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Winnard PT, Vesuna F, Bol GM, Gabrielson KL, Chenevix-Trench G, Ter Hoeve ND, van Diest PJ, Raman V. Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment. Cancer Lett 2024; 604:217260. [PMID: 39306228 DOI: 10.1016/j.canlet.2024.217260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 10/03/2024]
Abstract
Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.
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Affiliation(s)
- Paul T Winnard
- Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Farhad Vesuna
- Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Guus M Bol
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Medical Oncology, University Medical Center Utrecht Cancer Center, GA, Utrecht, the Netherlands
| | - Kathleen L Gabrielson
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Georgia Chenevix-Trench
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4029, Australia
| | - Natalie D Ter Hoeve
- Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, the Netherlands
| | - Paul J van Diest
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, the Netherlands
| | - Venu Raman
- Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, the Netherlands; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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2
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Otterlei Fjørtoft M, Huse K, Rye IH. The Tumor Immune Microenvironment in Breast Cancer Progression. Acta Oncol 2024; 63:359-367. [PMID: 38779867 PMCID: PMC11332517 DOI: 10.2340/1651-226x.2024.33008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/12/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND The tumor microenvironment significantly influences breast cancer development, progression, and metastasis. Various immune cell populations, including T cells, B cells, NK cells, and myeloid cells exhibit diverse functions in different breast cancer subtypes, contributing to both anti-tumor and pro-tumor activities. PURPOSE This review provides an overview of the predominant immune cell populations in breast cancer subtypes, elucidating their suppressive and prognostic effects. We aim to outline the role of the immune microenvironment from normal breast tissue to invasive cancer and distant metastasis. METHODS A comprehensive literature review was conducted to analyze the involvement of immune cells throughout breast cancer progression. RESULTS In breast cancer, tumors exhibit increased immune cell infiltration compared to normal tissue. Variations exist across subtypes, with higher levels observed in triple-negative and HER2+ tumors are linked to better survival. In contrast, ER+ tumors display lower immune infiltration, associated with poorer outcomes. Furthermore, metastatic sites commonly exhibit a more immunosuppressive microenvironment. CONCLUSION Understanding the complex interaction between tumor and immune cells during breast cancer progression is essential for future research and the development of immune-based strategies. This comprehensive understanding may pave the way for more effective treatment approaches and improved patients outcomes.
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Affiliation(s)
- Marit Otterlei Fjørtoft
- Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Oslo University Hospital, Radium Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kanutte Huse
- Department of Cancer Immunology, Institute for Cancer Research, Division of Cancer Medicine, Oslo University Hospital, Radium Hospital, Oslo, Norway
| | - Inga Hansine Rye
- Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Oslo University Hospital, Radium Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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3
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Liu R, Zhao Y, Su S, Kwabil A, Njoku PC, Yu H, Li X. Unveiling cancer dormancy: Intrinsic mechanisms and extrinsic forces. Cancer Lett 2024; 591:216899. [PMID: 38649107 DOI: 10.1016/j.canlet.2024.216899] [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: 03/19/2024] [Revised: 04/06/2024] [Accepted: 04/12/2024] [Indexed: 04/25/2024]
Abstract
Tumor cells disseminate in various distant organs at early stages of cancer progression. These disseminated tumor cells (DTCs) can stay dormant/quiescent without causing patient symptoms for years or decades. These dormant tumor cells survive despite curative treatments by entering growth arrest, escaping immune surveillance, and/or developing drug resistance. However, these dormant cells can reactivate to proliferate, causing metastatic progression and/or relapse, posing a threat to patients' survival. It's unclear how cancer cells maintain dormancy and what triggers their reactivation. What are better approaches to prevent metastatic progression and relapse through harnessing cancer dormancy? To answer these remaining questions, we reviewed the studies of tumor dormancy and reactivation in various types of cancer using different model systems, including the brief history of dormancy studies, the intrinsic characteristics of dormant cells, and the external cues at the cellular and molecular levels. Furthermore, we discussed future directions in the field and the strategies for manipulating dormancy to prevent metastatic progression and recurrence.
