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Bhowmick K, von Suskil M, Al-Odat OS, Elbezanti WO, Jonnalagadda SC, Budak-Alpdogan T, Pandey MK. Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells. Heliyon 2024; 10:e33091. [PMID: 39021902 PMCID: PMC11252793 DOI: 10.1016/j.heliyon.2024.e33091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/30/2024] [Accepted: 06/13/2024] [Indexed: 07/20/2024] Open
Abstract
Multiple Myeloma (MM) is a malignant expansion of plasma cells in the bone marrow (BM), resulting in a disease characterized by symptoms of end organ damage from light chain secretion, crowding of the BM, and bone lesions. Although the past two decades have been characterized by numerous novel therapies emerging, the disease remains incurable due to intrinsic or acquired drug resistance. A major player in MM's drug resistance arises from its intimate relationship with the BM microenvironment (BMME). Through stress-inducing conditions, soluble messengers, and physical adhesion to BM elements, the BMME activates numerous pathways in the myeloma cell. This not only propagates myeloma progression through survival and growth signals, but also specific mechanisms to circumvent therapeutic actions. In this review, we provide an overview of the BMME, the role of individual components in MM survival, and various therapy-specific resistance mechanisms reported in the literature.
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Affiliation(s)
- Kuntal Bhowmick
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Max von Suskil
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Omar S. Al-Odat
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Weam Othman Elbezanti
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
- Department of Hematology, MD Anderson Cancer Center at Cooper, Cooper University Health Care, Camden, NJ, USA
| | - Subash C. Jonnalagadda
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, USA
| | - Tulin Budak-Alpdogan
- Department of Hematology, MD Anderson Cancer Center at Cooper, Cooper University Health Care, Camden, NJ, USA
| | - Manoj K. Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
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2
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Yang Y, Li N, Wang TM, Di L. Natural Products with Activity against Lung Cancer: A Review Focusing on the Tumor Microenvironment. Int J Mol Sci 2021; 22:ijms221910827. [PMID: 34639167 PMCID: PMC8509218 DOI: 10.3390/ijms221910827] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/05/2021] [Accepted: 10/05/2021] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is one of the most prevalent malignancies worldwide. Despite the undeniable progress in lung cancer research made over the past decade, it is still the leading cause of cancer-related deaths and continues to challenge scientists and researchers engaged in searching for therapeutics and drugs. The tumor microenvironment (TME) is recognized as one of the major hallmarks of epithelial cancers, including the majority of lung cancers, and is associated with tumorigenesis, progression, invasion, and metastasis. Targeting of the TME has received increasing attention in recent years. Natural products have historically made substantial contributions to pharmacotherapy, especially for cancer. In this review, we emphasize the role of the TME and summarize the experimental proof demonstrating the antitumor effects and underlying mechanisms of natural products that target the TME. We also review the effects of natural products used in combination with anticancer agents. Moreover, we highlight nanotechnology and other materials used to enhance the effects of natural products. Overall, our hope is that this review of these natural products will encourage more thoughts and ideas on therapeutic development to benefit lung cancer patients.
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Affiliation(s)
| | - Ning Li
- Correspondence: (N.L.); (L.D.); Tel.: +86-551-6516-1115 (N.L.)
| | | | - Lei Di
- Correspondence: (N.L.); (L.D.); Tel.: +86-551-6516-1115 (N.L.)
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3
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Gabriely G, Quintana FJ. Role of AHR in the control of GBM-associated myeloid cells. Semin Cancer Biol 2019; 64:13-18. [PMID: 31128300 DOI: 10.1016/j.semcancer.2019.05.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 05/21/2019] [Accepted: 05/21/2019] [Indexed: 12/16/2022]
Abstract
Glioblastoma (GBM) is an aggressive and incurable brain tumor; its malignancy has been associated with the activity of tumor infiltrating myeloid cells. Myeloid cells play important roles in the tumor control by the immune response, but also in tumor progression. Indeed, GBM exploits multiple mechanisms to recruit and modulate myeloid cells. The Aryl Hydrocarbon Receptor (AHR) is a ligand activated transcription factor implicated in the regulation of myeloid cells. In this review, we will summarize current knowledge on the AHR role in the control of myeloid cells and its impact on GBM pathogenesis.
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Affiliation(s)
- Galina Gabriely
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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4
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Immune regulation and anti-cancer activity by lipid inflammatory mediators. Int Immunopharmacol 2018; 65:580-592. [PMID: 30447537 DOI: 10.1016/j.intimp.2018.10.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 10/02/2018] [Accepted: 10/17/2018] [Indexed: 12/19/2022]
Abstract
Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associated with poor outcomes, neutrophilia and lymphocytopenia. This contrasts with increased lymphocyte infiltration of tumors, which is correlated with improved outcomes. Lifestyle parameters, such as obesity and diets with high levels of saturated fat and/or omega (ω)-6 polyunsaturated fatty acids (PUFAs), can influence these inflammatory parameters, including an increase in extramedullary myelopoiesis (EMM). While tumor secretion of growth factors (GFs) and chemokines regulate tumor-immune-cell crosstalk, lifestyle choices also contribute to inflammation, abnormal pathology and leukocyte infiltration of tumors. A relationship between obesity and high-fat diets (notably saturated fats in Western diets) and inflammation, tumor incidence, metastasis and poor outcomes is generally accepted. However, the mechanisms of dietary promotion of an inflammatory microenvironment and targeted drugs to inhibit the clinical sequelae are poorly understood. Thus, modifications of obesity and dietary fat may provide preventative or therapeutic approaches to control tumor-associated inflammation and disease progression. Currently, the majority of basic and clinical research does not differentiate between obesity and fatty acid consumption as mediators of inflammatory and neoplastic processes. In this review, we discuss the relationships between dietary PUFAs, inflammation and neoplasia and experimental strategies to improve our understanding of these relationships. We conclude that dietary composition, notably the ratio of ω-3 vs ω-6 PUFA regulates tumor growth and the frequency and sites of metastasis that together, impact overall survival (OS) in mice.
