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1
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Failla CM, Carbone ML, Ramondino C, Bruni E, Orecchia A. Vascular Endothelial Growth Factor (VEGF) Family and the Immune System: Activators or Inhibitors? Biomedicines 2024; 13:6. [PMID: 39857591 PMCID: PMC11763294 DOI: 10.3390/biomedicines13010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 11/29/2024] [Accepted: 12/20/2024] [Indexed: 01/27/2025] Open
Abstract
The vascular endothelial growth factor (VEGF) family includes key mediators of vasculogenesis and angiogenesis. VEGFs are secreted by various cells of epithelial and mesenchymal origin and by some immune cells in response to physiological and pathological stimuli. In addition, immune cells express VEGF receptors and/or co-receptors and can respond to VEGFs in an autocrine or paracrine manner. This immunological role of VEGFs has opened the possibility of using the VEGF inhibitors already developed to inhibit tumor angiogenesis also in combination approaches with different immunotherapies to enhance the action of effector T lymphocytes against tumor cells. This review pursues to examine the current understanding of the interplay between VEGFs and the immune system, while identifying key areas that require further evaluation.
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Affiliation(s)
- Cristina Maria Failla
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy; (C.M.F.); (C.R.)
| | - Maria Luigia Carbone
- Clinical Trial Center, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy;
| | - Carmela Ramondino
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy; (C.M.F.); (C.R.)
| | - Emanuele Bruni
- Departmental Faculty of Medicine and Surgery, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy
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2
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Chan HW, Kuo DY, Shueng PW, Chuang HY. Visualizing the Tumor Microenvironment: Molecular Imaging Probes Target Extracellular Matrix, Vascular Networks, and Immunosuppressive Cells. Pharmaceuticals (Basel) 2024; 17:1663. [PMID: 39770505 PMCID: PMC11676442 DOI: 10.3390/ph17121663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
The tumor microenvironment (TME) is a critical factor in cancer progression, driving tumor growth, immune evasion, therapeutic resistance, and metastasis. Understanding the dynamic interactions within the TME is essential for advancing cancer management. Molecular imaging provides a non-invasive, real-time, and longitudinal approach to studying the TME, with techniques such as positron emission tomography (PET), magnetic resonance imaging (MRI), and fluorescence imaging offering complementary strengths, including high sensitivity, spatial resolution, and intraoperative precision. Recent advances in imaging probe development have enhanced the ability to target and monitor specific components of the TME, facilitating early cancer diagnosis, therapeutic monitoring, and deeper insights into tumor biology. By integrating these innovations, molecular imaging offers transformative potential for precision oncology, improving diagnostic accuracy and treatment outcomes through a comprehensive assessment of TME dynamics.
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Affiliation(s)
- Hui-Wen Chan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei City 112, Taiwan;
| | - Deng-Yu Kuo
- Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Pei-Wei Shueng
- Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City 112, Taiwan
| | - Hui-Yen Chuang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei City 112, Taiwan;
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3
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Jackett KN, Browne AT, Aber ER, Clements M, Kaplan RN. How the bone microenvironment shapes the pre-metastatic niche and metastasis. NATURE CANCER 2024; 5:1800-1814. [PMID: 39672975 DOI: 10.1038/s43018-024-00854-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/04/2024] [Indexed: 12/15/2024]
Abstract
The bone is a frequent metastatic site, with changes in the mineralized bone and the bone marrow milieu that can also prime other sites for metastasis by educating progenitor cells to support metastatic spread. Stromal and immune populations cooperatively maintain the organizationally complex bone niches and are dysregulated in the presence of a distant primary tumor and metastatic disease. Interrogating the bone niches that facilitate metastatic spread using innovative technologies holds the potential to aid in preventing metastasis in and mediated by the bone. Here, we review recent advances in bone niche biology and its adaptations in the context of cancer.
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Affiliation(s)
- Kailey N Jackett
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Alice T Browne
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Etan R Aber
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Miranda Clements
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Rosandra N Kaplan
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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4
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Scimeca M, Giacobbi E, Servadei F, Palumbo V, Palumbo C, Finazzi-Agrò E, Albisinni S, Mauriello A, Albonici L. Prognostic Value of PlGF Upregulation in Prostate Cancer. Biomedicines 2024; 12:2194. [PMID: 39457506 PMCID: PMC11505493 DOI: 10.3390/biomedicines12102194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide, with metastasis, particularly to bone, being the primary cause of mortality. Currently, prognostic markers like PSA levels and Gleason classification are limited in predicting metastasis, emphasizing the need for novel clinical biomarkers. New molecules predicting tumor progression have been identified over time. Some, such as the immune checkpoint inhibitors (ICIs) PD-1/PD-L1, have become valid markers as theranostic tools essential for prognosis and drug target therapy. However, despite the success of ICIs as an anti-cancer therapy for solid tumors, their efficacy in treating bone metastases has mainly proven ineffective, suggesting intrinsic resistance to this therapy in the bone microenvironment. This study explores the potential of immunological intratumoral biomarkers, focusing on placental growth factor (PlGF), Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), and Programmed Cell Death Protein 1 (PD-1), in predicting bone metastasis formation. METHODS we analyzed PCa samples from patients with and without metastasis by immunohistochemical analysis. RESULTS Results revealed that PlGF expression is significantly higher in primary tumors of patients that developed metastasis within five years from the histological diagnosis. Additionally, PlGF expression correlates with increased VEGFR1 and PD-1 levels, as well as the presence of intratumoral M2 macrophages. CONCLUSIONS These findings suggest that PlGF contributes to an immunosuppressive environment, thus favoring tumor progression and metastatic process. Results here highlight the potential of integrating these molecular markers with existing prognostic tools to enhance the accuracy of metastasis prediction in PCa. By identifying patients at risk for metastasis, clinicians can tailor treatment strategies more effectively, potentially improving survival outcomes and quality of life. This study underscores the importance of further research into the role of intratumoral biomarkers in PCa management.
