle index increases the risk of mortality among resectable pancreatic cancer patients: A retrospective study. World J Gastrointest Surg 2022; 14:1350-1362. [PMID: 36632124 PMCID: PMC9827571 DOI: 10.4240/wjgs.v14.i12.1350] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/29/2022] [Accepted: 12/06/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The only potential curative treatment for patients with pancreatic cancer is surgery; however, the prognosis remains poor. Measures of body composition based on computed tomography (CT) have been established as a reliable predictor of the prognosis of cancer patients after surgery.
AIM To elucidate the associations of body composition measures derived from preoperative CT scans with the prognosis of patients with pancreatic cancer.
METHODS One hundred fifteen patients undergoing pancreatic resection with curative intent for pancreatic cancer were retrospectively enrolled. A preoperative CT scan at the third lumbar vertebral level was performed to measure the skeletal muscle index (SMI), mean skeletal muscle radiodensity, subcutaneous adipose tissue index, and visceral to subcutaneous adipose tissue area ratio. The clinical and pathological data were collected. The effects of these factors on long-term survival were evaluated.
RESULTS Among the five body composition measures, only low SMI independently predicted overall survival (OS) [hazard ratio (HR): 2.307; 95% confidence interval (CI): 1.210-4.402] and recurrence-free survival (HR: 1.907; 95%CI: 1.147-3.171). Furthermore, patients with low SMI (vs high SMI) were older (68.8 ± 9.3 years vs 63.3 ± 8.4 years); low SMI was present in 27 of 56 patients (48.2%) aged 65 years and older and in 11 of 59 younger patients (18.6%). In addition, subgroup analyses revealed that the correlation between low SMI and OS was observed only in patients aged 65 years and older.
CONCLUSION Low preoperative SMI was more prevalent in elderly patients and was associated with a poor prognosis among pancreatic cancer patients, especially elderly patients.
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Affiliation(s)
- Zhi-Wei Cai
- Department of General Surgery, Hepato-Biliary-Pancreatic Center, Huadong Hospital, Shanghai 200040, China
| | - Jia-Lin Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Meng Liu
- Department of General Surgery, Hepato-Biliary-Pancreatic Center, Huadong Hospital, Shanghai 200040, China
| | - Hong-Wei Wang
- Department of General Surgery, Hepato-Biliary-Pancreatic Center, Huadong Hospital, Shanghai 200040, China
| | - Chong-Yi Jiang
- Department of General Surgery, Hepato-Biliary-Pancreatic Center, Huadong Hospital, Shanghai 200040, China
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Sadrkhanloo M, Entezari M, Orouei S, Ghollasi M, Fathi N, Rezaei S, Hejazi ES, Kakavand A, Saebfar H, Hashemi M, Goharrizi MASB, Salimimoghadam S, Rashidi M, Taheriazam A, Samarghandian S. STAT3-EMT axis in tumors: modulation of cancer metastasis, stemness and therapy response. Pharmacol Res 2022; 182:106311. [PMID: 35716914 DOI: 10.1016/j.phrs.2022.106311] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 02/07/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis of tumor cells and their spread to various organs and tissues of body, providing undesirable prognosis. In addition to migration, EMT increases stemness and mediates therapy resistance. Hence, pathways involved in EMT regulation should be highlighted. STAT3 is an oncogenic pathway that can elevate growth rate and migratory ability of cancer cells and induce drug resistance. The inhibition of STAT3 signaling impairs cancer progression and promotes chemotherapy-mediated cell death. Present review focuses on STAT3 and EMT interaction in modulating cancer migration. First of all, STAT3 is an upstream mediator of EMT and is able to induce EMT-mediated metastasis in brain tumors, thoracic cancers and gastrointestinal cancers. Therefore, STAT3 inhibition significantly suppresses cancer metastasis and improves prognosis of patients. EMT regulators such as ZEB1/2 proteins, TGF-β, Twist, Snail and Slug are affected by STAT3 signaling to stimulate cancer migration and invasion. Different molecular pathways such as miRNAs, lncRNAs and circRNAs modulate STAT3/EMT axis. Furthermore, we discuss how STAT3 and EMT interaction affects therapy response of cancer cells. Finally, we demonstrate targeting STAT3/EMT axis by anti-tumor agents and clinical application of this axis for improving patient prognosis.
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Affiliation(s)
- Mehrdokht Sadrkhanloo
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sima Orouei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Nikoo Fathi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shamin Rezaei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elahe Sadat Hejazi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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7
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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8
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Swain SM, Romac JMJ, Vigna SR, Liddle RA. Piezo1-mediated stellate cell activation causes pressure-induced pancreatic fibrosis in mice. JCI Insight 2022; 7:158288. [PMID: 35451372 PMCID: PMC9089793 DOI: 10.1172/jci.insight.158288] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/02/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic fibrosis is a complication of chronic pancreatitis and is a prominent feature of pancreatic cancer. Pancreatic fibrosis is commonly observed in patients with prolonged pancreatic duct obstruction, which elevates intrapancreatic pressure. We show here that increased pancreatic duct pressure causes fibrosis and describes the mechanism by which pressure increases deposition of extracellular matrix proteins and fibrosis. We found that pancreatic stellate cells (PSCs), the source of the extracellular matrix proteins in fibrosis, express the mechanically activated ion channel Piezo1. By increasing intracellular calcium, mechanical stress or the Piezo1 agonist Yoda1-activated PSCs manifest by loss of perinuclear fat droplets and increased TGF-β1, fibronectin, and type I collagen expression. These effects were blocked by the Piezo1 inhibitor GsMTx4 and absent in PSCs from mice with conditional genetic deletion of Piezo1 in stellate cells, as was pancreatic duct ligation-induced fibrosis. Although TRPV4 has been proposed to have direct mechanosensing properties, we discovered that PSCs from Trpv4-KO mice were protected against Yoda1-triggered activation. Moreover, mice devoid of TRPV4 were protected from pancreatic duct ligation-induced fibrosis. Thus, high pressure within the pancreas stimulates Piezo1 channel opening, and subsequent activation of TRPV4 leads to stellate cell activation and pressure-induced chronic pancreatitis and fibrosis.
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Affiliation(s)
- Sandip M Swain
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Joelle M-J Romac
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Steven R Vigna
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Rodger A Liddle
- Department of Medicine, Duke University, Durham, North Carolina, USA.,Department of Veterans Affairs Healthcare System, Durham, North Carolina, USA
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Qiao L, Chen Y, Liang N, Xie J, Deng G, Chen F, Wang X, Liu F, Li Y, Zhang J. Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies. Front Oncol 2022; 12:775238. [PMID: 35251963 PMCID: PMC8888452 DOI: 10.3389/fonc.2022.775238] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Radiotherapy exerts a crucial role in curing cancer, however, its treatment efficiency is mostly limited due to the presence of radioresistance. Epithelial-to-mesenchymal transition (EMT) is a biological process that endows the cancer cells with invasive and metastatic properties, as well as radioresistance. Many potential mechanisms of EMT-related radioresistance being reported have broaden our cognition, and hint us the importance of an overall understanding of the relationship between EMT and radioresistance. This review focuses on the recent progresses involved in EMT-related mechanisms in regulating radioresistance, irradiation-mediated EMT program, and the intervention strategies to increase tumor radiosensitivity, in order to improve radiotherapy efficiency and clinical outcomes of cancer patients.
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Affiliation(s)
- Lili Qiao
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Yanfei Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Ning Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Jian Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Guodong Deng
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Fangjie Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Xiaojuan Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Fengjun Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Yupeng Li
- Department of Oncology, Shandong First Medical University, Jinan, China.,Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Jiandong Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
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10
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Hamada S, Matsumoto R, Masamune A. HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14020411. [PMID: 35053572 PMCID: PMC8773475 DOI: 10.3390/cancers14020411] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/13/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic cancer progression involves interactions between cancer cells and stromal cells in harsh tumor microenvironments, which are characterized by hypoxia, few nutrients, and oxidative stress. Clinically, cancer cells overcome therapeutic interventions, such as chemotherapy and radiotherapy, to continue to survive. Activation of the adaptation mechanism is required for cancer cell survival under these conditions, and it also contributes to the acquisition of the malignant phenotype. Stromal cells, especially pancreatic stellate cells, play a critical role in the formation of a cancer-promoting microenvironment. We here review the roles of key molecules, hypoxia inducible factor-1 and KEAP1-NRF2, in stress response mechanisms for the adaptation to hypoxia and oxidative stress in pancreatic cancer cells and stellate cells. Various cancer-promoting properties associated with these molecules have been identified, and they might serve as novel therapeutic targets in the future. Abstract Pancreatic cancer is intractable due to early progression and resistance to conventional therapy. Dense fibrotic stroma, known as desmoplasia, is a characteristic feature of pancreatic cancer, and develops through the interactions between pancreatic cancer cells and stromal cells, including pancreatic stellate cells. Dense stroma forms harsh tumor microenvironments characterized by hypoxia, few nutrients, and oxidative stress. Pancreatic cancer cells as well as pancreatic stellate cells survive in the harsh microenvironments through the altered expression of signaling molecules, transporters, and metabolic enzymes governed by various stress response mechanisms. Hypoxia inducible factor-1 and KEAP1-NRF2, stress response mechanisms for hypoxia and oxidative stress, respectively, contribute to the aggressive behaviors of pancreatic cancer. These key molecules for stress response mechanisms are activated, both in pancreatic cancer cells and in pancreatic stellate cells. Both factors are involved in the mutual activation of cancer cells and stellate cells, by inducing cancer-promoting signals and their mediators. Therapeutic interventions targeting these pathways are promising approaches for novel therapies. In this review, we summarize the roles of stress response mechanisms, focusing on hypoxia inducible factor-1 and KEAP1-NRF2, in pancreatic cancer. In addition, we discuss the potential of targeting these molecules for the treatment of pancreatic cancer.