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Wu S, Zheng Q, Xing X, Dong Y, Wang Y, You Y, Chen R, Hu C, Chen J, Gao D, Zhao Y, Wang Z, Xue T, Ren Z, Cui J. Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:99. [PMID: 29728125 PMCID: PMC5935912 DOI: 10.1186/s13046-018-0761-z] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 04/13/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Higher matrix stiffness affects biological behavior of tumor cells, regulates tumor-associated gene/miRNA expression and stemness characteristic, and contributes to tumor invasion and metastasis. However, the linkage between higher matrix stiffness and pre-metastatic niche in hepatocellular carcinoma (HCC) is still largely unknown. METHODS We comparatively analyzed the expressions of LOX family members in HCC cells grown on different stiffness substrates, and speculated that the secreted LOXL2 may mediate the linkage between higher matrix stiffness and pre-metastatic niche. Subsequently, we investigated the underlying molecular mechanism by which matrix stiffness induced LOXL2 expression in HCC cells, and explored the effects of LOXL2 on pre-metastatic niche formation, such as BMCs recruitment, fibronectin production, MMPs and CXCL12 expression, cell adhesion, etc. RESULTS: Higher matrix stiffness significantly upregulated LOXL2 expression in HCC cells, and activated JNK/c-JUN signaling pathway. Knockdown of integrin β1 and α5 suppressed LOXL2 expression and reversed the activation of above signaling pathway. Additionally, JNK inhibitor attenuated the expressions of p-JNK, p-c-JUN, c-JUN and LOXL2, and shRNA-c-JUN also decreased LOXL2 expression. CM-LV-LOXL2-OE and rhLOXL2 upregulated MMP9 expression and fibronectin production obviously in lung fibroblasts. Moreover, activation of Akt pathway contributed to LOXL2-induced fibronectin upregulation. LOXL2 in CM as chemoattractant increased motility and invasion of BMCs, implicating a significant role of LOXL2 in BMCs recruitment. Except that, CM-LV-LOXL2-OE as chemoattractant also increased the number of migrated HCC cells, and improved chemokine CXCL12 expression in lung fibroblasts. The number of HCC cells adhered to surface of lung fibroblasts treated with CM-LV-LOXL2-OE was remarkably higher than that of the control cells. These results indicated that the secreted LOXL2 facilitated the motility of HCC cells and strengthened CTCs settlement on the remodeled matrix "soil". CONCLUSION Integrin β1/α5/JNK/c-JUN signaling pathway participates in higher matrix stiffness-induced LOXL2 upregulation in HCC cells. The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation.
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Affiliation(s)
- Sifan Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Qiongdan Zheng
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Xiaoxia Xing
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Yinying Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Yaohui Wang
- Department of Radiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yang You
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Rongxin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Chao Hu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Jie Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Dongmei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Yan Zhao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Zhiming Wang
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Tongchun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
| | - Jiefeng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
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Sceneay J, Griessinger CM, Hoffmann SHL, Wen SW, Wong CSF, Krumeich S, Kneilling M, Pichler BJ, Möller A. Tracking the fate of adoptively transferred myeloid-derived suppressor cells in the primary breast tumor microenvironment. PLoS One 2018; 13:e0196040. [PMID: 29677215 PMCID: PMC5909918 DOI: 10.1371/journal.pone.0196040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Accepted: 04/05/2018] [Indexed: 12/21/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid progenitor cells that are expanded in cancer and act as potent suppressors of the anti-tumor immune response. MDSCs consist of two major subsets, namely monocytic (M-) MDSCs and granulocytic (G-) MDSCs that differ with respect to their phenotype, morphology and mechanisms of suppression. Here, we cultured bone marrow cells with IL-6 and GM-CSF in vitro to generate a population of bone marrow MDSCs (BM-MDSCs) similar to G-MDSCs from tumor-bearing mice in regards to phenotype, morphology and suppressive-function. Through fluorescent labeling of these BM-MDSCs and optical imaging, we could visualize the recruitment and localization of BM-MDSCs in breast tumor-bearing mice in vivo. Furthermore, we were able to demonstrate that BM-MDSCs home to primary and metastatic breast tumors, but have no significant effect on tumor growth or progression. Ex vivo flow cytometry characterization of BM-MDSCs after adoptive transfer demonstrated both organ-and tumor-specific effects on their phenotype and differentiation, demonstrating the importance of the local microenvironment on MDSC fate and function. In this study, we have developed a method to generate, visualize and detect BM-MDSCs in vivo and ex vivo through optical imaging and flow cytometry, in order to understand the organ-specific changes rendered to MDSCs in breast cancer.
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Affiliation(s)
- Jaclyn Sceneay
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Christoph M. Griessinger
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Sabrina H. L. Hoffmann
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Shu Wen Wen
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Christina S. F. Wong
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Sophie Krumeich
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Manfred Kneilling
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Dermatology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Bernd J. Pichler
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Möller
- Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
- * E-mail:
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7
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Modulation of Tumor-Associated Macrophages (TAM) Phenotype by Platelet-Activating Factor (PAF) Receptor. J Immunol Res 2017; 2017:5482768. [PMID: 29445756 PMCID: PMC5763242 DOI: 10.1155/2017/5482768] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 11/07/2017] [Indexed: 12/20/2022] Open
Abstract
Platelet-activating factor (PAF) plays an important role in the pathogenesis of several types of tumors. The biological effects of PAF are mediated by the PAF receptor (PAFR), which can be expressed by tumor cells and host cells that infiltrate the tumor microenvironment. In the present study, we investigated the role of PAFR expressed by leukocytes that infiltrate two types of tumors, one that expresses PAFR (TC-1 carcinoma) and another that does not express the receptor (B16F10 melanoma) implanted in mice that express the receptor or not (PAFR KO). It was found that both tumors grew significantly less in PAFR KO than in wild-type (WT) mice. Analysis of the leukocyte infiltration shown in PAFR KO increased the frequency of neutrophils (Gr1+) and of CD8+ lymphocytes in B16F10 tumors and of CD4+ lymphocytes in TC-1 tumors. PAFR KO also had a higher frequency of M1-like (CD11c+) and lower M2-like (CD206+) macrophages infiltrated in both tumors. This was confirmed in macrophages isolated from the tumors that showed higher iNOS, lower arginase activity, and lower IL10 expression in PAFR KO tumors than WT mice. These data suggest that in the tumor microenvironment, endogenous PAF-like activity molecules bind PAFR in macrophages which acquire an M2-like profile and this promotes tumor growth.
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Abstract
肿瘤侵袭转移研究目前多聚焦肿瘤微环境对肿瘤细胞恶性生物学行为的调控解析, 而针对肿瘤细胞定植转移靶器官前, 由原发瘤诱导靶器官"土壤"微环境改变形成"预转移龛"的关注和认知却明显不足. 随着原发瘤来源肿瘤可溶性因子、膜泡、外泌体, 及募集骨髓衍生细胞在不同肿瘤动物模型转移靶器官中相继鉴定发现, 预转移龛加速促成转移在靶器官实现获得越来越多实验上的验证与支撑. 本文对肿瘤预转移龛形成的始动因素、细胞组分、形成调控、促转移发生机制进行总结综述, 并讨论预转移龛潜在的临床意义及其面临的挑战.
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Aparicio LMA, Fernandez IP, Cassinello J. Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy. Clin Transl Oncol 2017; 19:1175-1182. [PMID: 28409322 PMCID: PMC5599454 DOI: 10.1007/s12094-017-1657-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/25/2017] [Indexed: 12/18/2022]
Abstract
The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy.