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Affiliation(s)
- Manuel Scimeca
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (E.G.); (F.S.); (V.P.); (A.M.)
| | - Erica Giacobbi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (E.G.); (F.S.); (V.P.); (A.M.)
| | - Francesca Servadei
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (E.G.); (F.S.); (V.P.); (A.M.)
| | - Valeria Palumbo
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (E.G.); (F.S.); (V.P.); (A.M.)
| | - Camilla Palumbo
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Enrico Finazzi-Agrò
- Unit of Urology, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, Italy; (E.F.-A.); (S.A.)
| | - Simone Albisinni
- Unit of Urology, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, Italy; (E.F.-A.); (S.A.)
| | - Alessandro Mauriello
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (E.G.); (F.S.); (V.P.); (A.M.)
| | - Loredana Albonici
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
- Department of Biomedical Sciences, “Our Lady of Good Counsel” University, Rruga Dritan Hoxha, 1000 Tirana, Albania
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5
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Li Y, Zheng Y, Tan X, Du Y, Wei Y, Liu S. Extracellular vesicle-mediated pre-metastatic niche formation via altering host microenvironments. Front Immunol 2024; 15:1367373. [PMID: 38495881 PMCID: PMC10940351 DOI: 10.3389/fimmu.2024.1367373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/23/2024] [Indexed: 03/19/2024] Open
Abstract
The disordered growth, invasion and metastasis of cancer are mainly attributed to bidirectional cell-cell interactions. Extracellular vesicles (EVs) secreted by cancer cells are involved in orchestrating the formation of pre-metastatic niches (PMNs). Tumor-derived EVs mediate bidirectional communication between tumor and stromal cells in local and distant microenvironments. EVs carrying mRNAs, small RNAs, microRNAs, DNA fragments, proteins and metabolites determine metastatic organotropism, enhance angiogenesis, modulate stroma cell phenotypes, restructure the extracellular matrix, induce immunosuppression and modify the metabolic environment of organs. Evidence indicates that EVs educate stromal cells in secondary sites to establish metastasis-supportive microenvironments for seeding tumor cells. In this review, we provide a comprehensive overview of PMN formation and the underlying mechanisms mediated by EVs. Potential approaches to inhibit cancer metastasis by inhibiting the formation of PMNs are also presented.
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Affiliation(s)
- Ying Li
- Department of Blood Transfusion, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yan Zheng
- Department of Operating Room, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaojie Tan
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yongxing Du
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingxin Wei
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
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6
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Cai R, Tressler CM, Cheng M, Sonkar K, Tan Z, Paidi SK, Ayyappan V, Barman I, Glunde K. Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs. Sci Rep 2023; 13:18566. [PMID: 37903851 PMCID: PMC10616170 DOI: 10.1038/s41598-023-45832-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 10/24/2023] [Indexed: 11/01/2023] Open
Abstract
The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing proteins involved in the ECM remodeling of the premetastatic niche. Our in vitro model consisted of lung fibroblasts, which were exposed to factors secreted by nonmalignant breast epithelial cells, nonmetastatic breast cancer cells, or metastatic breast cancer cells. We assessed ECM remodeling in vivo in premetastatic lungs of female mice growing orthotopic primary breast tumor xenografts, as compared to lungs of control mice without tumors. Premetastatic lungs contained significantly upregulated Collagen (Col) Col4A5, matrix metalloproteinases (MMPs) MMP9 and MMP14, and decreased levels of MMP13 and lysyl oxidase (LOX) as compared to control lungs. These in vivo findings were consistent with several of our in vitro cell culture findings, which showed elevated Col14A1, Col4A5, glypican-1 (GPC1) and decreased Col5A1 and Col15A1 for ECM structural proteins, increased MMP2, MMP3, and MMP14 for ECM degrading enzymes, and decreased LOX, LOXL2, and prolyl 4-hydroxylase alpha-1 (P4HA1) for ECM processing proteins in lung fibroblasts conditioned with metastatic breast cancer cell media as compared to control. Taken together, our data show that premetastatic priming of lungs by primary breast tumors resulted in significant ECM remodeling which could facilitate metastasis by increasing interstitial fibrillar collagens and ECM stiffness (Col14A1), disruptions of basement membranes (Col4A5), and formation of leaky blood vessels (MMP2, MMP3, MMP9, and MMP14) to promote metastasis.
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Affiliation(s)
- Ruoqing Cai
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA
| | - Caitlin M Tressler
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA
| | - Menglin Cheng
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA
| | - Kanchan Sonkar
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA
| | - Zheqiong Tan
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Santosh Kumar Paidi
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Vinay Ayyappan
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA
| | - Ishan Barman
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Kristine Glunde
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building, Room 203, Baltimore, MD, 21205, USA.