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11
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Lee MJ, Na K, Shin H, Kim CY, Cho JY, Kang CM, Kim SH, Kim H, Choi HJ, Lee CK, Bae S, Son S, Paik YK. Early Diagnostic Ability of Human Complement Factor B in Pancreatic Cancer Is Partly Linked to Its Potential Tumor-Promoting Role. J Proteome Res 2021; 20:5315-5328. [PMID: 34766501 DOI: 10.1021/acs.jproteome.1c00805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Although plasma complement factor B (CFB, NX_P00751), both alone and in combination with CA19-9 (i.e., the ComB-CAN), previously exhibited a reliable diagnostic ability for pancreatic cancer (PC), its detectability of the early stages and the cancer detection mechanism remained elusive. We first evaluated the diagnostic accuracy of ComB-CAN using plasma samples from healthy donors (HDs), patients with chronic pancreatitis (CP), and patients with different PC stages (I/II vs III/IV). An analysis of the area under the curve (AUC) by PanelComposer using logistic regression revealed that ComB-CAN has a superior diagnostic ability for early-stage PC (97.1.% [95% confidence interval (CI): (97.1-97.2)]) compared with CFB (94.3% [95% CI: 94.2-94.4]) or CA19-9 alone (34.3% [95% CI: 34.1-34.4]). In the comparisons of all stages of patients with PC vs CP and HDs, the AUC values of ComB-CAN, CFB, and CA19-9 were 0.983 (95% CI: 0.983-0.983), 0.950 (95% CI: 0.950-0.951), and 0.873 (95% CI: 0.873-0.874), respectively. We then investigated the molecular mechanism underlying the detection of early-stage PC by using stable cell lines of CFB knockdown and CFB overexpression. A global transcriptomic analysis coupled to cell invasion assays of both CFB-modulated cell lines suggested that CFB plays a tumor-promoting role in PC, which likely initiates the PI3K-AKT cancer signaling pathway. Thus our study establishes ComB-CAN as a reliable early diagnostic marker for PC that can be clinically applied for early PC screening in the general public.
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Affiliation(s)
- Min Jung Lee
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Keun Na
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Heon Shin
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Chae-Yeon Kim
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Jin-Young Cho
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | | | | | | | | | | | - Sumi Bae
- JW Bioscience Corp., 2477, Nambusunhwan-ro, Seocho-gu, Seoul 06725, South Korea
| | - Sunghwa Son
- JW Holdings Corp., 2477, Nambusunhwan-ro, Seocho-gu, Seoul 06725, South Korea
| | - Young-Ki Paik
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
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12
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Li HB, Yang ZH, Guo QQ. Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review. Cell Commun Signal 2021; 19:117. [PMID: 34819086 PMCID: PMC8611916 DOI: 10.1186/s12964-021-00789-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/16/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting. Video Abstract.
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Affiliation(s)
- Hong-Bo Li
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009 Zhejiang Province China
| | - Zi-Han Yang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009 Zhejiang Province China
| | - Qing-Qu Guo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009 Zhejiang Province China
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13
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Chemotherapy: a double-edged sword in cancer treatment. Cancer Immunol Immunother 2021; 71:507-526. [PMID: 34355266 DOI: 10.1007/s00262-021-03013-3] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/07/2021] [Indexed: 12/24/2022]
Abstract
Chemotherapy is a well-known and effective treatment for different cancers; unfortunately, it has not been as efficient in the eradication of all cancer cells as been expected. The mechanism of this failure was not fully clarified, yet. Meanwhile, alterations in the physiologic conditions of the tumor microenvironment (TME) were suggested as one of the underlying possibilities. Chemotherapy drugs can activate multiple signaling pathways and augment the secretion of inflammatory mediators. Inflammation may show two opposite roles in the TME. On the one hand, inflammation, as an innate immune response, tries to suppress tumor growth but on the other hand, it might be not powerful enough to eradicate the cancer cells and even it can provide appropriate conditions for cancer promotion and relapse as well. Therefore, the administration of mild anti-inflammatory drugs during chemotherapy might result in more successful clinical results. Here, we will review and discuss this hypothesis. Most chemotherapy agents are triggers of inflammation in the tumor microenvironment through inducing the production of senescence-associated secretory phenotype (SASP) molecules. Some chemotherapy agents can induce systematic inflammation by provoking TLR4 signaling or triggering IL-1B secretion through the inflammasome pathway. NF-kB and MAPK are key signaling pathways of inflammation and could be activated by several chemotherapy drugs. Furthermore, inflammation can play a key role in cancer development, metastasis and exacerbation.
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14
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Magni L, Bouazzi R, Heredero Olmedilla H, Petersen PSS, Tozzi M, Novak I. The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells. Cells 2021; 10:cells10081928. [PMID: 34440697 PMCID: PMC8391419 DOI: 10.3390/cells10081928] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/30/2021] [Accepted: 07/23/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic stellate cells (PSCs) are important pancreatic fibrogenic cells that interact with pancreatic cancer cells to promote the progression of pancreatic ductal adenocarcinoma (PDAC). In the tumor microenvironment (TME), several factors such as cytokines and nucleotides contribute to this interplay. Our aim was to investigate whether there is an interaction between IL-6 and nucleotide signaling, in particular, that mediated by the ATP-sensing P2X7 receptor (P2X7R). Using human cell lines of PSCs and cancer cells, as well as primary PSCs from mice, we show that ATP is released from both PSCs and cancer cells in response to mechanical and metabolic cues that may occur in the TME, and thus activate the P2X7R. Functional studies using P2X7R agonists and inhibitors show that the receptor is involved in PSC proliferation, collagen secretion and IL-6 secretion and it promotes cancer cell migration in a human PSC-cancer cell co-culture. Moreover, conditioned media from P2X7R-stimulated PSCs activated the JAK/STAT3 signaling pathway in cancer cells. The monoclonal antibody inhibiting the IL-6 receptor, Tocilizumab, inhibited this signaling. In conclusion, we show an important mechanism between PSC-cancer cell interaction involving ATP and IL-6, activating P2X7 and IL-6 receptors, respectively, both potential therapeutic targets in PDAC.
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MESH Headings
- Animals
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/physiopathology
- Cell Communication
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Humans
- Interleukin-6/metabolism
- Male
- Mice
- Pancreatic Stellate Cells/metabolism
- Pancreatic Stellate Cells/physiology
- Receptors, Purinergic P2X7/metabolism
- STAT3 Transcription Factor/metabolism
- Signal Transduction
- Tumor Microenvironment
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15
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Feng H, Moriyama T, Ohuchida K, Sheng N, Iwamoto C, Shindo K, Shirahane K, Ikenaga N, Nagai S, Nakata K, Mizumoto K, Nakamura M. N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions. J Exp Clin Cancer Res 2021; 40:133. [PMID: 33858491 PMCID: PMC8050903 DOI: 10.1186/s13046-021-01939-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 04/06/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions. METHOD We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone's combination therapy on subcutaneous tumor formation and splenic xenografted mouse models. RESULTS In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone's combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level. CONCLUSION NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.
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Affiliation(s)
- Haimin Feng
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Taiki Moriyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Department of Endoscopic Diagnostics and Therapeutics, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
- Cancer Center of Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Nan Sheng
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Chika Iwamoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kengo Shirahane
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Naoki Ikenaga
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shuntaro Nagai
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kazuhiro Mizumoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Cancer Center of Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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16
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Emerging roles for the IL-6 family of cytokines in pancreatic cancer. Clin Sci (Lond) 2020; 134:2091-2115. [PMID: 32808663 PMCID: PMC7434989 DOI: 10.1042/cs20191211] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/29/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the expression of, and signalling through, cytokines, chemokines, and other cellular messengers. In recent years, there has been much attention focused on dual targeting of cancer cells and the tumour microenvironment. Here we review our current understanding of the role of IL-6, and the broader IL-6 cytokine family, in pancreatic cancer, including their contribution to pancreatic inflammation and various roles in pancreatic cancer pathogenesis. We also summarise potential opportunities for therapeutic targeting of these pathways as an avenue towards combating poor patient outcomes.