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Affiliation(s)
- Ruihua Liu
- School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, 010070, China; Department of Cell and Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, 43614, USA
| | - Yawei Zhao
- Department of Cell and Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, 43614, USA
| | - Shang Su
- Department of Cell and Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, 43614, USA
| | - Augustine Kwabil
- Department of Cell and Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, 43614, USA
| | - Prisca Chinonso Njoku
- Department of Cell and Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, 43614, USA
| | - Haiquan Yu
- School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, 010070, China.
| | - Xiaohong Li
- Department of Cell and Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, 43614, USA.
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4
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Richbourg NR, Irakoze N, Kim H, Peyton SR. Outlook and opportunities for engineered environments of breast cancer dormancy. SCIENCE ADVANCES 2024; 10:eadl0165. [PMID: 38457510 PMCID: PMC10923521 DOI: 10.1126/sciadv.adl0165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 02/01/2024] [Indexed: 03/10/2024]
Abstract
Dormant, disseminated breast cancer cells resist treatment and may relapse into malignant metastases after decades of quiescence. Identifying how and why these dormant breast cancer cells are triggered into outgrowth is a key unsolved step in treating latent, metastatic breast cancer. However, our understanding of breast cancer dormancy in vivo is limited by technical challenges and ethical concerns with triggering the activation of dormant breast cancer. In vitro models avoid many of these challenges by simulating breast cancer dormancy and activation in well-controlled, bench-top conditions, creating opportunities for fundamental insights into breast cancer biology that complement what can be achieved through animal and clinical studies. In this review, we address clinical and preclinical approaches to treating breast cancer dormancy, how precisely controlled artificial environments reveal key interactions that regulate breast cancer dormancy, and how future generations of biomaterials could answer further questions about breast cancer dormancy.
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Affiliation(s)
- Nathan R. Richbourg
- Department of Chemical Engineering, University of Massachusetts Amherst, MA 01003, USA
| | - Ninette Irakoze
- Department of Chemical Engineering, University of Massachusetts Amherst, MA 01003, USA
| | - Hyuna Kim
- Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst, MA 01003, USA
| | - Shelly R. Peyton
- Department of Chemical Engineering, University of Massachusetts Amherst, MA 01003, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst, MA 01003, USA
- Department of Biomedical Engineering, University of Massachusetts Amherst Amherst, MA 01003, USA
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5
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Ferrer-Diaz AI, Sinha G, Petryna A, Gonzalez-Bermejo R, Kenfack Y, Adetayo O, Patel SA, Hooda-Nehra A, Rameshwar P. Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells. Cell Commun Signal 2024; 22:119. [PMID: 38347590 PMCID: PMC10863086 DOI: 10.1186/s12964-024-01512-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 02/01/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets. METHODS Use of pharmacological inhibitor of H3K4 (WDR5-0103), knockdown (KD) of KMT2B or KMT2D in BCCs, real time PCR, western blot, response to chemotherapy, RNA-seq, and flow cytometry for circulating markers of CSCs and DNA hydroxylases in BC patients. In vivo studies using a dormancy model studied the effects of KMT2B/D to chemotherapy. RESULTS H3K4 methyltransferases sustain cell autonomous regulation of CSCs, impart chemoresistance, maintain cycling quiescence, and reduce migration and proliferation of BCCs. In vivo studies validated KMT2's role in dormancy and identified these genes as potential drug targets. DNA methylase (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to sustain circulating CSC-like in the blood of patients. CONCLUSION H3K4 methyltransferases and DNA methylation mediate cell autonomous regulation to sustain CSC. The findings provide crucial insights into epigenetic regulatory mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic targets, along with standard care. Stem cell and epigenetic markers in circulating BCCs could monitor treatment response and this could be significant for long BC remission to partly address health disparity.
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Affiliation(s)
- Alejandra I Ferrer-Diaz
- Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ, 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA
| | - Garima Sinha
- Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ, 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA
| | - Andrew Petryna
- Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ, 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA
| | | | - Yannick Kenfack
- Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ, 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA
| | | | - Shyam A Patel
- Division of Hematology and Oncology, Department of Medicine, UMass Memorial Medical Center, UMass Chan Medical School, Worcester, MA, USA
| | - Anupama Hooda-Nehra
- Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ, 07103, USA
- Rutgers Cancer Institute of New Jersey, Newark, NJ, USA
| | - Pranela Rameshwar
- Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ, 07103, USA.