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Rosner M, Horer S, Feichtinger M, Hengstschläger M. Multipotent fetal stem cells in reproductive biology research. Stem Cell Res Ther 2023; 14:157. [PMID: 37287077 DOI: 10.1186/s13287-023-03379-4] [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: 01/06/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Abstract
Due to the limited accessibility of the in vivo situation, the scarcity of the human tissue, legal constraints, and ethical considerations, the underlying molecular mechanisms of disorders, such as preeclampsia, the pathological consequences of fetomaternal microchimerism, or infertility, are still not fully understood. And although substantial progress has already been made, the therapeutic strategies for reproductive system diseases are still facing limitations. In the recent years, it became more and more evident that stem cells are powerful tools for basic research in human reproduction and stem cell-based approaches moved into the center of endeavors to establish new clinical concepts. Multipotent fetal stem cells derived from the amniotic fluid, amniotic membrane, chorion leave, Wharton´s jelly, or placenta came to the fore because they are easy to acquire, are not associated with ethical concerns or covered by strict legal restrictions, and can be banked for autologous utilization later in life. Compared to adult stem cells, they exhibit a significantly higher differentiation potential and are much easier to propagate in vitro. Compared to pluripotent stem cells, they harbor less mutations, are not tumorigenic, and exhibit low immunogenicity. Studies on multipotent fetal stem cells can be invaluable to gain knowledge on the development of dysfunctional fetal cell types, to characterize the fetal stem cells migrating into the body of a pregnant woman in the context of fetomaternal microchimerism, and to obtain a more comprehensive picture of germ cell development in the course of in vitro differentiation experiments. The in vivo transplantation of fetal stem cells or their paracrine factors can mediate therapeutic effects in preeclampsia and can restore reproductive organ functions. Together with the use of fetal stem cell-derived gametes, such strategies could once help individuals, who do not develop functional gametes, to conceive genetically related children. Although there is still a long way to go, these developments regarding the usage of multipotent fetal stem cells in the clinic should continuously be accompanied by a wide and detailed ethical discussion.
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Affiliation(s)
- Margit Rosner
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | - Stefanie Horer
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | | | - Markus Hengstschläger
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
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8
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Burciaga-Hernandez LA, Cueto-Villalobos CF, Ortega-Piñon N, Gonzalez-Curiel IE, Godina-Gonzalez S, Mendez-Frausto G, Aguilar-Esquivel AP, Maldonado-Lagunas V, Guerrero-de la Torre LE, Melendez-Zajgla J, Sanchez-Garcia EK, Mitre-Aguilar IB, Mendoza-Almanza G. Gene Expression Behavior of a Set of Genes in Platelet and Tissue Samples from Patients with Breast Cancer. Int J Mol Sci 2023; 24:ijms24098348. [PMID: 37176055 PMCID: PMC10179257 DOI: 10.3390/ijms24098348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
The tumor microenvironment (TME) is constituted by a great diversity of highly dynamic cell populations, each of which contributes ligands, receptors, soluble proteins, mRNAs, and miRNAs, in order to regulate cellular activities within the TME and even promote processes such as angiogenesis or metastasis. Intravasated platelets (PLT) undergo changes in the TME that convert them into tumor-educated platelets (TEP), which supports the development of cancer, angiogenesis, and metastasis through the degranulation and release of biomolecules. Several authors have reported that the deregulation of PF4, VEGF, PDGF, ANG-1, WASF3, LAPTM4B, TPM3, and TAC1 genes participates in breast cancer progression, angiogenesis, and metastasis. The present work aimed to analyze the expression levels of this set of genes in tumor tissues and platelets derived from breast cancer patients by reverse transcription-quantitative polymerase chain reaction (RTqPCR) assays, in order to determine if there was an expression correlation between these sources and to take advantage of the new information to be used in possible diagnosis by liquid biopsy. Data from these assays showed that platelets and breast cancer tumors present similar expression levels of a subset of these genes' mRNAs, depending on the molecular subtype, comorbidities, and metastasis presence.
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Affiliation(s)
- Luis A Burciaga-Hernandez
- Maestría en Ciencias Biomédicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
- Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Zacatecas 98068, Mexico
| | | | - Nancy Ortega-Piñon
- Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Zacatecas 98068, Mexico
| | - Irma E Gonzalez-Curiel
- Laboratorio de InmunotoxicologÍa y Terapéutica Experimental, Unidad Académica de Ciencias QuÍmicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
| | - Susana Godina-Gonzalez
- Laboratorio de Biomarcadores, Unidad Académica de Ciencias QuÍmicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
| | - Gwendolyne Mendez-Frausto
- Laboratorio de InmunotoxicologÍa y Terapéutica Experimental, Unidad Académica de Ciencias QuÍmicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
| | | | - Vilma Maldonado-Lagunas
- Laboratorio de Epigenetica, Instituto Nacional de Medicina Genomica (INMEGEN), Ciudad de México 14610, Mexico
| | - Luis E Guerrero-de la Torre
- Maestría en Ciencias Biomédicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
- Hospital General Zacatecas "Luz González Cosío", Zacatecas 98160, Mexico
| | - Jorge Melendez-Zajgla
- Laboratorio de Genomica Funcional del Cancer, Instituto Nacional de Medicina Genomica (INMEGEN), Ciudad de México 14610, Mexico
| | - Erika K Sanchez-Garcia
- Laboratorio de Epigenetica, Instituto Nacional de Medicina Genomica (INMEGEN), Ciudad de México 14610, Mexico
| | - Irma B Mitre-Aguilar
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran (INCMNSZ), Ciudad de México 14080, Mexico
| | - Gretel Mendoza-Almanza
- Maestría en Ciencias Biomédicas, Universidad Autónoma de Zacatecas, Zacatecas 98160, Mexico
- Laboratorio de Epigenetica, Instituto Nacional de Medicina Genomica (INMEGEN), Ciudad de México 14610, Mexico
- Consejo Nacional de Ciencia y Tecnología, Ciudad de México 03940, Mexico