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17
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Wada Y, Tokuda K, Morine Y, Okikawa S, Yamashita S, Ikemoto T, Imura S, Saito Y, Yamada S, Shimada M. The inhibitory effect of TU-100 on hepatic stellate cell activation in the tumor microenvironment. Oncotarget 2020; 11:4593-4604. [PMID: 33346211 PMCID: PMC7733620 DOI: 10.18632/oncotarget.27835] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/19/2020] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION The tumor microenvironment is involved in acquiring tumor malignancies of colorectal liver metastasis (CRLM). We have reported that TU-100 (Daikenchuto) suppresses hepatic stellate cell (HSC) activation in obstructive jaundice. In this study, we report new findings as the direct and indirect inhibitory effects of TU-100 on cancer cell growth through the suppression of HSC activation. MATERIALS AND METHODS The HSCs (LX2) were cultured in colon cancer cells (HCT116 and HT29)-conditioned medium (CM) with or without TU-100 treatment (90, 270, 900 μg/ml). Activated HSCs (aHSCs) were detected by α-SMA and IL-6 mRNA expressions and cytokine arrays of HSC's culture supernatants. Cancer cell growth was analyzed for proliferation and migration ability, compared with TU-100 treatment. To investigate the direct anti-tumor effect of TU-100, cancer cells were cultured in the presence of aHSC-CM and TU-100 (90, 270, 900) or aHSC-CM alone, and assessed autophagosomes, conversion to LC3-II protein, and Beclin-1 mRNA expression. RESULTS Colon cancer-CM significantly increased α-SMA and IL-6 mRNA expressions of aHSC. α-SMA and IL-6 mRNA expressions of aHSC, and IL-6 secretions from aHSCs were significantly decreased with TU-100 (270, 900) treatment, compared to colon cancer-CM alone. Compared with normal culture medium, aHSC-CM led to a significantly increased cell number and modified HSC-CM (TU-100; 270, 900) significantly suppressed cancer cell growth and migration. TU-100 (900) treatment induced autophagy and significantly promoted the autophagic cell death. CONCLUSIONS TU-100 inhibited colon cancer cell malignant potential by both suppressing HSC activation and inducing directly autophagy of cancer cells.
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Affiliation(s)
- Yuma Wada
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.,These authors contributed equally to this work
| | - Kazunori Tokuda
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.,These authors contributed equally to this work
| | - Yuji Morine
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Shohei Okikawa
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Shoko Yamashita
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Satoru Imura
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yu Saito
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Shinichiro Yamada
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
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18
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Kesh K, Garrido VT, Dosch A, Durden B, Gupta VK, Sharma NS, Lyle M, Nagathihalli N, Merchant N, Saluja A, Banerjee S. Stroma secreted IL6 selects for "stem-like" population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways. Cell Death Dis 2020; 11:967. [PMID: 33177492 PMCID: PMC7658205 DOI: 10.1038/s41419-020-03168-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 10/26/2020] [Accepted: 10/27/2020] [Indexed: 12/17/2022]
Abstract
Pancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contribute to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to the aggressive biology of cancer along with its immune-evasive microenvironment. In this study, we show that in pancreatic tumors, the developing stroma increases tumor initiation frequency in pancreatic cancer cells in vivo by enriching for CD133 + aggressive "stem-like" cells. Additionally, the stromal fibroblasts secrete IL6 as the major cytokine, increases glycolytic flux in the pancreatic tumor cells, and increases lactate efflux in the microenvironment via activation of the STAT signaling pathway. We also show that the secreted lactate favors activation of M2 macrophages in the tumor microenvironment, which excludes CD8 + T cells in the tumor. Our data additionally confirms that the treatment of pancreatic tumors with anti-IL6 antibody results in tumor regression as well as decreased CD133 + population within the tumor. Furthermore, inhibiting the lactate efflux in the microenvironment reduces M2 macrophages, and makes pancreatic tumors more responsive to anti-PD1 therapy. This suggests that stromal IL6 driven metabolic reprogramming plays a significant role in the development of an immune-evasive microenvironment. In conclusion, our study shows that targeting the metabolic pathways affected by stromal IL6 can make pancreatic tumors amenable to checkpoint inhibitor therapy.
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Affiliation(s)
- Kousik Kesh
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Vanessa T Garrido
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Austin Dosch
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Brittany Durden
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Vineet K Gupta
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Nikita S Sharma
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Michael Lyle
- WeliChem Biotech Inc, Vancouver, British Columbia, Canada
| | - Nagaraj Nagathihalli
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Nipun Merchant
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Ashok Saluja
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Sulagna Banerjee
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA. .,Sylvester Comprehensive Cancer Center, Miami, FL, USA.
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19
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Xia SH. Prospect and clinical value of oxymatrine in prevention and treatment of pancreatic fibrosis. Shijie Huaren Xiaohua Zazhi 2020; 28:819-826. [DOI: 10.11569/wcjd.v28.i17.819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Studies have confirmed that pancreatic stellate cell activation is the central event in the initiation and development of pancreatic fibrosis (PF), but the specific mechanism of PF is still unknown, and there is no specific treatment for PF. Some basic studies have confirmed that oxymatrine (OMT) has a certain therapeutic effect on PF, but further research is needed. It can be predicted that OMT has a far-reaching research prospect and good clinical application value for the prevention and treatment of PF, and is also conducive to the better development and utilization of traditional Chinese herbal medicine radix sophorae flavescentis.
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Affiliation(s)
- Shi-Hai Xia
- Gastroenterology Department of Medical Center of the Chinese People's Armed Police Force (Institute of Digestive Diseases of Medical Center), Medical Center for Hepatobiliary, Pancreatic and Splenic Disease of the Chinese People's Armed Police Force, Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment, Tianjin 300162, China
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20
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Sun B, Shi Y, Li Y, Jiang J, Liang S, Duan J, Sun Z. Short-term PM 2.5 exposure induces sustained pulmonary fibrosis development during post-exposure period in rats. JOURNAL OF HAZARDOUS MATERIALS 2020; 385:121566. [PMID: 31761645 DOI: 10.1016/j.jhazmat.2019.121566] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/21/2019] [Accepted: 10/29/2019] [Indexed: 05/05/2023]
Abstract
Up to now, while some toxicological studies have identified pulmonary fibrosis immediately induced by long-term PM2.5 exposure, there has been no evidence indicating, whether short-term exposure can lead to post-exposure development of pulmonary fibrosis. Here, we treated rats with PM2.5 for 1 month (10 times), followed by normal feeding for 18 months. 18F-FDG intake, which is linked with the initiation and development of pulmonary fibrosis in living bodies, was found to gradually increase in lung following exposure through micro PET/CT imaging. Histolopathological examination revealed continuous deterioration of pulmonary injury post-exposure. Collagen deposition and hydroxyproline content continued to increase all along in the post-exposure duration, indicating pulmonary fibrosis development. Chronic and persistent induction of pulmonary inflammatory gene expression (Tnf, Il1b, Il6, Ccl2, and Icam1), epithelial mesenchymal transition (EMT, reduction of E-cadherin and elevation of fibronectin) and RelA/p65 upregulation, as well as serum inflammatory cytokine production, were also found in PM2.5-treated rats. Pulmonary oxidative stress, manifested by increase of MDA and decrease of GSH and SOD, was induced during exposure but disappeared in later post-exposure duration. These results suggested that short-term PM2.5 exposure could lead to sustained post-exposure pulmonary fibrosis development, which was mediated by oxidative-stress-initiated NF-κB/inflammation/EMT pathway.
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Affiliation(s)
- Baiyang Sun
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Yanfeng Shi
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Yang Li
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Jinjin Jiang
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Shuang Liang
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China.
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China.
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21
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Bazzichetto C, Conciatori F, Luchini C, Simionato F, Santoro R, Vaccaro V, Corbo V, Falcone I, Ferretti G, Cognetti F, Melisi D, Scarpa A, Ciuffreda L, Milella M. From Genetic Alterations to Tumor Microenvironment: The Ariadne's String in Pancreatic Cancer. Cells 2020; 9:cells9020309. [PMID: 32012917 PMCID: PMC7072496 DOI: 10.3390/cells9020309] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/18/2020] [Accepted: 01/23/2020] [Indexed: 02/06/2023] Open
Abstract
The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies
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Affiliation(s)
- Chiara Bazzichetto
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Fabiana Conciatori
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
- Correspondence: ; Tel.: +39-06-52665185
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy;
| | - Francesca Simionato
- Division of Oncology, University of Verona, 37126 Verona, Italy; (F.S.); (M.M.)
| | - Raffaela Santoro
- Medicine-Digestive Molecular Clinical Oncology Research Unit, University of Verona, 37126 Verona, Italy; (R.S.); (D.M.)
| | - Vanja Vaccaro
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Vincenzo Corbo
- ARC-Net Research Centre, University and Hospital Trust of Verona, 37126 Verona, Italy; (V.C.); (A.S.)
| | - Italia Falcone
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Gianluigi Ferretti
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Francesco Cognetti
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Davide Melisi
- Medicine-Digestive Molecular Clinical Oncology Research Unit, University of Verona, 37126 Verona, Italy; (R.S.); (D.M.)
| | - Aldo Scarpa
- ARC-Net Research Centre, University and Hospital Trust of Verona, 37126 Verona, Italy; (V.C.); (A.S.)
| | - Ludovica Ciuffreda
- SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Michele Milella
- Division of Oncology, University of Verona, 37126 Verona, Italy; (F.S.); (M.M.)