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Affiliation(s)
- L M A Aparicio
- Medical Oncology Department, Hospital Universitario A Coruña, Xubias s/n, 15615, La Coruña, Spain.
| | - I P Fernandez
- Medical Oncology Department, Hospital Universitario de Cabueñes, Gijón, Spain
| | - J Cassinello
- Medical Oncology Department, Hospital Universitario de Guadalajara, Guadalajara, Spain
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Toor SM, Syed Khaja AS, El Salhat H, Bekdache O, Kanbar J, Jaloudi M, Elkord E. Increased Levels of Circulating and Tumor-Infiltrating Granulocytic Myeloid Cells in Colorectal Cancer Patients. Front Immunol 2016; 7:560. [PMID: 28008330 PMCID: PMC5143474 DOI: 10.3389/fimmu.2016.00560] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/21/2016] [Indexed: 12/21/2022] Open
Abstract
Increased levels of myeloid cells, especially myeloid-derived suppressor cells (MDSCs), have been reported to correlate with bad prognosis and reduced survival in cancer patients. However, limited data are available on their conclusive phenotypes and their correlation with clinical settings. The aim of this study was to investigate levels and phenotype of myeloid cells in peripheral blood and tumor microenvironment (TME) of colorectal cancer (CRC) patients, compared to blood from healthy donors (HDs) and paired, adjacent non-tumor colon tissue. Flow cytometric analysis was performed to examine the expression of different myeloid markers in fresh peripheral blood samples from CRC patients and HDs, and tissue-infiltrating immune cells from CRC patients. We found significantly higher levels of cells expressing myeloid markers and lacking the expression of major histocompatibility complex class II molecule HLA-DR in blood and tumor of CRC patients. Further analysis revealed that these cells were granulocytic and expressed Arginase 1 indicative of their suppressive phenotype. These expanded cells could be neutrophils or granulocytic MDSCs, and we refer to them as granulocytic myeloid cells (GMCs) due to the phenotypical and functional overlap between these cell subsets. Interestingly, the expansion of peripheral GMCs correlated with higher stage and histological grade of cancer, thereby suggesting their role in cancer progression. Furthermore, an increase in CD33+CD11b+HLA-DR-CD14-CD15- immature myeloid cells was also observed in CRC tumor tissue. Our work shows that GMCs are expanded in circulation and TME of CRC patients, which provides further insights for developing immunotherapeutic approaches targeting these cell subsets to enhance antitumor immune and clinical responses.
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Affiliation(s)
- Salman M. Toor
- College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Azharuddin Sajid Syed Khaja
- College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
- Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Haytham El Salhat
- Oncology Department, Al Noor Hospital, Abu Dhabi, United Arab Emirates
| | | | | | | | - Eyad Elkord
- College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
- Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- Institute of Cancer Sciences, University of Manchester, Manchester, UK
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11
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Ferone G, Song JY, Sutherland KD, Bhaskaran R, Monkhorst K, Lambooij JP, Proost N, Gargiulo G, Berns A. SOX2 Is the Determining Oncogenic Switch in Promoting Lung Squamous Cell Carcinoma from Different Cells of Origin. Cancer Cell 2016; 30:519-532. [PMID: 27728803 PMCID: PMC5065004 DOI: 10.1016/j.ccell.2016.09.001] [Citation(s) in RCA: 169] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 07/05/2016] [Accepted: 09/07/2016] [Indexed: 11/18/2022]
Abstract
Lung squamous cell carcinoma (LSCC) is a devastating malignancy with no effective treatments, due to its complex genomic profile. Therefore, preclinical models mimicking its salient features are urgently needed. Here we describe mouse models bearing various combinations of genetic lesions predominantly found in human LSCC. We show that SOX2 but not FGFR1 overexpression in tracheobronchial basal cells combined with Cdkn2ab and Pten loss results in LSCC closely resembling the human counterpart. Interestingly, Sox2;Pten;Cdkn2ab mice develop LSCC with a more peripheral location when Club or Alveolar type 2 (AT2) cells are targeted. Our model highlights the essential role of SOX2 in commanding the squamous cell fate from different cells of origin and represents an invaluable tool for developing better intervention strategies.
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MESH Headings
- Animals
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Proliferation/genetics
- Disease Models, Animal
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Mice
- Receptor, Fibroblast Growth Factor, Type 1/biosynthesis
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- SOXB1 Transcription Factors/genetics
- Transcription, Genetic
- Tumor Microenvironment
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Affiliation(s)
- Giustina Ferone
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Ji-Ying Song
- Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Kate D Sutherland
- ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Rajith Bhaskaran
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Building 5, Moscow 143026, Russia
| | - Kim Monkhorst
- Division of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Jan-Paul Lambooij
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Natalie Proost
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Gaetano Gargiulo
- Department of Molecular Oncology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
| | - Anton Berns
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Building 5, Moscow 143026, Russia.
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12
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Hind LE, Lurier EB, Dembo M, Spiller KL, Hammer DA. Effect of M1-M2 Polarization on the Motility and Traction Stresses of Primary Human Macrophages. Cell Mol Bioeng 2016; 9:455-465. [PMID: 28458726 PMCID: PMC5404741 DOI: 10.1007/s12195-016-0435-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 04/01/2016] [Indexed: 01/12/2023] Open
Abstract
Macrophages become polarized by cues in their environment and this polarization causes a functional change in their behavior. Two main subsets of polarized macrophages have been described. M1, or "classically activated" macrophages, are pro-inflammatory and M2, or "alternatively activated" macrophages, are anti-inflammatory. In this study, we investigated the motility and force generation of primary human macrophages polarized down the M1 and M2 pathways using chemokinesis assays and traction force microscopy on polyacrylamide gels. We found that M1 macrophages are significantly less motile and M2 macrophages are significantly more motile than unactivated M0 macrophages. We also showed that M1 macrophages generate significantly less force than M0 or M2 macrophages. We further found that M0 and M2, but not M1, macrophage force generation is dependent on ROCK signaling, as identified using the chemical inhibitor Y27632. Finally, using the chemical inhibitor blebbistatin, we found that myosin contraction is required for force generation by M0, M1, and M2 macrophages. This study represents the first investigation of the changes in the mechanical motility mechanisms used by macrophages after polarization.
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Affiliation(s)
- Laurel E. Hind
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
| | - Emily B. Lurier
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA
| | - Micah Dembo
- Department of Biomedical Engineering, Boston University, Boston, MA
| | - Kara L. Spiller
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA
| | - Daniel A. Hammer
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA
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13
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Mittal V, El Rayes T, Narula N, McGraw TE, Altorki NK, Barcellos-Hoff MH. The Microenvironment of Lung Cancer and Therapeutic Implications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 890:75-110. [PMID: 26703800 DOI: 10.1007/978-3-319-24932-2_5] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an "activated/reprogramed" stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities.