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9
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Organotropism of breast cancer metastasis: A comprehensive approach to the shared gene network. GENE REPORTS 2023. [DOI: 10.1016/j.genrep.2023.101749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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10
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Liu C, Mohan SC, Wei J, Seki E, Liu M, Basho R, Giuliano AE, Zhao Y, Cui X. Breast cancer liver metastasis: Pathogenesis and clinical implications. Front Oncol 2022; 12:1043771. [PMID: 36387238 PMCID: PMC9641291 DOI: 10.3389/fonc.2022.1043771] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/04/2022] [Indexed: 09/30/2023] Open
Abstract
Breast cancer is the most common malignant disease in female patients worldwide and can spread to almost every place in the human body, most frequently metastasizing to lymph nodes, bones, lungs, liver and brain. The liver is a common metastatic location for solid cancers as a whole, and it is also the third most common metastatic site for breast cancer. Breast cancer liver metastasis (BCLM) is a complex process. Although the hepatic microenvironment and liver sinusoidal structure are crucial factors for the initial arrest of breast cancer and progression within the liver, the biological basis of BCLM remains to be elucidated. Importantly, further understanding of the interaction between breast cancer cells and hepatic microenvironment in the liver metastasis of breast cancer will suggest ways for the development of effective therapy and prevention strategies for BCLM. In this review, we provide an overview of the recent advances in the understanding of the molecular mechanisms of the hepatic microenvironment in BCLM formation and discuss current systemic therapies for treating patients with BCLM as well as potential therapeutic development based on the liver microenvironment-associated signaling proteins governing BCLM.
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Affiliation(s)
- Cuiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Srivarshini C. Mohan
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Jielin Wei
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ekihiro Seki
- Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Manran Liu
- Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Reva Basho
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- The Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA, United States
| | - Armando E. Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yanxia Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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11
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Abstract
Organ-specific metastasis to secondary organs is dependent on the formation of a supportive pre-metastatic niche. This tissue-specific microenvironmental response is thought to be mediated by mutational and epigenetic changes to primary tumour cells resulting in altered cross-talk between cell types. This response is augmented through the release of tumour and stromal signalling mediators including cytokines, chemokines, exosomes and growth factors. Although researchers have elucidated some of the cancer-promoting features that are bespoke to organotropic metastasis to the lungs, it remains unclear if these are organ-specific or generic between organs. Understanding the mechanisms that mediate the metastasis-promoting synergy between the host microenvironment, immunity, and pulmonary structures may elucidate predictive, prognostic and therapeutic markers that could be targeted to reduce the metastatic burden of disease. Herein, we give an updated summary of the known cellular and molecular mechanisms that contribute to the formation of the lung pre-metastatic niche and tissue-specific metastasis.
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Affiliation(s)
- Oliver Cucanic
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
| | - Rae H Farnsworth
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
| | - Steven A Stacker
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
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12
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Tu S, Mao D, Shi M, Zhang H, Liu C, Li X, Zhao Y, Chen Y, Liu Y. Icaritin ameliorates extracellular microparticles‐induced inflammatory pre‐metastatic niche via modulating the
cGAS‐STING
signaling. Phytother Res 2022; 36:2127-2142. [PMID: 35257426 DOI: 10.1002/ptr.7433] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/27/2021] [Accepted: 11/18/2021] [Indexed: 11/09/2022]
Affiliation(s)
- Shumei Tu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Dengxuan Mao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Mengxin Shi
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Huangqin Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Congyan Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Xiaoqi Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Yang Zhao
- Department of Biochemistry and Molecular Biology School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine Nanjing China
| | - Yan Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Yuping Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
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Rosner M, Hengstschläger M. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:26-34. [PMID: 35641164 PMCID: PMC8895487 DOI: 10.1093/stcltm/szab003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/12/2021] [Indexed: 12/03/2022] Open
Abstract
It is the hope of clinicians and patients alike that stem cell-based therapeutic products will increasingly become applicable remedies for many diseases and injuries. Whereas some multipotent stem cells are already routinely used in regenerative medicine, the efficacious and safe clinical translation of pluripotent stem cells is still hampered by their inherent immunogenicity and tumorigenicity. In addition, stem cells harbor the paracrine potential to affect the behavior of cells in their microenvironment. On the one hand, this property can mediate advantageous supportive effects on the overall therapeutic concept. However, in the last years, it became evident that both, multipotent and pluripotent stem cells, are capable of inducing adjacent cells to become motile. Not only in the context of tumor development but generally, deregulated mobilization and uncontrolled navigation of patient’s cells can have deleterious consequences for the therapeutic outcome. A more comprehensive understanding of this ubiquitous stem cell feature could allow its proper clinical handling and could thereby constitute an important building block for the further development of safe therapies.