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22
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Pancreatic Stellate Cells Promote Tumor Progression by Promoting an Immunosuppressive Microenvironment in Murine Models of Pancreatic Cancer. Pancreas 2020; 49:120-127. [PMID: 31856087 DOI: 10.1097/mpa.0000000000001464] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with poor prognosis. Pancreatic stellate cells (PSCs) play a vital role in PDAC development. The aim of this study was to explore tumor microenvironment response to PSCs in an orthotopic pancreatic cancer mouse model and to assess if PSCs secreted factors that can facilitate an immunosuppressive microenvironment. METHODS Pancreatic ductal adenocarcinoma orthotopic tumor model, derived from coinjection of Panc02 cells plus PSCs, was used to investigate tumor proliferation, metastasis, and the population of immune cells in vivo, including regulatory T cells, M2-type macrophages, myeloid-derived suppressor cells, CD8 T cells, CD4 T cells, M1-type macrophages, natural killer (NK), and NK T cells. RESULTS Pancreatic stellate cells promoted PDAC growth not only induced cell proliferation and metastasis, but also significantly increased the suppressive immune cell population of regulatory T cells, M2-type macrophages, and myeloid-derived suppressor cells. In addition, PSCs decreased the immune cell population of CD8 T, CD4 T cells, and M1-type macrophages in the spleen and tumor tissues of the tumor-bearing mice. Moreover, PSCs decreased the population of NK and NK T cells in the tumor tissues. CONCLUSIONS Our findings support PSCs playing multiple roles in PDAC development via promoting immunosuppressive microenvironment.
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23
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Wu CJ, Sundararajan V, Sheu BC, Huang RYJ, Wei LH. Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity. Cancers (Basel) 2019; 12:cancers12010024. [PMID: 31861720 PMCID: PMC7017004 DOI: 10.3390/cancers12010024] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/13/2019] [Accepted: 12/17/2019] [Indexed: 12/12/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.
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Affiliation(s)
- Chin-Jui Wu
- Department of Obstetrics & Gynecology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan; (C.-J.W.); (B.-C.S.)
| | - Vignesh Sundararajan
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore 117599, Singapore;
| | - Bor-Ching Sheu
- Department of Obstetrics & Gynecology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan; (C.-J.W.); (B.-C.S.)
| | - Ruby Yun-Ju Huang
- Department of Obstetrics and Gynaecology, National University of Singapore, Singapore 119077, Singapore;
- School of Medicine, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Lin-Hung Wei
- Department of Obstetrics & Gynecology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan; (C.-J.W.); (B.-C.S.)
- Correspondence: ; Tel.: +886-2-2312-3456 (ext. 71570); Fax: +886-2-2311-4965
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24
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Sakamoto S, Kagawa S, Kuwada K, Ito A, Kajioka H, Kakiuchi Y, Watanabe M, Kagawa T, Yoshida R, Kikuchi S, Kuroda S, Tazawa H, Fujiwara T. Intraperitoneal cancer-immune microenvironment promotes peritoneal dissemination of gastric cancer. Oncoimmunology 2019; 8:e1671760. [PMID: 31741772 PMCID: PMC6844331 DOI: 10.1080/2162402x.2019.1671760] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 09/12/2019] [Accepted: 09/18/2019] [Indexed: 12/13/2022] Open
Abstract
A solid tumor consists of cancer and stromal cells, which comprise the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are usually abundant in the TME, contributing to tumor progression. In cases of peritoneal dissemination of gastric cancer (GC), the contribution of intraperitoneal TAMs remains unclear. Macrophages from peritoneal washings of GC patients were analyzed, and the link between intraperitoneal TAMs and GC cells was investigated to clarify the interaction between them in peritoneal dissemination. Macrophages were predominant among leukocytes constituting the microenvironment of the peritoneal cavity. The proportion of CD163-positive TAMs was significantly higher in stage IV than in stage I GC. Co-culture with TAMs potentiated migration and invasion of GC. IL-6 was the most increased in the medium of in vitro co-culture of macrophages and GC, and IL-6 elevation was also observed in the peritoneal washes with peritoneal dissemination. An elevated concentration of intraperitoneal IL-6 was correlated with a poor prognosis in clinical cases. In conclusion, intraperitoneal TAMs are involved in promoting peritoneal dissemination of GC via secreted IL-6. TAM-derived IL-6 could be a potential therapeutic target for peritoneal dissemination of GC.
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Affiliation(s)
- Shuichi Sakamoto
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan
| | - Kazuya Kuwada
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Atene Ito
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroki Kajioka
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshihiko Kakiuchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Megumi Watanabe
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tetsuya Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ryuichi Yoshida
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoru Kikuchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan
| | - Shinji Kuroda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Hiroshi Tazawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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25
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Cold Atmospheric Plasma-Treated PBS Eliminates Immunosuppressive Pancreatic Stellate Cells and Induces Immunogenic Cell Death of Pancreatic Cancer Cells. Cancers (Basel) 2019; 11:cancers11101597. [PMID: 31635070 PMCID: PMC6826654 DOI: 10.3390/cancers11101597] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a low response to treatment and a five-year survival rate below 5%. The ineffectiveness of treatment is partly because of an immunosuppressive tumor microenvironment, which comprises tumor-supportive pancreatic stellate cells (PSCs). Therefore, new therapeutic strategies are needed to tackle both the immunosuppressive PSC and pancreatic cancer cells (PCCs). Recently, physical cold atmospheric plasma consisting of reactive oxygen and nitrogen species has emerged as a novel treatment option for cancer. In this study, we investigated the cytotoxicity of plasma-treated phosphate-buffered saline (pPBS) using three PSC lines and four PCC lines and examined the immunogenicity of the induced cell death. We observed a decrease in the viability of PSC and PCC after pPBS treatment, with a higher efficacy in the latter. Two PCC lines expressed and released damage-associated molecular patterns characteristic of the induction of immunogenic cell death (ICD). In addition, pPBS-treated PCC were highly phagocytosed by dendritic cells (DCs), resulting in the maturation of DC. This indicates the high potential of pPBS to trigger ICD. In contrast, pPBS induced no ICD in PSC. In general, pPBS treatment of PCCs and PSCs created a more immunostimulatory secretion profile (higher TNF-α and IFN-γ, lower TGF-β) in coculture with DC. Altogether, these data show that plasma treatment via pPBS has the potential to induce ICD in PCCs and to reduce the immunosuppressive tumor microenvironment created by PSCs. Therefore, these data provide a strong experimental basis for further in vivo validation, which might potentially open the way for more successful combination strategies with immunotherapy for PDAC.
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26
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Dong Z, Zhang H, Gong X, Wei W, Lv Y, Chen Z, Wang R, Yi J, Shen Y, Jin S. The Role of the Tumor Microenvironment in Neuropilin 1-Induced Radiation Resistance in Lung Cancer Cells. J Cancer 2019; 10:4017-4030. [PMID: 31417646 PMCID: PMC6692609 DOI: 10.7150/jca.28163] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 05/29/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Neuropilin 1 (NRP1) is a pleiotropic receptor which can interact with multiple ligands and their receptors. It plays an important role in the process of axonal growth, angiogenesis, tumor metastasis and radiation resistance in endothelial cells and some tumor cells. Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis, and has received considerable attention in recent years. Material and Methods: In this study, A549 lung cancer cell lines with different NRP1 expression levels were constructed in vitro, a two-dimensional (2D), three-dimensional (3D) co-culture system and tumor-bearing model was established in SCID mice. Western blot, qRT-PCR, immunofluorescence, cytometric bead array and flow cytometry were used to investigate the effect of the tumor microenvironment in NRP1-induced lung cancer cell radiation resistance. Results: In 2D or 3D co-culture system, NRP1 could be regulated inflammatory factors such as TNF, IL-6 IL-8 and IL-17 and the related chemokines MCP-1, IP-10 and RANTES in the tumor microenvironment, which in turn induced radiation resistance in lung cancer cells. In addition, different expression levels of NRP1 in 2D, 3D culture systems and tumor-bearing models were able to significantly regulate cell phenotype, proliferative capacity, epithelial-mesenchymal transition (EMT) and the radiation resistance of A549 cells. Conclusion: Our results verified that NRP1, inflammatory factors, chemokines and related signaling pathways, which affect the transformation of related cell components and thus lung cancer cell immune tolerance and migratory ability, all play an important role in radiation resistance.