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MESH Headings
- Antibodies, Monoclonal/therapeutic use
- Antineoplastic Agents/therapeutic use
- Carcinogenesis/drug effects
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Cell Communication/drug effects
- Drug Resistance, Neoplasm/genetics
- Epithelial-Mesenchymal Transition/drug effects
- Epithelial-Mesenchymal Transition/genetics
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Diseases, Obstructive/complications
- Lung Diseases, Obstructive/drug therapy
- Lung Diseases, Obstructive/genetics
- Lung Diseases, Obstructive/metabolism
- Lung Neoplasms/complications
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Mesenchymal Stem Cells/drug effects
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Pulmonary Emphysema/complications
- Pulmonary Emphysema/drug therapy
- Pulmonary Emphysema/genetics
- Pulmonary Emphysema/metabolism
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
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Affiliation(s)
- Vivek Mittal
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
| | - Tina El Rayes
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Weill Cornell Graduate School of Medical Sciences, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Navneet Narula
- Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Timothy E McGraw
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Nasser K Altorki
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, New York University School of Medicine, 566 First Avenue, New York, NY, 10016, USA.
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14
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Shay G, Hazlehurst L, Lynch CC. Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities. J Mol Med (Berl) 2015; 94:21-35. [PMID: 26423531 DOI: 10.1007/s00109-015-1345-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 09/13/2015] [Accepted: 09/17/2015] [Indexed: 12/19/2022]
Abstract
Multiple myeloma is a plasma cell skeletal malignancy. While therapeutic agents such as bortezomib and lenalidomide have significantly improved overall survival, the disease is currently incurable with the emergence of drug resistance limiting the efficacy of chemotherapeutic strategies. Failure to cure the disease is in part due to the underlying genetic heterogeneity of the cancer. Myeloma progression is critically dependent on the surrounding microenvironment. Defining the interactions between myeloma cells and the more genetically stable hematopoietic and mesenchymal components of the bone microenvironment is critical for the development of new therapeutic targets. In this review, we discuss recent advances in our understanding of how microenvironmental elements contribute to myeloma progression and, therapeutically, how those elements can or are currently being targeted in a bid to eradicate the disease.
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Affiliation(s)
- G Shay
- Tumor Biology Department, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Blvd, Tampa, FL, 33612, USA
| | - L Hazlehurst
- Department of Pharmaceutical Sciences and The Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University, Morgantown, WV, 26506, USA
| | - C C Lynch
- Tumor Biology Department, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Blvd, Tampa, FL, 33612, USA.
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15
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Deshane JS, Redden DT, Zeng M, Spell ML, Zmijewski JW, Anderson JT, Deshane RJ, Gaggar A, Siegal GP, Abraham E, Dransfield MT, Chaplin DD. Subsets of airway myeloid-derived regulatory cells distinguish mild asthma from chronic obstructive pulmonary disease. J Allergy Clin Immunol 2015; 135:413-424.e15. [PMID: 25420684 PMCID: PMC4323991 DOI: 10.1016/j.jaci.2014.08.040] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 08/07/2014] [Accepted: 08/21/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND Subsets of myeloid-derived regulatory cells (MDRCs), which are phenotypically similar to the myeloid-derived suppressor cells found in patients with cancer, have recently been appreciated as critical regulators of airway inflammation in mouse models of asthma. OBJECTIVE We test the hypothesis that subsets of airway MDRCs contribute differentially to the inflammatory milieu in human asthma and chronic obstructive pulmonary disease (COPD). METHODS We used bronchoalveolar lavage to identify and characterize human airway MDRCs from 10 healthy subjects, 9 patients with mild asthma, and 8 patients with COPD, none of whom were treated with inhaled or systemic corticosteroids. We defined subsets of airway MDRCs using flow cytometry, the molecular mediators they produce, and their abilities to regulate proliferation of polyclonally activated autologous T lymphocytes. RESULTS We found substantial differences in the functional potential of MDRC subsets in healthy subjects, patients with asthma, and patients with COPD, with these differences regulated by the nitrosative and oxidative free radicals and cytokines they produced. Nitric oxide-producing MDRCs suppressed and superoxide-producing MDRCs enhanced proliferation of polyclonally activated autologous CD4 T cells. HLA-DR(+)CD11b(+)CD11c(+)CD163(-) superoxide-producing MDRCs, which stimulated proliferation of autologous T cells, comprised a high fraction of MDRCs in the airways of patients with mild asthma or COPD but not those of healthy control subjects. CD11b(+)CD14(+)CD16(-)HLA-DR(-) nitric oxide-producing MDRCs, which suppressed T-cell proliferation, were present in high numbers in airways of patients with mild asthma but not patients with COPD or healthy control subjects. CONCLUSION Subsets of airway MDRCs conclusively discriminate patients with mild asthma, patients with COPD, and healthy subjects from each other. The distinctive activities of these MDRCs in patients with asthma or COPD might provide novel targets for new therapeutics for these common disorders. [Corrected]
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Affiliation(s)
- Jessy S Deshane
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Ala; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Ala; Comprehensive Arthritis, Musculoskeletal and Autoimmunity Center, University of Alabama at Birmingham, Birmingham, Ala.
| | - David T Redden
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Ala; Comprehensive Arthritis, Musculoskeletal and Autoimmunity Center, University of Alabama at Birmingham, Birmingham, Ala
| | - Meiqin Zeng
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Ala
| | - Marion L Spell
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala
| | - Jaroslaw W Zmijewski
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Ala
| | - John T Anderson
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala
| | - Rohit J Deshane
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Ala
| | - Amit Gaggar
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala; Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Ala
| | - Gene P Siegal
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Ala; Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Ala; Department of Surgery, University of Alabama at Birmingham, Birmingham, Ala
| | - Edward Abraham
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Ala
| | - Mark T Dransfield
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala
| | - David D Chaplin
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Ala; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Ala; Comprehensive Arthritis, Musculoskeletal and Autoimmunity Center, University of Alabama at Birmingham, Birmingham, Ala.
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16
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Meseure D, Drak Alsibai K, Nicolas A. Pivotal role of pervasive neoplastic and stromal cells reprogramming in circulating tumor cells dissemination and metastatic colonization. CANCER MICROENVIRONMENT : OFFICIAL JOURNAL OF THE INTERNATIONAL CANCER MICROENVIRONMENT SOCIETY 2014; 7:95-115. [PMID: 25523234 PMCID: PMC4275542 DOI: 10.1007/s12307-014-0158-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 10/06/2014] [Indexed: 01/01/2023]
Abstract
Reciprocal interactions between neoplastic cells and their microenvironment are crucial events in carcinogenesis and tumor progression. Pervasive stromal reprogramming and remodeling that transform a normal to a tumorigenic microenvironment modify numerous stromal cells functions, status redox, oxidative stress, pH, ECM stiffness and energy metabolism. These environmental factors allow selection of more aggressive cancer cells that develop important adaptive strategies. Subpopulations of cancer cells acquire new properties associating plasticity, stem-like phenotype, unfolded protein response, metabolic reprogramming and autophagy, production of exosomes, survival to anoikis, invasion, immunosuppression and therapeutic resistance. Moreover, by inducing vascular transdifferentiation of cancer cells and recruiting endothelial cells and pericytes, the tumorigenic microenvironment induces development of tumor-associated vessels that allow invasive cells to gain access to the tumor vessels and to intravasate. Circulating cancer cells can survive in the blood stream by interacting with the intravascular microenvironment, extravasate through the microvasculature and interact with the metastatic microenvironment of target organs. In this review, we will focus on many recent paradigms involved in the field of tumor progression.