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Affiliation(s)
- Margit Rosner
- Institute of Medical Genetics, Center of Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Markus Hengstschläger
- Institute of Medical Genetics, Center of Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
- Corresponding author: Markus Hengstschläger, PhD, Professor, Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090 Vienna, Austria. Tel: +43 1 40160 56500; Fax: +43 1 40160 956501;
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Yang Y, Tang F, Zhao X. miR-27b-3p is highly expressed in serum of patients with preeclampsia and has clinical significance. Endocr Metab Immune Disord Drug Targets 2021; 22:612-619. [PMID: 34879814 DOI: 10.2174/1871530321666211208152709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/04/2021] [Accepted: 10/20/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Preeclampsia (PE) is defined as a salient complication of late pregnancy. microRNAs (miRNAs) have emerged as critical biological regulators in PE. This study determined miR-27b-3p expression in serum of PE patients and investigated its clinical significance in PE. METHODS Totally 130 pregnant women including 90 PE patients (51 mild PE and 39 severe PE) and 40 healthy controls were enrolled in this study. miR-27b-3p expression in the serum of PE patients and healthy controls was detected using RT-qPCR. The correlation among miR-27b-3p expression and 24-h urine protein, systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine, and fetal birth weight was analyzed using Pearson's correlation coefficient. The targeting relationship between miR-27b-3p and PPARG was verified. PPARG protein level in PE patients was detected using ELISA kits. The predictive efficiency of miR-27b-3p and PPARG in PE was analyzed using the receiver operating characteristic (ROC) curve. RESULTS Compared to normal pregnant women, PE pregnant women, especially severe PE patients had higher miR-27b-3p expression. miR-27b-3p was positively correlated with 24-h urine protein, SBP, DBP, and serum creatinine, but negatively correlated with fetal birth weight. PPARG was poorly expressed in PE patients and negatively correlated with miR-27b-3p. ROC curve showed that both miR-27b-3p and PPARG had good predictive efficacy on PE. CONCLUSION miR-27b-3p expression in serum of pregnant women with PE was positively correlated with the severity of PE symptoms, suggesting the involvement of miR-27b-3p in PE occurrence.
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Affiliation(s)
- Yang Yang
- Obstetrics department，ShuLan(hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou City, Zhejiang. China
| | - Fang Tang
- Medical Affairs, Hospital of Obstetrics and Gynecology affiliated to Medical college of zhejiang University, Hangzhou City, Zhejiang. China
| | - Xuezhi Zhao
- Gynecology department, Hospital of Obstetrics and Gynecology affiliated to Medical college of zhejiang University, Hangzhou City, Zhejiang, 310000. China
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15
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Jia H, Wang X, Liu W, Qin X, Hu B, Ma Q, Lv C, Lu J. Cimicifuga dahurica extract inhibits the proliferation, migration and invasion of breast cancer cells MDA-MB-231 and MCF-7 in vitro and in vivo. JOURNAL OF ETHNOPHARMACOLOGY 2021; 277:114057. [PMID: 33771643 DOI: 10.1016/j.jep.2021.114057] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/20/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cimicifuga dahurica (Turcz.) Maxim (C. dahurica) has a long history of treating breast cancer. From the Qing Dynasty to the Tang Dynasty and even earlier, C. dahurica has been documented in the treatment of breast carbuncle (Breast cancer is classified as breast carbuncle in Chinese medicine). In traditional prescriptions such as "Sheng Ge Decoction", "Sheng Ma Powder" and "Breast Carbuncle Pill", as the main medicine, C. dahurica plays an important role. At present, the systematic studies on the in vitro and in vivo effects of Cimicifuga against breast cancer are rare, especially the C. dahurica. AIM OF THE STUDY In this article, we evaluated the in vitro activity and in vivo effects of CREE (extract of the root of C. dahurica) against breast cancer, and discussed the possible mechanism of CREE in promoting breast cancer cell apoptosis. MATERIALS AND METHODS The main component in the CREE was analyzed by HPLC. The effects of CREE on the proliferation, migration and invasion of human breast cancer cells were evaluated through SRB, colony assay, LDH release, wound healing and transwell assay. The pro-apoptotic effect of CREE was investigated in Hochest33342 and Annexin V-FITC/PI assay. To verify the results of CREE in vivo effects, we applied nude mice subcutaneous xenograft experiments. The possible mechanism of CREE treating breast cancer was investigated through mitochondrial membrane potential and western blot experiments. RESULTS CREE contains cycloartane triterpene saponins. CREE can significantly inhibit the proliferation, migration and invasion of human breast cancer MCF-7 and MDA-MB-231 cells in vitro and it can effectively inhibit the growth of MDA-MB-231 cell subcutaneous tumors in vivo. Besides, we also found that CREE up-regulated the expression levels of Bax, caspase-9/3 and cytochrome C, and down-regulated the expression of Bcl-2. Therefore, regulation of the mitochondrial pathway may be one of the mechanisms by which CREE promotes breast cancer cell apoptosis. CONCLUSIONS CREE exhibits sufficient anti-breast cancer activity in vivo and in vitro, this study provides persuasive evidence for the further research and development of C. dahurica.
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Affiliation(s)
- Hui Jia
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China.
| | - Xinying Wang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China.
| | - Wenwu Liu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China.
| | - Xiaochun Qin
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Bei Hu
- Department of Pharmacy, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang City, 110840, Liaoning Province, China.
| | - Qun Ma
- Department of Pharmacy, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang City, 110840, Liaoning Province, China.
| | - Chongning Lv
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China.
| | - Jincai Lu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China; Liaoning Provincial Key Laboratory of TCM Resources Conservation and Development, Shenyang Pharmaceutical University, Shenyang, 110006, PR China.