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Affiliation(s)
- Zhuo Dong
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Haiyang Zhang
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China.,Department of Prosthodontics Dentistry, The Stomatology Hospital of Jilin University, Changchun, 130021, China
| | - Xinkou Gong
- Department of Radiology, The 2 nd Hospital of Jilin University, Changchun, 130021, China
| | - Wei Wei
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Yahui Lv
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Zhiyuan Chen
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Rui Wang
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Junxuan Yi
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Yannan Shen
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Shunzi Jin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
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27
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Kim SH, Lee MJ, Hwang HK, Lee SH, Kim H, Paik YK, Kang CM. Prognostic potential of the preoperative plasma complement factor B in resected pancreatic cancer: A pilot study. Cancer Biomark 2019; 24:335-342. [DOI: 10.3233/cbm-181847] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Sung Hyun Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, College of Medicine, Yonsei University, Seoul, Korea
- Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
| | - Min Jung Lee
- Yonsei Proteome Research Center, Yonsei University, Seoul, Korea
- Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Korea
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Ho Kyung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, College of Medicine, Yonsei University, Seoul, Korea
- Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
| | - Sung Hwan Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, College of Medicine, Yonsei University, Seoul, Korea
- Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hoguen Kim
- Department of Pathology, College of Medicine, Yonsei University, Seoul, Korea
| | - Young-Ki Paik
- Yonsei Proteome Research Center, Yonsei University, Seoul, Korea
- Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Korea
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, College of Medicine, Yonsei University, Seoul, Korea
- Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
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28
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Li C, An MX, Jiang JY, Yao HB, Li S, Yan J, Li XY, Wang HQ. BAG3 Suppresses Loading of Ago2 to IL6 mRNA in Pancreatic Ductal Adenocarcinoma. Front Oncol 2019; 9:225. [PMID: 31001483 PMCID: PMC6454118 DOI: 10.3389/fonc.2019.00225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 03/13/2019] [Indexed: 01/16/2023] Open
Abstract
Pancreatic stellate cells (PSCs) are a subset of pancreatic cancer-associated fibroblasts, which play a critical role in pancreatic fibrosis, a characteristic feature of pancreatic cancer. The interplay between PSCs and pancreatic cancer cells is vital for promotion of tumor progression and metastasis. BAG3 is correlated with poor prognostics in patients with pancreatic ductal adenocarcinoma (PDAC), however, the exact mechanisms remain largely unknown. In this study, we demonstrated that BAG3 downregulation decreased IL6 release by PDACs, and IL6 reduction was, at least partially, responsible for suppression of PSCs activation by PDACs with BAG3 downmodulation. Importantly, BAG3 expression positively correlated with fibrosis in pancreatic cancer tissue. With regard to the underlying mechanism, we demonstrated that BAG3 knockdown facilitated recruitment of Agonaute 2 (Ago2) to IL6 mRNA, resulting in destabilization of IL6 mRNA. In addition, the current study demonstrated that phosphorylation at Serine (Ser) 387 site was required for recruitment of Ago2-containing miRISC to IL6 mRNA and BAG3 knockdown facilitated Ago2 loading to IL6 mRNA via increasing its phosphorylation at Ser 387. This study shed new light on the tumor-promoting role of BAG3 in PDAC tumors, suggesting BAG3 might represent an interesting therapeutic opportunity to PDAC patients.
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Affiliation(s)
- Chao Li
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China.,Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Ming-Xin An
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Jing-Yi Jiang
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Han-Bing Yao
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Si Li
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Jing Yan
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Xin-Yu Li
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Hua-Qin Wang
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China.,Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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29
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MicroRNA let-7d targets thrombospondin-1 and inhibits the activation of human pancreatic stellate cells. Pancreatology 2019; 19:196-203. [PMID: 30393009 DOI: 10.1016/j.pan.2018.10.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 10/08/2018] [Accepted: 10/28/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The microRNA (miRNA) let-7d is linked to the formation of pancreatic cancer-related fibrosis. In this study, the mechanism by which let-7d regulates the activation of the human pancreatic stellate cell (hPSC) was evaluated. METHODS The transient transfection of a let-7d mimic in the hPSCs was performed, and the altered thrombospondin 1 (THBS1) expression was confirmed by western blotting and real-time qPCR. Targeting of the 3'-untranslated region (UTR) of THBS1 by let-7d was investigated by the luciferase assays. After hPSC transfection using THBS1 siRNA, the fibrosis markers (α-SMA and collagen 1A1) were evaluated by western blotting and real-time qPCR. The correlation between tumor fibrosis and let-7d or THBS1 was estimated using the data from The Cancer Genome Atlas project. Finally, the effects of genistein on the hPSCs were evaluated. RESULTS We found that a let-7d mimic inhibits THBS1 expression by targeting its 3'-UTR. THBS1 inhibition by siRNA inhibited hPSC activation. An in silico analysis revealed that let-7d and THBS1 expression are negatively correlated. Additionally, let-7d was negatively correlated with the stromal score, while THBS1 was positively correlated with this score. Genistein substantially induced let-7d and decreased the expression of fibrosis marker along with the inhibition of THBS1. CONCLUSIONS Let-7d inhibited hPSC activation by targeting THBS1. Genistein induced the expression of let-7d and might modulate pancreatic fibrosis.
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Ishii N, Araki K, Yokobori T, Hagiwara K, Gantumur D, Yamanaka T, Handa T, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Harimoto N, Masamune A, Umezawa K, Kuwano H, Shirabe K. Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts. Cancer Sci 2019; 110:334-344. [PMID: 30353606 PMCID: PMC6317962 DOI: 10.1111/cas.13847] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 10/15/2018] [Accepted: 10/17/2018] [Indexed: 12/11/2022] Open
Abstract
Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer-associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)-6, IL-8, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
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Affiliation(s)
- Norihiro Ishii
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Kenichiro Araki
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Takehiko Yokobori
- Research Program for Omics‐based Medical ScienceDivision of Integrated Oncology ResearchGunma University Initiative for Advanced Research (GIAR)MaebashiJapan
| | - Kei Hagiwara
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Dorgormaa Gantumur
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Takahiro Yamanaka
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Tadashi Handa
- Department of Diagnostic PathologyGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Mariko Tsukagoshi
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Takamichi Igarashi
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Akira Watanabe
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Norio Kubo
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Norifumi Harimoto
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Atsushi Masamune
- Division of GastroenterologyGraduate School of MedicineTohoku UniversitySendaiJapan
| | - Kazuo Umezawa
- Department of Molecular Target MedicineAichi Medical University School of MedicineNagakuteJapan
| | - Hiroyuki Kuwano
- Division of Gastroenterological SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
| | - Ken Shirabe
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of General Surgical ScienceGraduate School of MedicineGunma UniversityMaebashiJapan
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Yang L, Shang Z, Long S, Wang N, Shan G, Zhang R. Roles of genetic and microenvironmental factors in cancer epithelial-to-mesenchymal transition and therapeutic implication. Exp Cell Res 2018; 370:190-197. [PMID: 30075173 DOI: 10.1016/j.yexcr.2018.07.046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 07/27/2018] [Accepted: 07/28/2018] [Indexed: 01/11/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells lose their cell-cell contacts resulting in the formation of mesenchymal cells with migratory properties. Increasing evidence indicate EMT plays a key role in the invasion, metastasis and therapeutic resistance of cancer and maintenance of the phenotype of cancer stem cells (CSCs), which makes the prognosis of patients worse. The progression of cancer from epithelial tissue towards a malignant phenotype is driven by multiple factors that remodel the tissue architecture. This review summarizes and analyzes current studies of genetic and microenvironmental factors in inducing and maintaining cancer EMT and therapeutic implications. This will enable a better understanding of the contribution of EMT-associated factors to cancer progression and highlights that genetic factors and tumor microenvironment responsible for EMT could be used as attractive targets for therapeutic intervention.
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Affiliation(s)
- Liuqi Yang
- Department of Immunology, Basic Medical School, Guizhou Medical University, Guiyang 550004, China.
| | - Zhengling Shang
- Department of Immunology, Basic Medical School, Guizhou Medical University, Guiyang 550004, China
| | - Shiqi Long
- Department of Immunology, Basic Medical School, Guizhou Medical University, Guiyang 550004, China
| | - Nianxue Wang
- Department of Immunology, Basic Medical School, Guizhou Medical University, Guiyang 550004, China
| | - Ge Shan
- Department of Immunology, Basic Medical School, Guizhou Medical University, Guiyang 550004, China
| | - Ruya Zhang
- Department of Immunology, Basic Medical School, Guizhou Medical University, Guiyang 550004, China
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Feng R, Morine Y, Ikemoto T, Imura S, Iwahashi S, Saito Y, Shimada M. Nab-paclitaxel interrupts cancer-stromal interaction through C-X-C motif chemokine 10-mediated interleukin-6 downregulation in vitro. Cancer Sci 2018; 109:2509-2519. [PMID: 29902349 PMCID: PMC6113502 DOI: 10.1111/cas.13694] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 05/17/2018] [Accepted: 06/08/2018] [Indexed: 12/20/2022] Open
Abstract
Cancer‐associated fibroblasts (CAF), derived from stroma of cancer tissues, interact with cancer cells and play an important role in cancer initiation, growth, and metastasis. Nab‐paclitaxel (nab‐PTX) is a 130 nm albumin‐binding paclitaxel and recommended for many types of cancer chemotherapy. The nab‐PTX stromal‐disrupting effect during pancreatic cancer treatment has been reported. The aim of the present study was to determine the role of nab‐PTX in cancer cells and CAF interaction. Cancer cells (MIA PaCa‐2 and Panc‐1) were cocultured with CAF or treated with CAF conditioned medium, after which their migration and invasion ability, epithelial‐mesenchymal transition (EMT)‐related marker expression and C‐X‐C motif chemokine 10 (CXCL10) expression and secretion were detected. Nab‐PTX treatment was carried out during the coculture system or during preparation of CAF conditioned medium. Then cancer cell migration and invasion ability, EMT‐related marker expression, CXCL10 expression and secretion, and interleukin‐6 (IL‐6) expression and secretion by CAF were checked After coculture with CAF, migration and invasion ability of cancer cells increased. CAF also downregulated E‐cadherin and upregulated N‐cadherin and vimentin expression in cancer cells. During coculture or stimulation with cancer cell‐cultured medium, CAF significantly increased IL‐6 expression and secretion. However, nab‐PTX in the coculture system canceled CAF‐induced migration and invasion promotion and EMT‐related gene changes. Moreover, nab‐PTX increased CXCL10 expression of cancer cells which blocked CAF IL‐6 expression and secretion. Nab‐PTX treatment could increase CXCL10 expression of cancer cells which blocks CAF cancer cell migration and invasion‐promoting effect by inhibiting IL‐6 expression.