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Affiliation(s)
- Didier Meseure
- Platform of Investigative Pathology and Department of Biopathology, Curie Institute, 26 rue d'Ulm, 75248, Paris, Cedex 05, France,
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17
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Gutknecht MF, Bouton AH. Functional significance of mononuclear phagocyte populations generated through adult hematopoiesis. J Leukoc Biol 2014; 96:969-80. [PMID: 25225678 PMCID: PMC4226790 DOI: 10.1189/jlb.1ri0414-195r] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 08/14/2014] [Accepted: 08/15/2014] [Indexed: 12/23/2022] Open
Abstract
Tissue homeostasis requires a complete repertoire of functional macrophages in peripheral tissues. Recent evidence indicates that many resident tissue macrophages are seeded during embryonic development and persist through adulthood as a consequence of localized proliferation. Mononuclear phagocytes are also produced during adult hematopoiesis; these cells are then recruited to sites throughout the body, where they function in tissue repair and remodeling, resolution of inflammation, maintenance of homeostasis, and disease progression. The focus of this review is on mononuclear phagocytes that comprise the nonresident monocyte/macrophage populations in the body. Key features of monocyte differentiation are presented, focusing primarily on the developmental hierarchy that is established through this process, the markers used to identify discrete cell populations, and novel, functional attributes of these cells. These features are then explored in the context of the tumor microenvironment, where mononuclear phagocytes exhibit extensive plasticity in phenotype and function.
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Affiliation(s)
- Michael F Gutknecht
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Amy H Bouton
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
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18
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Abstract
It is rapidly becoming evident that the formation of tumor-promoting pre-metastatic niches in secondary organs adds a previously unrecognized degree of complexity to the challenge of curing metastatic disease. Primary tumor cells orchestrate pre-metastatic niche formation through secretion of a variety of cytokines and growth factors that promote mobilization and recruitment of bone marrow-derived cells to future metastatic sites. Hypoxia within the primary tumor, and secretion of specific microvesicles termed exosomes, are emerging as important processes and vehicles for tumor-derived factors to modulate pre-metastatic sites. It has also come to light that reduced immune surveillance is a novel mechanism through which primary tumors create favorable niches in secondary organs. This review provides an overview of our current understanding of underlying mechanisms of pre-metastatic niche formation and highlights the common links as well as discrepancies between independent studies. Furthermore, the possible clinical implications, links to metastatic persistence and dormancy, and novel approaches for treatment of metastatic disease through reversal of pre-metastatic niche formation are identified and explored.
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19
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Sceneay J, Parker BS, Smyth MJ, Möller A. Hypoxia-driven immunosuppression contributes to the pre-metastatic niche. Oncoimmunology 2014; 2:e22355. [PMID: 23482904 PMCID: PMC3583916 DOI: 10.4161/onci.22355] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Primary tumor cells create favorable microenvironments in secondary organs, termed pre-metastatic niches, that promote the formation of metastases. Using immune competent syngenic breast cancer mouse models, we have recently demonstrated that factors secreted by hypoxic tumor cells condition pre-metastatic niches by recruiting CD11b+/Ly6Cmed/Ly6G+ myeloid cells and suppressing natural killer cell functions.
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Affiliation(s)
- Jaclyn Sceneay
- Cancer Genomics and Genetics Laboratory; Peter MacCallum Cancer Centre; East Melbourne, VIC Australia ; Department of Pathology and Sir Peter MacCallum Department of Oncology; The University of Melbourne; Parkville; VIC Australia
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20
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Myeloid derived suppressor cells in physiological and pathological conditions: the good, the bad, and the ugly. Immunol Res 2014; 57:172-84. [PMID: 24203443 DOI: 10.1007/s12026-013-8455-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Myeloid derived suppressor cells (MDSCs), a heterogeneous population of myeloid progenitors, are recognized as a key element in tumor escape and progression. The importance of MDSCs in human malignancies has been demonstrated in recent years, and new approaches targeting their suppressive/tolerogenic action are currently being tested in both preclinical model and clinical trials. However, emerging evidence suggests that MDSCs may play a prominent role as regulator of the physiologic, the chronic, and the pathologic immune responses. This review will focus on the biology of MDSC in light of these new findings and the possible role of this myeloid population not only in the progression of the tumor but also in its initiation.
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21
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Fernández A, Oliver L, Alvarez R, Fernández LE, Mesa C. GM3-containing nanoparticles in immunosuppressed hosts: Effect on myeloid-derived suppressor cells. World J Immunol 2014; 4:98-106. [DOI: 10.5411/wji.v4.i2.98] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 05/27/2014] [Accepted: 06/27/2014] [Indexed: 02/05/2023] Open
Abstract
Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tumor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. Myeloid-derived suppressor cells (MDSCs) are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8+ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be critical for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes (VSSP) is a nanoparticulated adjuvant specifically designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3 ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8+ T cells, Th1 polarization, and enhances CD8+ T cell response in tumor-free mice. Currently, four cancer vaccines using VSSP as the adjuvant are in Phase I and II clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specific CD8+ T cell responses in two immunocompromised scenarios; in tumor-bearing mice and during chemotherapy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vaccine adjuvants currently in preclinical or clinical studies.