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16
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Jia H, Liu M, Wang X, Jiang Q, Wang S, Santhanam RK, Lv C, Zhao Q, Lu J. Cimigenoside functions as a novel γ-secretase inhibitor and inhibits the proliferation or metastasis of human breast cancer cells by γ-secretase/Notch axis. Pharmacol Res 2021; 169:105686. [PMID: 34022397 DOI: 10.1016/j.phrs.2021.105686] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/11/2021] [Accepted: 05/17/2021] [Indexed: 12/14/2022]
Abstract
Breast cancer (BC) occurrence and development tremendously affect female health. Currently breast cancer targeted drugs are still scarce. Natural products have become the main source of targeted drug for breast cancer due to low toxicity and high efficiency. Cimigenoside, natural compound isolated and purified from Cimicifuga dahurica (Turcz.) Maxim has been suggested to utilize for breast cancer treatment, however the mechanism of action has not been elucidated yet. In this article, the antitumor potential of Cimigenoside against breast cancer in vitro and in vivo study. Moreover, we further predicted the possible binding mode of Cimigenoside with γ-secretase through molecular docking studies. The results show that Cimigenoside has a significant inhibitory effect towards the proliferation or metastasis of breast cancer cells via suppressing the Notch signaling pathway-mediated mitochondrial apoptosis and EMT (epithelial mesenchymal transition). In terms of mechanism, Cimigenoside could inhibit the activation of PSEN-1, the catalytic subunit of γ-secretase, and also by cleaving the Notch protein mediated by PSEN-1. Overall, our findings provide scientific support to utilize Cimigenoside as an effective targeted drug for clinical treatment of BC.
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Affiliation(s)
- Hui Jia
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110006, PR China.
| | - Mingyue Liu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
| | - Xinying Wang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110006, PR China.
| | - Qiyu Jiang
- Center for Clinical Laboratory, The Fifth Medical Center, General Hospital of Chinese PLA, Beijing 100039, PR China.
| | - Shu Wang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
| | - Ramesh Kumar Santhanam
- Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, Kuala Nerus 21030, Terengganu, Malaysia.
| | - Chongning Lv
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110006, PR China.
| | - Qingchun Zhao
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Department of Pharmacy, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang 110840, Liaoning, PR China.
| | - Jincai Lu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110006, PR China; Liaoning Provincial Key Laboratory of TCM Resources Conservation and Development, Shenyang Pharmaceutical University, Shenyang 110006, PR China.
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17
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Du Y, Shi X, Ma W, Wen P, Yu P, Wang X, Fang P, Chen A, Gao Z, Cui K. Phthalates promote the invasion of hepatocellular carcinoma cells by enhancing the interaction between Pregnane X receptor and E26 transformation specific sequence 1. Pharmacol Res 2021; 169:105648. [PMID: 33965509 DOI: 10.1016/j.phrs.2021.105648] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/02/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023]
Abstract
Phthalates (PAEs) are considered endocrine-disrupting chemicals (EDCs), a series of compounds able to disrupt the normal regulation of the human endocrine-system. In the present study, we investigated the roles of four PAEs, butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), dimethyl phthalate (DMP), and diethyl phthalate (DEP), in hepatocellular carcinoma (HCC) cells. We define novel roles for the PAEs on the migration of HCC cells via their enhancing of the interaction between the pregnane X receptor (PXR) and E26 transformation specific sequence 1 (ETS-1). Our results indicate that PAEs induced the transcriptional activation of ETS-1 and PXR. PXR activated by PAEs could bind to ETS-1 directly and enhanced the activity of ETS-1, which resulted in the induction of invasion-related ETS-1 target genes. The "LXXLL" motif in the ETS-1C-terminal was essential for the interaction between PXR and ETS-1 induced by PAEs. Treatment of PAEs promoted the nuclear accumulation of ETS-1 or the recruitment of ETS-1, but not in cells expressing ETS-1 with a mutated LXXLL motif in its downstream gene promoter region, or following transfection of PXR siRNA. Treatment with the PXR antagonist ketoconazole almost completely inhibited the effects of PAEs. Moreover, PAEs enhanced the in vitro or in vivo invasion of HCC cells via PXR/ETS-1. Therefore, our results not only contribute to a better understanding of HCC, but also extended the roles of EDCs regulating human malignancies.
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Affiliation(s)
- Yabing Du
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Xiaoyi Shi
- Department of Hepatobiliary and Pancreatic Surgery/Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities/ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Wang Ma
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Peihao Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Pu Yu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Xin Wang
- School of Environmental Science and Engineering, Chang'an University, Xi'an 710064, Shaanxi Province, PR China.
| | - Pengli Fang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Aixia Chen
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Zhiqiang Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
| | - Kang Cui
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
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Elucidation of underlying molecular mechanism of 5-Fluorouracil chemoresistance and its restoration using fish oil in experimental colon carcinoma. Mol Cell Biochem 2021; 476:1517-1527. [PMID: 33392922 DOI: 10.1007/s11010-020-03999-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/20/2020] [Indexed: 02/07/2023]
Abstract
Latest strategies for cancer treatment primarily focus on the use of chemosensitizers to enhance therapeutic outcome. N-3 PUFAs have emerged as the strongest candidate for the prevention of colorectal cancer (CRC). Our previous studies have demonstrated that fish oil (FO) rich in n-3 PUFAs not only increased therapeutic potential of 5-Fluorouracil(5-FU) in colon cancer but also ameliorated its toxicity. Henceforth, the present study is designed to elucidate mechanistic insights of FO as a chemosensitizer to circumvent drug resistance in experimental colon carcinoma. The colon cancer was induced by 1,2-dimethylhydrazine(DMH)/dextran sulfate sodium(DSS) in male Balb/c mice and these animals were treated with 5-FU(12.5 mg/kg b.w.), FO(0.2 ml), or 5-FU + FO(12.5 mg/kg b.w + 0.2 ml) orally for 14 days. The molecular mechanism of overcoming 5-FU resistance using FO in colon cancer was delineated by estimating expression of cancer stem cell markers using flowcytometric method and drug transporters by immunohistochemistry and immunoblotting. Additionally, distribution profile of 5-FU and its cytotoxic metabolite, 5-FdUMP at target(colon), and non-target sites (serum, kidney, liver, spleen) was assessed using high-performance liquid chromatography(HPLC) method. The observations revealed that expression of CSCs markers was remarkably reduced after using fish oil along with 5-FU in carcinogen-treated animals. Interestingly, the use of FO alongwith 5-FU also significantly declined the expression of drug transporters (ABCB1,ABCC5) and consequently resulted in an increased cellular uptake of 5-FU and its metabolite, 5-FdUMP at target site (colon). It could be possibly associated with change in permeability of cell membrane owing to the alteration in membrane fluidity. The present study revealed the mechanistic insights of FO as a MDR revertant which successfully restored 5-FU-mediated chemoresistance in experimental colon carcinoma.