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Affiliation(s)
- Rui Feng
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University of Graduate School, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University of Graduate School, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University of Graduate School, Tokushima, Japan
| | - Satoru Imura
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University of Graduate School, Tokushima, Japan
| | - Shuichi Iwahashi
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University of Graduate School, Tokushima, Japan
| | - Yu Saito
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University of Graduate School, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University of Graduate School, Tokushima, Japan
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Masamune A, Hamada S, Yoshida N, Nabeshima T, Shimosegawa T. Pyruvate Kinase Isozyme M2 Plays a Critical Role in the Interactions Between Pancreatic Stellate Cells and Cancer Cells. Dig Dis Sci 2018; 63:1868-1877. [PMID: 29619774 DOI: 10.1007/s10620-018-5051-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 03/28/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The interaction between pancreatic cancer cells and pancreatic stellate cells plays a pivotal role in the progression of pancreatic cancer. Pyruvate kinase isozyme M2 is a key enzyme in glycolysis. Previous studies have shown that pyruvate kinase isozyme M2 is overexpressed in pancreatic cancer and that it regulates the aggressive behaviors of pancreatic cancer cells. AIMS To clarify the role of pyruvate kinase isozyme M2 in the interactions between pancreatic cancer cells and pancreatic stellate cells. METHODS Pyruvate kinase isozyme M2-knockdown pancreatic cancer cells (Panc-1 and SUIT-2 cells) and pancreatic stellate cells were generated by the introduction of small interfering RNA-expressing vector against pyruvate kinase isozyme M2. Cell proliferation, migration, and epithelial-mesenchymal transition were examined in vitro. The impact of pyruvate kinase isozyme M2 knockdown on the growth of subcutaneous tumors was examined in nude mice in vivo. RESULTS Pyruvate kinase isozyme M2-kockdown pancreatic cancer cells and pancreatic stellate cells showed decreased proliferation and migration compared to their respective control cells. Pancreatic stellate cell-induced proliferation, migration, and epithelial-mesenchymal transition were inhibited when pyruvate kinase isozyme M2 expression was knocked down in pancreatic cancer cells. In vivo, co-injection of pancreatic stellate cells increased the size of the tumor developed by the control SUIT-2 cells, but the effects were less evident when pyruvate kinase isozyme M2 was knocked down in SUIT-2 cells or pancreatic stellate cells. CONCLUSIONS Our results suggested a critical role of pyruvate kinase isozyme M2 in the interaction between pancreatic cancer cells and pancreatic stellate cells.
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Affiliation(s)
- Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
| | - Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Naoki Yoshida
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Tatsuhide Nabeshima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
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Yu J, Ding Z, Yang Y, Liu S. Increased platelet-to-lymphocytes ratio is associated with poor long-term prognosis in patients with pancreatic cancer after surgery. Medicine (Baltimore) 2018; 97:e11002. [PMID: 29923983 PMCID: PMC6023787 DOI: 10.1097/md.0000000000011002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Several studies reported platelet-to-lymphocytes ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) were associated with the mid-term survival or cancer stage in pancreatic cancer. However, the relationship between these markers and the long-term prognosis of pancreatic cancer is still unknown. We investigated the relationship between PLR, NLR, RDW, and the long-term prognosis of pancreatic cancer.We included 182 pancreatic cancer patients who received operation at Linzi District People 's Hospital between August 2010 and January 2017. PLR, NLR, and RDW control data was obtained from 150 health volunteers from January 2011 to January 2017. Blood biochemical data before operation, preoperative computed tomography information, and pathological data of the pancreatic cancer patients were retrospectively collected for further analysis. Independent long-term prognostic significance of PLR, NLR, and RDW were analyzed in pancreatic cancer patients.PLR, NLR, and RDW were significantly increased in pancreatic cancer group compared with the control. Receiver operating characteristic (ROC) curve analysis showed the optimal cut-off values of PLR, NLR, and RDW were 150, 1.73, and 13.2 respectively. Overall survival (OS) analysis showed pancreatic cancer patients with PLR≥150 (median time, 24 vs 37.5 months, P = .005) or RDW≥13.2 (median time, 27 months vs 37.5 months, P = .018) had lower postoperative 5 year OS compared with pancreatic cancer patients with PLR<150 or RDW<13.2. Univariate and multivariable Cox regression analysis for postoperative 5 year OS data showed PLR≥150 (HR = 2.451, 95% CI 1.215-4.947; P = .012) was still associated with the OS independently. Disease free survival (DFS) analysis showed pancreatic cancer patients with PLR≥150 (median time, 24 months vs 38 months, P = .002) or RDW≥13.2 (median time, 24 months vs 37.5 months, P = .006) had lower postoperative 5 year DFS compared with pancreatic cancer patients with PLR<150 or RDW<13.2. Univariate and multivariable Cox regression analysis for postoperative 5 year DFS data showed PLR≥150 (HR = 2.712, 95% CI 1.367-5.379; P = .004) was independently associated with the DFS.In the present study, we find hematological biomarkers PLR≥150 is an independently predictive risk factor for the postoperative long-term prognosis in pancreatic cancer patients. Our study may provide a convenient way for the prognostic assessment of pancreatic cancer patients.
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Affiliation(s)
- Jinming Yu
- Department of Laboratory, Linzi District People's Hospital, Zibo
| | | | - Yuanming Yang
- Department of Blood Transfusion, Affiliated Hospital of Medical College, Qingdao University, Qingdao
| | - Shanli Liu
- Department of Laboratory, Changle People's Hospital, Changle, China
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Activation of Signal Transduction and Activator of Transcription 3 Signaling Contributes to Helicobacter-Associated Gastric Epithelial Proliferation and Inflammation. Gastroenterol Res Pract 2018; 2018:9050715. [PMID: 29849601 PMCID: PMC5911338 DOI: 10.1155/2018/9050715] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 12/25/2017] [Accepted: 01/14/2018] [Indexed: 02/08/2023] Open
Abstract
Background/Aim Although IL-6-mediated activation of the signal transduction and activator of transcription 3 (STAT3) axis is involved in inflammation and cancer, the role of STAT3 in Helicobacter-associated gastric inflammation and carcinogenesis is unclear. This study investigated the role of STAT3 in gastric inflammation and carcinogenesis and examined the molecular mechanism of Helicobacter-induced gastric phenotypes. Methods To evaluate the contribution of STAT3 to gastric inflammation and carcinogenesis, we used wild-type (WT) and gastric epithelial conditional Stat3-knockout (Stat3Δgec) mice. Mice were infected with Helicobacter felis and euthanized at 18 months postinfection. Mouse gastric organoids were treated with recombinant IL-6 (rIL-6) or rIL-11 and a JAK inhibitor (JAKi) to assess the role of IL-6/STAT3 signaling in vitro. Results Inflammation and mucous metaplasia were more severe in WT mice than in Stat3Δgec mice. The epithelial cell proliferation rate and STAT3 activation were increased in WT mice. Application of rIL-6 and rIL-11 induced expression of intestinal metaplasia-associated genes, such as Tff2; this induction was suppressed by JAKi administration. Conclusions Loss of STAT3 signaling in the gastric mucosa leads to decreased epithelial cell proliferation, atrophy, and metaplasia in the setting of Helicobacter infection. Therefore, activation of STAT3 signaling may play a key role in Helicobacter-associated gastric carcinogenesis.
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Ma B, Yang L, Jing R, Liu J, Quan Y, Hui Q, Li J, Qin L, Pei C. Effects of Interleukin-6 on posterior capsular opacification. Exp Eye Res 2018; 172:94-103. [PMID: 29617629 DOI: 10.1016/j.exer.2018.03.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 03/02/2018] [Accepted: 03/13/2018] [Indexed: 01/17/2023]
Abstract
The purpose of this work was to determine the effects of interleukin-6 (IL-6) on the development of posterior capsular opacification (PCO) in vitro and in vivo. Western blot and real-time PCR were used to test the IL-6-induced epithelial-mesenchymal transition (EMT) marker α-smooth muscle actin (α-SMA), the extracellular matrix (ECM) markers fibronectin (Fn) and type I collagen (COL-1), transforming growth factor β2 (TGF-β2), and the activation and role of the JAK/STAT3 signaling pathway in human lens epithelial cells (HLECs). Immunocytofluorescence staining was performed to detect gp130 and IL-6Rα expression in HLECs. Rat PCO models were then established to examine the impact of STAT3 knockdown by shRNA adeno-associated virus on PCO development, and immunohistochemical staining was performed to detect the expression of Fn in the anterior and posterior capsule in vivo. We found that IL-6 promotes the expression of Fn, COL-1, TGF-β2, p-JAK2 and p-STAT3 in HLECs but exerts little effect on α-SMA. The JAK/STAT3 inhibitor WP1066 effectively suppressed the IL-6-induced expression of Fn and COL-1 in lens epithelial cells. STAT3 knockdown effectively inhibited the development of PCO in rats and significantly reduced the expression of Fn in the anterior and posterior capsule. These data suggest that IL-6 contributes to the development of PCO by promoting TGF-β2 activation and ECM synthesis through a JAK/STAT3 signaling-dependent mechanism. Furthermore, inhibiting JAK/STAT3 signaling effectively impairs both PCO development in rats and ECM synthesis in the lens capsule.