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22
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Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 2014; 1319:47-65. [DOI: 10.1111/nyas.12469] [Citation(s) in RCA: 302] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Samantha Solito
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
| | | | - Laura Pinton
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
| | - Vera Damuzzo
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
| | - Susanna Mandruzzato
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
- Istituto Oncologico Veneto; IOV-IRCCS; Padova Italy
| | - Vincenzo Bronte
- Pathology and Diagnostics; Verona University Hospital; Verona Italy
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23
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Xu X, Cai Y, Wei Y, Donate F, Juarez J, Parry G, Chen L, Meehan EJ, Ahn RW, Ugolkov A, Dubrovskyi O, O'Halloran TV, Huang M, Mazar AP. Identification of a new epitope in uPAR as a target for the cancer therapeutic monoclonal antibody ATN-658, a structural homolog of the uPAR binding integrin CD11b (αM). PLoS One 2014; 9:e85349. [PMID: 24465541 PMCID: PMC3897428 DOI: 10.1371/journal.pone.0085349] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 12/04/2013] [Indexed: 12/21/2022] Open
Abstract
The urokinase plasminogen activator receptor (uPAR) plays a role in tumor progression and has been proposed as a target for the treatment of cancer. We recently described the development of a novel humanized monoclonal antibody that targets uPAR and has anti-tumor activity in multiple xenograft animal tumor models. This antibody, ATN-658, does not inhibit ligand binding (i.e. uPA and vitronectin) to uPAR and its mechanism of action remains unclear. As a first step in understanding the anti-tumor activity of ATN-658, we set out to identify the epitope on uPAR to which ATN-658 binds. Guided by comparisons between primate and human uPAR, epitope mapping studies were performed using several orthogonal techniques. Systematic site directed and alanine scanning mutagenesis identified the region of aa 268–275 of uPAR as the epitope for ATN-658. No known function has previously been attributed to this epitope Structural insights into epitope recognition were obtained from structural studies of the Fab fragment of ATN-658 bound to uPAR. The structure shows that the ATN-658 binds to the DIII domain of uPAR, close to the C-terminus of the receptor, corroborating the epitope mapping results. Intriguingly, when bound to uPAR, the complementarity determining region (CDR) regions of ATN-658 closely mimic the binding regions of the integrin CD11b (αM), a previously identified uPAR ligand thought to be involved in leukocyte rolling, migration and complement fixation with no known role in tumor progression of solid tumors. These studies reveal a new functional epitope on uPAR involved in tumor progression and demonstrate a previously unrecognized strategy for the therapeutic targeting of uPAR.
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Affiliation(s)
- Xiang Xu
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yuan Cai
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America ; State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, China
| | - Ying Wei
- Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Fernando Donate
- Agensys, St. Santa Monica, California, United States of America
| | - Jose Juarez
- GNF, San Diego, California, United States of America
| | - Graham Parry
- Attenuon, San Diego, California, United States of America
| | - Liqing Chen
- Department of Chemistry, University of Alabama in Huntsville, Huntsville, Alabama, United States of America
| | - Edward J Meehan
- Department of Chemistry, University of Alabama in Huntsville, Huntsville, Alabama, United States of America
| | - Richard W Ahn
- Department of Chemistry, Northwestern University, Evanston, Illinois, United States of America
| | - Andrey Ugolkov
- Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, United States of America
| | - Oleksii Dubrovskyi
- Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, United States of America
| | - Thomas V O'Halloran
- Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, United States of America ; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois, United States of America ; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America ; Department of Chemistry, Northwestern University, Evanston, Illinois, United States of America
| | - Mingdong Huang
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Andrew P Mazar
- Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, United States of America ; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois, United States of America ; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America
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24
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Arina A, Schreiber K, Binder DC, Karrison TG, Liu RB, Schreiber H. Adoptively transferred immune T cells eradicate established tumors despite cancer-induced immune suppression. THE JOURNAL OF IMMUNOLOGY 2013; 192:1286-93. [PMID: 24367029 DOI: 10.4049/jimmunol.1202498] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Myeloid-derived CD11b(+)Gr1(+) suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are considered a major obstacle for effective adoptive T cell therapy. Myeloid cells suppress naive T cell proliferation ex vivo and can prevent the generation of T cell responses in vivo. We find, however, that adoptively transferred immune T cells eradicate well-established tumors in the presence of MDSCs and TAMs, which are strongly immunosuppressive ex vivo. These MDSCs and TAMs were comparable in numbers and immunosuppressive capacity among different tumor models. Longitudinal microscopy of tumors in vivo revealed that after T cell transfer, tumor vasculature and cancer cells disappeared simultaneously. During T cell-mediated tumor destruction, the tumor stroma contained abundant myeloid cells (mainly TAMs) that retained their suppressive properties. Preimmunized but not naive mice resisted immune suppression caused by an unrelated tumor burden, supporting the idea that in vivo, myeloid immunosuppressive cells can suppress naive but not memory T cell responses.
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Affiliation(s)
- Ainhoa Arina
- Department of Pathology, University of Chicago, Chicago, IL 60637
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Peranzoni E, Rivas-Caicedo A, Bougherara H, Salmon H, Donnadieu E. Positive and negative influence of the matrix architecture on antitumor immune surveillance. Cell Mol Life Sci 2013; 70:4431-48. [PMID: 23649148 PMCID: PMC11113382 DOI: 10.1007/s00018-013-1339-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 03/18/2013] [Accepted: 04/08/2013] [Indexed: 12/15/2022]
Abstract
The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells.
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Affiliation(s)
- Elisa Peranzoni
- Inserm, U1016, Institut Cochin, Paris, France
- Cnrs UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, France
| | - Ana Rivas-Caicedo
- Alta Tecnología en Laboratorios SA de CV, Comoporis #45, El Caracol, Mexico, Mexico
| | - Houcine Bougherara
- Inserm, U1016, Institut Cochin, Paris, France
- Cnrs UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, France
| | - Hélène Salmon
- Department of Oncological Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029 USA
| | - Emmanuel Donnadieu
- Inserm, U1016, Institut Cochin, Paris, France
- Cnrs UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, France
- Département d’Immunologie et d’Hématologie, Institut Cochin, 22 Rue Méchain, 75014 Paris, France
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Gagliano T, Bellio M, Gentilin E, Molè D, Tagliati F, Schiavon M, Cavallesco NG, Andriolo LG, Ambrosio MR, Rea F, Degli Uberti E, Zatelli MC. mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids. Endocr Relat Cancer 2013; 20:463-75. [PMID: 23653462 DOI: 10.1530/erc-13-0042] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs.
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Affiliation(s)
- Teresa Gagliano
- Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Via Savonarola 9, Ferrara, Italy
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Solito S, Pinton L, Damuzzo V, Mandruzzato S. Highlights on molecular mechanisms of MDSC-mediated immune suppression: paving the way for new working hypotheses. Immunol Invest 2013; 41:722-37. [PMID: 23017143 DOI: 10.3109/08820139.2012.678023] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
MDSCs have been recognized in the last years as tolerogenic cells, potentially dangerous in the context of neoplasia, since they are able to induce tolerance to a variety of anti-tumor effectors, including CD4(+) and CD8(+) T cells. It is currently believed that the origin of MDSCs is due to an arrest of the myeloid differentiation process caused by tumor-secreted factors released in the tumor microenvironment that are able to exert an effect on myeloid progenitors, rendering them unable to terminally differentiate into dendritic cells, granulocytes and macrophages. As a consequence, these immature myeloid cells acquire suppressive activity through the activation of several mechanisms, controlled by different transcription factors. The lack of consensus about the phenotypical characterization of human MDSCs is the result of the existence of different MDSC subsets, most likely depending on the tumor in which they expand and on the tumor specific cytokine cocktail driving their activation. This, in turn, might also influence the mechanisms of MDSC-mediated immune suppression. In this review article we address the role of tumor-derived factors (TDFs) in MDSC-recruitment and activation, discuss the complex heterogeneity of MDSC phenotype and analyze the crosstalk between activated T cells and MDSCs.