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Mendoza-Almanza G, Burciaga-Hernández L, Maldonado V, Melendez-Zajgla J, Olmos J. Role of platelets and breast cancer stem cells in metastasis. World J Stem Cells 2020; 12:1237-1254. [PMID: 33312396 PMCID: PMC7705471 DOI: 10.4252/wjsc.v12.i11.1237] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/23/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.
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Affiliation(s)
| | | | - Vilma Maldonado
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Melendez-Zajgla
- Génómica funcional del cáncer, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Olmos
- Biotecnología Marina, Centro de Investigación Científica y de Estudios Superiores de Ensenada, Ensenada 22860, Mexico
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Imaging Early-Stage Metastases Using an 18F-Labeled VEGFR-1-Specific Single Chain VEGF Mutant. Mol Imaging Biol 2020; 23:340-349. [PMID: 33156495 DOI: 10.1007/s11307-020-01555-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/11/2020] [Accepted: 10/13/2020] [Indexed: 12/26/2022]
Abstract
PURPOSE Metastatic breast cancer is the second leading cause of cancer-related death in women. The 5-year survival rate for metastatic breast cancer has remained near 26.9 % for over a decade. The recruitment of hematopoietic stem cells with high expression of the vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in early stages of metastasis formation. We propose the use of an 18F-labeled single-chain version of VEGF121, re-engineered to be selective for VEGFR-1 (scVR1), as a positron emission tomography (PET) imaging agent to non-invasively image early-stage metastases. PROCEDURES scVR1 was 18F-labeled via a biorthogonal click reaction between site-specifically trans-cyclooctene functionalized scVR1 and an Al18F labeled tetrazine-NODA (1,4,7-triazacyclononane-1,4-diiacetic acid). The [18F]AlF-NODA-scVR1 was purified using a PD10 column and subsequently analyzed on HPLC to determine radiochemical purity. Animal experiments were performed in 6-8-week-old female BALB/c mice bearing orthotopic primary 4T1 breast tumors or 4T1 metastatic lesions. The [18F]AlF-NODA-scVR1 tracer was administered via tail vein injection; PET imaging and ex vivo analysis was performed 2 h post-injection. RESULTS The [18F]AlF-NODA-scVR1 was prepared with a 98.2 ± 1.5 % radiochemical purity and an apparent molar activity of 7.5 ± 1.2 GBq/μmol. The specific binding of scVR1 to VEGFR-1 was confirmed via bead-based assay. The ex vivo biodistribution showed tumor uptake of 3.5 ± 0.5 % ID/g and was readily observable in PET images. Metastasis formation was detected with [18F]AlF-NODA-scVR1 tracer showing colocalization with bioluminescent imaging as well as ex vivo autoradiography and immunofluorescent staining of VEGFR-1. CONCLUSIONS The diagnostic capabilities of the [18F]AlF-NODA-scVR1 PET tracer was confirmed in both orthotopic and metastatic murine cancer models. These results support the potential use of [18F]AlF-NODA-scVR1 as a PET tracer that could image metastases, providing clinicians with an additional tool to assess a patient's need for adjuvant therapies.
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Lacal PM, Atzori MG, Ruffini F, Scimeca M, Bonanno E, Cicconi R, Mattei M, Bernardini R, D'Atri S, Tentori L, Graziani G. Targeting the vascular endothelial growth factor receptor-1 by the monoclonal antibody D16F7 to increase the activity of immune checkpoint inhibitors against cutaneous melanoma. Pharmacol Res 2020; 159:104957. [PMID: 32485280 DOI: 10.1016/j.phrs.2020.104957] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/01/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023]
Abstract
The vascular endothelial growth factor receptor-1 (VEGFR-1) is a membrane receptor for VEGF-A, placenta growth factor (PlGF) and VEGF-B that plays a crucial role in melanoma invasiveness, vasculogenic mimicry and tumor-associated angiogenesis. Furthermore, activation of VEGFR-1 is involved in the mobilization of myeloid progenitors from the bone marrow that infiltrate the tumor. Myeloid-derived suppressor cells and tumor-associated macrophages have been involved in tumor progression and resistance to cancer treatment with immune checkpoint inhibitors (ICIs). We have recently demonstrated that the anti-VEGFR-1 monoclonal antibody (mAb) D16F7 developed in our laboratories is able to inhibit melanoma growth in preclinical in vivo models and to reduce monocyte/macrophage progenitor mobilization and tumor infiltration by myeloid cells. Aim of the study was to investigate whether the anti-VEGFR-1 mAb D16F7 affects the activity of protumoral M2 macrophages in vitro in response to PlGF and inhibits the recruitment of these cells to the melanoma site in vivo. Finally, we tested whether, through its multi-targeted action, D16F7 mAb might increase the efficacy of ICIs against melanoma. The results indicated that VEGFR-1 expression is up-regulated in human activated M2 macrophages compared to activated M1 cells and exposure to the D16F7 mAb decreases in vitro chemotaxis of activated M2 macrophages. In vivo treatment with the anti-VEGFR-1 mAb D16F7 of B6D2F1 mice injected with syngeneic B16F10 melanoma cells resulted in tumor growth inhibition associated with the modification of tumor microenvironment that involves a decrease of melanoma infiltration by M2 macrophages and PD-1+ and FoxP3+ cells. These alterations result in increased M1/M2 and CD8+/FoxP3+ ratios, which favor an antitumor and immunostimulating milieu. Accordingly, D16F7 mAb increased the antitumor activity of the ICIs anti-CTLA-4 and anti-PD-1 mAbs. Overall, these data reinforce the role of VEGFR-1-mediated-signalling as a valid target for reducing tumor infiltration by protumoral macrophages and for improving the efficacy of immunotherapy with ICIs.