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Affiliation(s)
- Bo Ma
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Lan Yang
- Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, Zhejiang 315040, China
| | - Ruihua Jing
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Jie Liu
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yumeng Quan
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qiaoyan Hui
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Jingming Li
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Li Qin
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Cheng Pei
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
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Park JK, Kim Y, Kim H, Jeon J, Kim TW, Park JH, Hwnag YI, Lee WJ, Kang JS. The anti-fibrotic effect of GV1001 combined with gemcitabine on treatment of pancreatic ductal adenocarcinoma. Oncotarget 2018; 7:75081-75093. [PMID: 27655706 PMCID: PMC5342724 DOI: 10.18632/oncotarget.12057] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 08/23/2016] [Indexed: 02/07/2023] Open
Abstract
GV1001 is a telomerase-based cancer vaccine made of a 16-mer telomerase reverse transcriptase (TERT) peptide, and human TERT, the rate-limiting subunit of the telomerase complex, is an attractive target for cancer vaccination. The aim of this study was to evaluate the effect of telomerase peptide vaccination, GV1001 combined with gemcitabine in treatment of pancreatic ductal adenocarcinoma (PDAC). Human PDAC cell lines were used in vitro experiment and also, PDAC xenograft mice model was established using PANC1, AsPC1 and CD133+ AsPC1 (PDAC stem cell). Treatment groups were divided as follows; control, gemcitabine, GV1001, gemcitabine and GV1001 combination. The inflammatory cytokines were measured from the blood, and xenograft tumor specimens were evaluated. GV1001 treatment alone did not affect the proliferation or the apoptosis of PDAC cells. Gemcitabine alone and gemcitabine with GV1001 groups had significantly reduced in tumor size and showed abundant apoptosis compared to other treatment groups. Surprisingly, xenograft PDAC tumor specimens of gemcitabine alone group had been replaced by severe fibrosis whereas gemcitabine with GV1001 group had significantly less fibrosis. Blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β increased in gemcitabine alone group, however, it was decreased in gemcitabine with GV1001 group. GV1001 combined with gemcitabine treatment showed significant loss of fibrosis in tumor tissue as well as tumor cell death. Therefore, further investigation of GV1001 effect combined with gemcitabine treatment may give us useful insights to overcome the hurdle in anti-cancer drug delivery over massive fibrosis around PDACs.
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Affiliation(s)
- Joo Kyung Park
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yejin Kim
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Hyemin Kim
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Jane Jeon
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Tae Wan Kim
- Department of Ophthalmology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - Ji-Hong Park
- Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do, Korea
| | - Young-Il Hwnag
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Wang Jae Lee
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Seung Kang
- Laboratory of Vitamin C and Anti-Oxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
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Fujii-Nishimura Y, Yamazaki K, Masugi Y, Douguchi J, Kurebayashi Y, Kubota N, Ojima H, Kitago M, Shinoda M, Hashiguchi A, Sakamoto M. Mesenchymal-epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells. Pathol Int 2018; 68:214-223. [DOI: 10.1111/pin.12641] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 12/29/2017] [Indexed: 01/06/2023]
Affiliation(s)
- Yoko Fujii-Nishimura
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Ken Yamazaki
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Yohei Masugi
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Junya Douguchi
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Yutaka Kurebayashi
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Naoto Kubota
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Hidenori Ojima
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Minoru Kitago
- Department of Surgery; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Masahiro Shinoda
- Department of Surgery; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Akinori Hashiguchi
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
| | - Michiie Sakamoto
- Department of Pathology; Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
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Fu Y, Liu S, Zeng S, Shen H. The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma. Mol Cancer 2018; 17:62. [PMID: 29458370 PMCID: PMC5817854 DOI: 10.1186/s12943-018-0815-z] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 02/12/2018] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a "partner in crime" to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure. In addition to multiple paracrine signaling pathways, recent research has confirmed that PSCs-mediated tumor microenvironment may influence behaviors of PDAC via diverse mechanisms, such as rewiring metabolic networks, suppressing immune responses. These new activities are closely linked with treatment and prognosis of PDAC. In this review, we discuss the recent advances regarding new functions of activated PSCs, including PSCs-cancer cells interaction, mechanisms involved in immunosuppressive regulation, and metabolic reprogramming. It's clear that these updated experimental or clinical studies of PSCs may provide a promising approach for PDAC treatment in the near future.
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Affiliation(s)
- Yaojie Fu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Shanshan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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40
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Farajzadeh Valilou S, Keshavarz-Fathi M, Silvestris N, Argentiero A, Rezaei N. The role of inflammatory cytokines and tumor associated macrophages (TAMs) in microenvironment of pancreatic cancer. Cytokine Growth Factor Rev 2018; 39:46-61. [PMID: 29373197 DOI: 10.1016/j.cytogfr.2018.01.007] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/24/2017] [Accepted: 01/11/2018] [Indexed: 02/07/2023]
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Song H, Zhang Y. Regulation of pancreatic stellate cell activation by Notch3. BMC Cancer 2018; 18:36. [PMID: 29304760 PMCID: PMC5756326 DOI: 10.1186/s12885-017-3957-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 12/21/2017] [Indexed: 01/18/2023] Open
Abstract
Background Activated pancreatic stellate cells (PaSCs) are the key cellular source of cancer-associated fibroblasts in the pancreatic stroma of patients with pancreatic ductal adenocarcinoma (PDAC), however, the activation mechanism of PaSCs is not yet known. The Notch signaling pathway, components of which are expressed in stromal cells, is involved in the fibrosis of several organs, including the lung and liver. In the current study, we investigated whether Notch signal transduction is involved in PaSC activation in PDAC. Methods The expression of Notch signaling pathway components in human PDAC was examined via immunohistochemical staining and assessed in mouse PaSCs using RT-qPCR and western blotting. Notch3 expression in both PDAC stromal cells and activated mouse PaSCs was evaluated using immunofluorescence, RT-qPCR and western blotting. The impact of siRNA-mediated Notch3 knockdown on PaSC activation was detected with RT-qPCR and western blotting, and the impact on PaSC proliferation and migration was detected using CCK-8 assays and scratch experiments. The effect of conditioned medium from PaSCs activated with Notch3 siRNA on pancreatic cancer (LTPA) cells was also detected with CCK-8 assays and scratch experiments. The data were analyzed for statistical significance using Student’s t-test. Results Notch3 was overexpressed in both human PDAC stromal cells and activated mouse PaSCs, and Notch3 knockdown with Notch3 siRNA decreased the proliferation and migration of mouse PaSCs. The levels of markers related to PaSC activation, such as α-smooth muscle actin (α-SMA), collagen I and fibronectin, decreased in response to Notch3 knockdown, indicating that Notch3 plays an important role in PaSC activation. Furthermore, we confirmed that inhibition of PaSC activation via Notch3 siRNA reduced the proliferation and migration of PaSC-induced mouse pancreatic cancer (LTPA) cells. Conclusions Notch3 inhibition in PaSCs can inhibit the activation, proliferation and migration of PaSCs and reduce the PaSC-induced pro-tumorigenic effect. Therefore, Notch3 silencing in PaSCs is a potential novel therapeutic option for patients with PDAC. Electronic supplementary material The online version of this article (10.1186/s12885-017-3957-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Haiyan Song
- Department of Biochemistry and Molecular Biology, Cancer Institute, Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Capital Medical University, No. 10 Xitoutiao, You An Men, Fengtai District, Beijing, 100069, People's Republic of China
| | - Yuxiang Zhang
- Department of Biochemistry and Molecular Biology, Cancer Institute, Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Capital Medical University, No. 10 Xitoutiao, You An Men, Fengtai District, Beijing, 100069, People's Republic of China.
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Experimental models of pancreatic cancer desmoplasia. J Transl Med 2018; 98:27-40. [PMID: 29155423 DOI: 10.1038/labinvest.2017.127] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 10/12/2017] [Accepted: 10/12/2017] [Indexed: 01/18/2023] Open
Abstract
Desmoplasia is a fibro-inflammatory process and a well-established feature of pancreatic cancer. A key contributor to pancreatic cancer desmoplasia is the pancreatic stellate cell. Various in vitro and in vivo methods have emerged for the isolation, characterization, and use of pancreatic stellate cells in models of cancer-associated fibrosis. In addition to cell culture models, genetically engineered animal models have been established that spontaneously develop pancreatic cancer with desmoplasia. These animal models are currently being used for the study of pancreatic cancer pathogenesis and for evaluating therapeutics against pancreatic cancer. Here, we review various in vitro and in vivo models that are being used or have the potential to be used to study desmoplasia in pancreatic cancer.