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Affiliation(s)
- Samantha Solito
- Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova, Padova, Italy
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28
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Parekh VV, Wu L, Olivares-Villagómez D, Wilson KT, Van Kaer L. Activated invariant NKT cells control central nervous system autoimmunity in a mechanism that involves myeloid-derived suppressor cells. THE JOURNAL OF IMMUNOLOGY 2013; 190:1948-60. [PMID: 23345328 DOI: 10.4049/jimmunol.1201718] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Invariant NKT (iNKT) cells are a subset of T lymphocytes that recognize glycolipid Ags presented by the MHC class I-related protein CD1d. Activation of iNKT cells with glycolipid Ags, such as the marine sponge-derived reagent α-galactosylceramide (α-GalCer), results in the rapid production of a variety of cytokines and activation of many other immune cell types. These immunomodulatory properties of iNKT cells have been exploited for the development of immunotherapies against a variety of autoimmune and inflammatory diseases, but mechanisms by which activated iNKT cells confer disease protection have remained incompletely understood. In this study, we demonstrate that glycolipid-activated iNKT cells cooperate with myeloid-derived suppressor cells (MDSCs) in protecting mice against the development of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for multiple sclerosis. We show that α-GalCer induced the expansion and immunosuppressive activities of MDSCs in the spleen of mice induced for development of EAE. Disease protection in these animals also correlated with recruitment of MDSCs to the CNS. Depletion of MDSCs abrogated the protective effects of α-GalCer against EAE and, conversely, adoptive transfer of MDSCs from α-GalCer-treated mice ameliorated passive EAE induced in recipient animals. The cytokines GM-CSF, IL-4, and IFN-γ, produced by activated iNKT cells, and inducible NO synthase, arginase-1, and IL-10 produced by MDSCs, contributed to these effects. Our findings have revealed cooperative immunosuppressive interactions between iNKT cells and MDSCs that might be exploited for the development of improved immunotherapies for multiple sclerosis and other autoimmune and inflammatory diseases.
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Affiliation(s)
- Vrajesh V Parekh
- Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Sevko A, Umansky V. Myeloid-derived suppressor cells interact with tumors in terms of myelopoiesis, tumorigenesis and immunosuppression: thick as thieves. J Cancer 2012; 4:3-11. [PMID: 23386900 PMCID: PMC3564242 DOI: 10.7150/jca.5047] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 11/20/2012] [Indexed: 12/20/2022] Open
Abstract
Tumor progression is often associated with chronic inflammation in the tumor microenvironment, which is mediated by numerous cytokines, chemokines and growth factors produced by cancer and stroma cells. All these mediators support tumor development and immunosuppression in autocrine and/or paracrine ways. Neutralization of chronic inflammatory conditions can lead to the restoration of anti-tumor immune responses. Among stroma cells infiltrating tumors, myeloid-derived suppressor cells (MDSCs) represent one of the most important players mediating immunosuppression. These cells may not only inhibit an anti-tumor immunity but also directly stimulate tumorigenesis as well as tumor growth and expansion. Therefore, understanding the mechanisms of generation, migration to the tumor site and activation of MDSC is necessary for the development of new strategies of tumor immunotherapy.
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Affiliation(s)
- Alexandra Sevko
- Skin Cancer Unit, German Cancer Research Center, Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, 69120 Heidelberg, Germany
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30
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Forrester JV, Xu H. Good news-bad news: the Yin and Yang of immune privilege in the eye. Front Immunol 2012; 3:338. [PMID: 23230433 PMCID: PMC3515883 DOI: 10.3389/fimmu.2012.00338] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 10/23/2012] [Indexed: 12/27/2022] Open
Abstract
The eye and the brain are prototypical tissues manifesting immune privilege (IP) in which immune responses to foreign antigens, particularly alloantigens are suppressed, and even completely inhibited. Explanations for this phenomenon are numerous and mostly reflect our evolving understanding of the molecular and cellular processes underpinning immunological responses generally. IP is now viewed as a property of many tissues and the level of expression of IP varies not only with the tissue but with the nature of the foreign antigen and changes in the limited conditions under which privilege can operate as a mechanism of immunological tolerance. As a result, IP functions normally as a homeostatic mechanism preserving normal function in tissues, particularly those with highly specialized function and limited capacity for renewal such as the eye and brain. However, IP is relatively easily bypassed in the face of a sufficiently strong immunological response, and the privileged tissues may be at greater risk of collateral damage because its natural defenses are more easily breached than in a fully immunocompetent tissue which rapidly rejects foreign antigen and restores integrity. This two-edged sword cuts its swathe through the eye: under most circumstances, IP mechanisms such as blood-ocular barriers, intraocular immune modulators, induction of T regulatory cells, lack of lymphatics, and other properties maintain tissue integrity; however, when these are breached, various degrees of tissue damage occur from severe tissue destruction in retinal viral infections and other forms of uveoretinal inflammation, to less severe inflammatory responses in conditions such as macular degeneration. Conversely, ocular IP and tumor-related IP can combine to permit extensive tumor growth and increased risk of metastasis thus threatening the survival of the host.
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Affiliation(s)
- John V. Forrester
- Laboratory of Immunology, Lion’s Eye Institute, University of Western AustraliaPerth, WA, Australia
- Ocular Immunology Laboratory, Section of Immunology and Infection, Institute of Medical Sciences, University of AberdeenAberdeen, UK
| | - Heping Xu
- Laboratory of Immunology, Lion’s Eye Institute, University of Western AustraliaPerth, WA, Australia
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Sceneay J, Chow MT, Chen A, Halse HM, Wong CSF, Andrews DM, Sloan EK, Parker BS, Bowtell DD, Smyth MJ, Möller A. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res 2012; 72:3906-11. [PMID: 22751463 DOI: 10.1158/0008-5472.can-11-3873] [Citation(s) in RCA: 292] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hypoxia within a tumor acts as a strong selective pressure that promotes angiogenesis, invasion, and metastatic spread. In this study, we used immune competent bone marrow chimeric mice and syngeneic orthotopic mammary cancer models to show that hypoxia in the primary tumor promotes premetastatic niche formation in secondary organs. Injection of mice with cell-free conditioned medium derived from hypoxic mammary tumor cells resulted in increased bone marrow-derived cell infiltration into the lung in the absence of a primary tumor and led to increased metastatic burden in mammary and melanoma experimental metastasis models. By characterizing the composition of infiltrating bone marrow-derived cells, we identified CD11b+/Ly6Cmed/Ly6G+ myeloid and CD3-/NK1.1+ immune cell lineages as key constituents of the premetastatic niche. Furthermore, the cytotoxicity of natural killer (NK) cells was significantly decreased, resulting in a reduced antitumor response that allowed metastasis formation in secondary organs to a similar extent as ablation of NK cells. In contrast, metastatic burden was decreased when active NK cells were present in premetastatic lungs. Together, our findings suggest that primary tumor hypoxia provides cytokines and growth factors capable of creating a premetastatic niche through recruitment of CD11b+/Ly6Cmed/Ly6G+ myeloid cells and a reduction in the cytotoxic effector functions of NK cell populations.