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Affiliation(s)
- Pedro Miguel Lacal
- Laboratory of Molecular Oncology, IDI-IRCCS, Via Monti di Creta 104, 00167, Rome, Italy
| | - Maria Grazia Atzori
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Federica Ruffini
- Laboratory of Molecular Oncology, IDI-IRCCS, Via Monti di Creta 104, 00167, Rome, Italy
| | - Manuel Scimeca
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy; Fondazione Umberto Veronesi (FUV), Piazza Velasca 5, 20122, Milan, Italy; Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy
| | - Elena Bonanno
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy
| | - Rosella Cicconi
- "Centro di Servizi Interdipartimentale - Stazione per la Tecnologia Animale", University of Rome Tor Vergata, Italy
| | - Maurizio Mattei
- "Centro di Servizi Interdipartimentale - Stazione per la Tecnologia Animale", University of Rome Tor Vergata, Italy; Department of Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Roberta Bernardini
- "Centro di Servizi Interdipartimentale - Stazione per la Tecnologia Animale", University of Rome Tor Vergata, Italy
| | - Stefania D'Atri
- Laboratory of Molecular Oncology, IDI-IRCCS, Via Monti di Creta 104, 00167, Rome, Italy
| | - Lucio Tentori
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
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Zheng Y, Wang N, Wang S, Yang B, Situ H, Zhong L, Lin Y, Wang Z. XIAOPI formula inhibits the pre-metastatic niche formation in breast cancer via suppressing TAMs/CXCL1 signaling. Cell Commun Signal 2020; 18:48. [PMID: 32213179 PMCID: PMC7098160 DOI: 10.1186/s12964-020-0520-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 01/29/2020] [Indexed: 02/07/2023] Open
Abstract
Background Recent findings suggested that premetastatic niche (PMN) is a prerequisite in mediating cancer metastasis. Previously we demonstrated that XIAOPI formula could inhibit breast cancer lung metastasis via inhibiting tumor associated macrophages (TAMs)-secreted CXCL1. Herein, we aimed to explore the effects of XIAOPI formula on preventing breast cancer PMN formation and its underlying molecular mechanisms. Methods CXCL1 expression of TAMs was detected by qPCR and Western blotting assay. The influences of XIAOPI formula on the proliferation of TAMs and 4 T1 in the co-culture system were tested by CCK8 or EdU staining. Transwell experiment was applied to determine the effects of XIAOPI formula on the invasion ability of HSPCs and 4 T1. Breast cancer xenografts were built by inoculating 4 T1 cells into the mammary pads of Balb/c mice and lung metastasis was monitored by luciferase imaging. Immune fluorescence assay was used to test the epithelial-mesenchymal transition process and PMN formation in the lung tissues. The effects of XIAOPI formula on TAMs phenotype, hematopoietic stem/progenitor cells (HSPCs) and myeloid-derived suppressor cells (MDSCs) were determined by flow cytometry. Results It was found that XIAOPI formula could inhibit the proliferation and polarization of M2 phenotype macrophages, and reduce CXCL1 expression in a dose-dependent manner. However, M1 phenotype macrophages were not significantly affected by XIAOPI formula. TAMs/CXCL1 signaling was subsequently found to stimulate the recruitment of c-Kit+/Sca-1+ HSPCs and their differentiation into CD11b+/Gr-1+ MDSCs, which were symbolic events accounting for PMN formation. Moreover, XIAOPI formula was effective in inhibiting HSPCs activation and suppressing the proliferation and metastasis of breast cancer cells 4 T1 induced by HSPCs and TAMs co-culture system, implying that XIAOPI was effective in preventing PMN formation in vitro. Breast cancer xenograft experiments further demonstrated that XIAOPI formula could inhibit breast cancer PMN formation and subsequent lung metastasis in vivo. The populations of HSPCs in the bone marrow and MDSCs in the lung tissues were all remarkably declined by XIAOPI formula treatment. However, the inhibitory effects of XIAOPI formula could be relieved by CXCL1 overexpression in the TAMs. Conclusions Taken together, our study provided preclinical evidence supporting the application of XIAOPI formula in preventing breast cancer PMN formation, and highlighted TAMs/CXCL1 as a potential therapeutic strategy for PMN targeting therapy.
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