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43
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Fibrosis-related miRNAs as serum biomarkers for pancreatic ductal adenocarcinoma. Oncotarget 2017; 9:4451-4460. [PMID: 29435115 PMCID: PMC5796986 DOI: 10.18632/oncotarget.23377] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 11/29/2017] [Indexed: 12/17/2022] Open
Abstract
We investigated whether serum microRNAs (miRNAs) could be diagnostic or prognostic markers in pancreatic ductal adenocarcinoma (PDAC). We first identified miRNAs showing altered expression in human pancreatic stellate cells (hPSCs) co-cultured with PDAC cells (Panc-1 and BxPC-3) as compared to hPSCs cultured alone. Among the miRNAs with altered expression, let-7d exhibited reduced expression in an in silico analysis of The Cancer Genome Atlas data. Inhibition of let-7d resulted in enhanced expression of fibrosis-related genes. We extracted serum miRNA from 45 PDAC patients and 42 healthy controls and quantified expression let-7d using digital PCR. Based on the level of let-7d expression, we were able to distinguish between PDAC patients and controls. Additionally, reduced let-7d expression correlated with poor overall survival. Thus, fibrosis-related miRNAs may be serum biomarkers for PDAC.
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44
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Wu Q, Tian Y, Zhang J, Zhang H, Gu F, Lu Y, Zou S, Chen Y, Sun P, Xu M, Sun X, Xia C, Chi H, Ying Zhu A, Tang D, Wang D. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. Oncotarget 2017; 8:102721-102738. [PMID: 29254283 PMCID: PMC5731993 DOI: 10.18632/oncotarget.21970] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with poor prognosis because it is highly resistant to traditional chemotherapy and radiotherapy and it has a low rate of surgical resection eligibility. Pancreatic stellate cells (PSC) have become a research hotspot in recent years, and play a vital role in PDAC microenvironment by secreting soluble factors such as transforming growth factor β, interleukin-6, stromal cell-derived factor-1, hepatocyte growth factor and galectin-1. These PSC-derived cytokines and proteins contribute to PSC activation, participating in PDAC cell proliferation, migration, fibrosis, angiogenesis, immunosuppression, epithelial-mesenchymal transition, and chemoradiation resistance, leading to malignant outcome. Consequently, targeting these cytokines and proteins or their downstream signaling pathways is promising for treating PDAC.
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Affiliation(s)
- Qi Wu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Ying Tian
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Jingqiu Zhang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Hongpeng Zhang
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Fengming Gu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Yongdie Lu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Shengnan Zou
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Yuji Chen
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Pengxiang Sun
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Mengyue Xu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Xiaoming Sun
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Chao Xia
- Nanjing Medical University, Nanjing, P.R. China
| | - Hao Chi
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - A Ying Zhu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
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Masamune A, Yoshida N, Hamada S, Takikawa T, Nabeshima T, Shimosegawa T. Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. Biochem Biophys Res Commun 2017; 495:71-77. [PMID: 29111329 DOI: 10.1016/j.bbrc.2017.10.141] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 10/26/2017] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of α-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor β1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment.
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Affiliation(s)
- Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Naoki Yoshida
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Takikawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tatsuhide Nabeshima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Ansari D, Carvajo M, Bauden M, Andersson R. Pancreatic cancer stroma: controversies and current insights. Scand J Gastroenterol 2017; 52:641-646. [PMID: 28276831 DOI: 10.1080/00365521.2017.1293726] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Pancreatic cancer is characterized by a dense stromal response. The stroma includes a heterogeneous mass of cells, including pancreatic stellate cells, fibroblasts, immune cells and nerve cells, as well as extracellular matrix proteins, cytokines and growth factors, which interact with the tumor cells. Previous research has indicated that stromal elements contribute to tumor growth and aggressiveness. However, recent studies suggest that some elements of the stroma may actually restrain the tumor. This review focuses on the complex interactions between the stromal microenvironment and tumor cells, discussing molecular mechanisms and potential future diagnostic and therapeutic approaches by targeting the stroma.
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Affiliation(s)
- Daniel Ansari
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
| | - Maria Carvajo
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
| | - Monika Bauden
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
| | - Roland Andersson
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
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47
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Chu Q, Shen D, He L, Wang H, Liu C, Zhang W. Prognostic significance of SOCS3 and its biological function in colorectal cancer. Gene 2017; 627:114-122. [DOI: 10.1016/j.gene.2017.06.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 06/05/2017] [Accepted: 06/07/2017] [Indexed: 01/22/2023]
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Abstract
PURPOSE OF REVIEW Pancreatic stellate cells (PSCs) play an integral role in the pathogenesis of pancreatitis and pancreatic cancer. With the developing knowledge of this important cell type, we are at the cusp of developing effective therapies for the above diseases based upon targeting the PSC and modulating its function. RECENT FINDINGS The major themes of the recent PSC literature include: PSC interactions with the extracellular matrix and other stromal components; intracellular calcium physiology as drivers of mechanical interactions and necrosis; the relationship between proinflammatory, protumoural, angiogenic, and metabolic pathways in pancreatic necrosis, fibrosis, and carcinogenesis; and targeting of the stroma for antitumoural and antifibrotic effects. SUMMARY Traditionally, there have been few treatment options for pancreatitis and pancreatic cancer. The elucidation of the wide-ranging functions of PSCs provide an opportunity for treatments based on stromal reprogramming.
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49
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Van Audenaerde JRM, De Waele J, Marcq E, Van Loenhout J, Lion E, Van den Bergh JMJ, Jesenofsky R, Masamune A, Roeyen G, Pauwels P, Lardon F, Peeters M, Smits ELJ. Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells. Oncotarget 2017; 8:56968-56979. [PMID: 28915646 PMCID: PMC5593617 DOI: 10.18632/oncotarget.18185] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 04/14/2017] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC). The potency of IL-15 to promote NK cell-mediated killing was evaluated phenotypically and functionally. In addition, NK cell and immune checkpoint ligands on PSC were charted. We demonstrate that IL-15 activated NK cells kill both PCC and PSC lines (range 9-35% and 20-50%, respectively) in a contact-dependent manner and significantly higher as compared to resting NK cells. Improved killing of these pancreatic cell lines is, at least partly, dependent on IL-15 induced upregulation of TIM-3 and NKG2D. Furthermore, we confirm significant killing of primary PSC by IL-15 activated NK cells in an ex vivo autologous system. Screening for potential targets for immunotherapeutic strategies, we demonstrate surface expression of both inhibitory (PD-L1, PD-L2) and activating (MICA/B, ULBPs and Galectin-9) ligands on primary PSC. These data underscore the therapeutic potential of IL-15 to promote NK cell-mediated cytotoxicity as a treatment of pancreatic cancer and provide promising future targets to tackle remaining PSC.
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Affiliation(s)
- Jonas R M Van Audenaerde
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Jorrit De Waele
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Elly Marcq
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Jinthe Van Loenhout
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Eva Lion
- Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Johan M J Van den Bergh
- Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Ralf Jesenofsky
- Department of Medicine II, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Geert Roeyen
- Department of Hepatobiliary, Endocrine and Transplantation Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Patrick Pauwels
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Department of Pathology, Antwerp University Hospital, Antwerp, Belgium
| | - Filip Lardon
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Marc Peeters
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Department of Oncology, Multidisciplinary Oncological Centre Antwerp, Antwerp University Hospital, Antwerp, Belgium
| | - Evelien L J Smits
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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50
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Yoshida N, Masamune A, Hamada S, Kikuta K, Takikawa T, Motoi F, Unno M, Shimosegawa T. Kindlin-2 in pancreatic stellate cells promotes the progression of pancreatic cancer. Cancer Lett 2017; 390:103-114. [PMID: 28093281 DOI: 10.1016/j.canlet.2017.01.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 12/02/2016] [Accepted: 01/10/2017] [Indexed: 01/10/2023]
Abstract
Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with pancreatic ductal adenocarcinoma (PDAC). Kindlin-2 is a focal adhesion protein that regulates the activation of integrins. This study aimed to clarify the role of kindlin-2 in PSCs in pancreatic cancer. Kindlin-2 expression in 79 resected pancreatic cancer tissues was examined by immunohistochemical staining. Kindlin-2-knockdown immortalized human PSCs were established using small interfering RNA. Pancreatic cancer cells were treated with conditioned media of PSCs, and the cell proliferation and migration were examined. SUIT-2 pancreatic cancer cells were subcutaneously injected into nude mice alone or with PSCs and the size of the tumors was monitored. Kindlin-2 expression was observed in PDAC and the peritumoral stroma. Stromal kindlin-2 expression was associated with shorter recurrence-free survival time after R0 resection. Knockdown of kindlin-2 resulted in decreased proliferation, migration, and cytokine expression in PSCs. The PSC-induced proliferation and migration of pancreatic cancer cells were suppressed by kindlin-2 knockdown in PSCs. In vivo, co-injection of PSCs increased the size of the tumors, but this effect was abolished by kindlin-2 knockdown in PSCs. In conclusion, kindlin-2 in PSCs promoted the progression of pancreatic cancer.
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Affiliation(s)
- Naoki Yoshida
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuhiro Kikuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Takikawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Fuyuhiko Motoi
- Division of Hepato-Biliary-Pancreatic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Division of Hepato-Biliary-Pancreatic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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