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Affiliation(s)
- Jaclyn Sceneay
- Cancer Genomics and Genetics Laboratory, Cancer Immunology Program, and Metastasis Research Group, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia
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Viola A, Sarukhan A, Bronte V, Molon B. The pros and cons of chemokines in tumor immunology. Trends Immunol 2012; 33:496-504. [PMID: 22726608 DOI: 10.1016/j.it.2012.05.007] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Revised: 05/11/2012] [Accepted: 05/16/2012] [Indexed: 12/30/2022]
Abstract
Innate and adaptive immune cells can intervene during tumor progression at different stages including initiation, angiogenesis, local spreading and distant metastasis formation. The net effect can be favorable or detrimental to tumor development, depending on the composition and activation status of the immune infiltrate. Chemokines can determine the distribution of immune cells in the tumor microenvironment and also affect stroma composition. Here we consider how a complex network of chemokines plays a key role in dictating the fate of a tumor. Although the field is in its infancy, we also highlight how targeting chemokines offers a tool to modulate the tumor environment with the aim of enhancing immune-mediated rejection of cancer.
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Affiliation(s)
- Antonella Viola
- Istituto Clinico Humanitas IRCCS and Department of Translational Medicine, University of Milan, Via Manzoni 113, 20089 Rozzano, Milan, Italy
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33
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Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 2012; 61:1373-85. [PMID: 22215137 DOI: 10.1007/s00262-011-1178-0] [Citation(s) in RCA: 220] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 11/30/2011] [Indexed: 12/15/2022]
Abstract
PURPOSE Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). EXPERIMENTAL DESIGN Peripheral blood, bone marrow, and tumor samples were collected from pancreatic cancer patients, analyzed for MDSC (CD15(+)CD11b(+)) by flow cytometry and compared to cancer-free controls. The suppressive capacity of MDSC (CD11b(+)Gr-1(+)) and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid, a potent aminobisphosphonate previously shown to target MDSC. The tumor microenvironment was analyzed for MDSC (Gr1(+)CD11b(+)), effector T cells, and tumor cytokine levels. RESULTS Patients with PA demonstrated increased frequency of MDSC in the bone marrow and peripheral circulation which correlated with disease stage. Normal pancreas tissue showed no MDSC infiltrate, while human tumors avidly recruited MDSC. Murine tumors similarly recruited MDSC that suppressed CD8(+) T cells in vitro and accelerated tumor growth in vivo. Treatment with zoledronic acid impaired intratumoral MDSC accumulation resulting in delayed tumor growth rate, prolonged median survival, and increased recruitment of T cells to the tumor. This was associated with a more robust type 1 response with increased levels of IFN-γ and decreased levels of IL-10. CONCLUSIONS MDSC are important mediators of tumor-induced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that efforts to block MDSC may represent a novel treatment strategy for pancreatic cancer.
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Wasserman J, Diese L, VanGundy Z, London C, Carson WE, Papenfuss TL. Suppression of canine myeloid cells by soluble factors from cultured canine tumor cells. Vet Immunol Immunopathol 2011; 145:420-30. [PMID: 22244518 DOI: 10.1016/j.vetimm.2011.12.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 12/19/2011] [Accepted: 12/21/2011] [Indexed: 01/05/2023]
Abstract
BACKGROUND Cancer profoundly affects immunity and causes immunosuppression that contributes to tumor escape, metastases and resistance to therapy. The mechanisms by which cancer cells influence immune cells are not fully known but both innate and adaptive immune cells can be altered by cancer. Myeloid cells are innate immune cells that comprise the mononuclear phagocytic system (MPS) and include monocytes, macrophages, dendritic cells (DCs) and their progenitors. Myeloid cells play important roles in both the promotion and regulation of immune responses. Dysregulated myeloid cells are increasingly being recognized as contributing to cancer-related immunosuppression. This study investigated whether soluble factors produced by canine tumor cells inhibited canine myeloid cell function. METHODS These studies investigated the utility of using the canine DH82 cell line for assessment of canine myeloid responses to tumor-derived soluble factors (TDSFs). Phenotypic comparisons to canine bone marrow-derived DCs (BM-DCs) and bone marrow-derived macrophages (BM-MΦs) were performed and expression of myeloid cell markers CD11b, CD11c, CD80, and major histocompatibility complex (MHC) class II were evaluated by flow cytometry. Phenotypic and functional changes of DC populations were then determined following exposure to tumor-conditioned media (TCM) from canine osteosarcoma, melanoma and mammary carcinoma cell lines. RESULTS We found that the canine BM-DCs and the DH82 cell line shared similar CD11b, CD11c and MHC II expression and morphologic characteristics that were distinct from canine BM-MΦs. Myeloid cells exposed to TDSFs showed decreased expression of MHC class II and CD80, had reduced phagocytic activity and suppressed the proliferation of responder immune cells. CONCLUSION These results show that soluble factors secreted from canine tumor cells suppress the activation and function of canine myeloid cells. Our results suggest that, similar to humans, dysregulated myeloid cells may contribute to immunosuppression in dogs with cancer.
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Affiliation(s)
- J Wasserman
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
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On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol 2011; 82:296-309. [PMID: 21798756 DOI: 10.1016/j.critrevonc.2011.06.004] [Citation(s) in RCA: 251] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Revised: 05/25/2011] [Accepted: 06/27/2011] [Indexed: 01/13/2023] Open
Abstract
Inconsistencies plague our understanding of the role of neutrophils in cancer and the literature provides evidence for a duality in neutrophil activity on the outcome of cancer. Here, the different effects of neutrophils during the multiple subprocesses of cancer development and progression are overviewed, in order to gain insight into the features of both antitumoral and protumoral tumor-associated neutrophils (TAN). Neutrophils can counteract the progression of malignancies through tumor cytotoxicity, tumor rejection and enhancement of antitumoral immune memory. These cells have recently been phenotypically denominated N1 neutrophils. Recent studies indicate that cytokines, such as TGF-β and IFN-β, are involved in directing neutrophil polarization by the tumor microenvironment. With the opposite polarity, N2 neutrophils may be detrimental for the host and beneficial for tumor growth, invasion and metastasis, e.g. through proteolysis of extracellullar matrix components, promotion of angiogenesis and mediation of immunosuppression.
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