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Bhatia R, Chang J, Munoz JL, Walker ND. Forging New Therapeutic Targets: Efforts of Tumor Derived Exosomes to Prepare the Pre-Metastatic Niche for Cancer Cell Dissemination and Dormancy. Biomedicines 2023; 11:1614. [PMID: 37371709 PMCID: PMC10295689 DOI: 10.3390/biomedicines11061614] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Tumor-derived exosomes play a multifaceted role in preparing the pre-metastatic niche, promoting cancer dissemination, and regulating cancer cell dormancy. A brief review of three types of cells implicated in metastasis and an overview of other types of extracellular vesicles related to metastasis are described. A central focus of this review is on how exosomes influence cancer progression throughout metastatic disease. Exosomes are crucial mediators of intercellular communication by transferring their cargo to recipient cells, modulating their behavior, and promoting tumor pro-gression. First, their functional role in cancer cell dissemination in the peripheral blood by facilitating the establishment of a pro-angiogenic and pro-inflammatory niche is described during organotro-pism and in lymphatic-mediated metastasis. Second, tumor-derived exosomes can transfer molecular signals that induce cell cycle arrest, dormancy, and survival pathways in disseminated cells, promoting a dormant state are reviewed. Third, several studies highlight exosome involvement in maintaining cellular dormancy in the bone marrow endosteum. Finally, the clinical implications of exosomes as biomarkers or diagnostic tools for cancer progression are also outlined. Understanding the complex interplay between tumor-derived exosomes and the pre-metastatic niche is crucial for developing novel therapeutic strategies to target metastasis and prevent cancer recurrence. To that end, several examples of how exosomes or other nanocarriers are used as a drug delivery system to inhibit cancer metastasis are discussed. Strategies are discussed to alter exosome cargo content for better loading capacity or direct cell targeting by integrins. Further, pre-clinical models or Phase I clinical trials implementing exosomes or other nanocarriers to attack metastatic cancer cells are highlighted.
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Affiliation(s)
- Ranvir Bhatia
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joanna Chang
- Department of Biological Sciences, University of Maryland, Baltimore, MD 21250, USA
| | - Jessian L Munoz
- Division of Perinatal Surgery, Texas Children's Hospital, Houston, TX 77030, USA
- Division of Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nykia D Walker
- Department of Biological Sciences, University of Maryland, Baltimore, MD 21250, USA
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7
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Nahas GR, Sherman LS, Sinha G, El Far MH, Petryna A, Munoz SM, Silverio KA, Shaker M, Neopane P, Mariotti V, Rameshwar P. Increased expression of musashi 1 on breast cancer cells has implication to understand dormancy and survival in bone marrow. Aging (Albany NY) 2023; 15:3230-3248. [PMID: 36996499 PMCID: PMC10449290 DOI: 10.18632/aging.204620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 03/13/2023] [Indexed: 03/31/2023]
Abstract
Breast cancer (BC) stem cells (CSCs) resist treatment and can exist as dormant cells in tissues such as the bone marrow (BM). Years before clinical diagnosis, BC cells (BCCs) could migrate from the primary site where the BM niche cells facilitate dedifferentiation into CSCs. Additionally, dedifferentiation could occur by cell autonomous methods. Here we studied the role of Msi 1, a RNA-binding protein, Musashi I (Msi 1). We also analyzed its relationship with the T-cell inhibitory molecule programmed death-ligand 1 (PD-L1) in CSCs. PD-L1 is an immune checkpoint that is a target in immune therapy for cancers. Msi 1 can support BCC growth through stabilization of oncogenic transcripts and modulation of stem cell-related gene expression. We reported on a role for Msi 1 to maintain CSCs. This seemed to occur by the differentiation of CSCs to more matured BCCs. This correlated with increased transition from cycling quiescence and reduced expression of stem cell-linked genes. CSCs co-expressed Msi 1 and PD-L1. Msi 1 knockdown led to a significant decrease in CSCs with undetectable PD-L1. This study has implications for Msi 1 as a therapeutic target, in combination with immune checkpoint inhibitor. Such treatment could also prevent dedifferentiation of breast cancer to CSCs, and to reverse tumor dormancy. The proposed combined treatment might be appropriate for other solid tumors.
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Affiliation(s)
- George R. Nahas
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Lauren S. Sherman
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Garima Sinha
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Markos H. El Far
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Andrew Petryna
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Steven M. Munoz
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Kimberly A. Silverio
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Maran Shaker
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Pujan Neopane
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Veronica Mariotti
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Pranela Rameshwar
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
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8
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Pradhan L, Moore D, Ovadia EM, Swedzinski SL, Cossette T, Sikes RA, van Golen K, Kloxin AM. Dynamic bioinspired coculture model for probing ER + breast cancer dormancy in the bone marrow niche. SCIENCE ADVANCES 2023; 9:eade3186. [PMID: 36888709 PMCID: PMC9995072 DOI: 10.1126/sciadv.ade3186] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 02/03/2023] [Indexed: 05/28/2023]
Abstract
Late recurrences of breast cancer are hypothesized to arise from disseminated tumor cells (DTCs) that reactivate after dormancy and occur most frequently with estrogen receptor-positive (ER+) breast cancer cells (BCCs) in bone marrow (BM). Interactions between the BM niche and BCCs are thought to play a pivotal role in recurrence, and relevant model systems are needed for mechanistic insights and improved treatments. We examined dormant DTCs in vivo and observed DTCs near bone lining cells and exhibiting autophagy. To study underlying cell-cell interactions, we established a well-defined, bioinspired dynamic indirect coculture model of ER+ BCCs with BM niche cells, human mesenchymal stem cells (hMSCs) and fetal osteoblasts (hFOBs). hMSCs promoted BCC growth, whereas hFOBs promoted dormancy and autophagy, regulated in part by tumor necrosis factor-α and monocyte chemoattractant protein 1 receptor signaling. This dormancy was reversible by dynamically changing the microenvironment or inhibiting autophagy, presenting further opportunities for mechanistic and targeting studies to prevent late recurrence.
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Affiliation(s)
- Lina Pradhan
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA
| | - DeVonte Moore
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
| | - Elisa M. Ovadia
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA
| | - Samantha L. Swedzinski
- Department of Materials Science and Engineering, University of Delaware, Newark, DE 19716, USA
| | - Travis Cossette
- Office of Laboratory Animal Medicine, University of Delaware, Newark, DE 19716, USA
| | - Robert A. Sikes
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Kenneth van Golen
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - April M. Kloxin
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA
- Department of Materials Science and Engineering, University of Delaware, Newark, DE 19716, USA
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Harihar S, Welch DR. KISS1 metastasis suppressor in tumor dormancy: a potential therapeutic target for metastatic cancers? Cancer Metastasis Rev 2023; 42:183-196. [PMID: 36720764 PMCID: PMC10103016 DOI: 10.1007/s10555-023-10090-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 01/25/2023] [Indexed: 02/02/2023]
Abstract
Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative, growth-arrested, or therapy-resistant tumor cells. Devising effective approaches targeting dormant tumor cells has been a focus of cancer clinicians for decades. However, progress has been limited due to limited understanding of the tumor dormancy process. Studies on tumor dormancy have picked up pace and have resulted in the identification of several regulators. This review focuses on KISS1, a metastasis suppressor gene that suppresses metastasis by keeping tumor cells in a state of dormancy at ectopic sites. The review explores mechanistic insights of KISS1 and discusses its potential application as a therapeutic against metastatic cancers by eliminating quiescent cells or inducing long-term dormancy in tumor cells.
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Affiliation(s)
- Sitaram Harihar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India
| | - Danny R. Welch
- Department of Cancer Biology, The Kansas University Medical Center, Kansas City, USA
- The University of Kansas Comprehensive Cancer Center, 3901 Rainbow Blvd. Kansas City, Kansas City, KS 66160, USA
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10
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Yang R, Jia L, Lu G, Lv Z, Cui J. Symptomatic bone marrow metastases in breast cancer: A retrospective cohort study. Front Oncol 2022; 12:1042773. [PMID: 36605432 PMCID: PMC9808780 DOI: 10.3389/fonc.2022.1042773] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/18/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Breast cancer symptomatic bone marrow metastasis (BMM) is rare and has a poor prognosis. Chemotherapy is usually the primary treatment, but it has limited efficacy, resulting in dose reduction and a decrease in quality of life due to the adverse effects of the agent. Other than chemotherapy, there are no other treatment studies for BMM. This study aimed to explore the clinicopathological characteristics of BMM patients with breast cancer, the prognosis using different treatment modalities, and the risk factors that affect the prognosis. Methods This retrospective study included patients diagnosed with breast cancer BMM from January 2018 to January 2022 in the Cancer Center of the First Hospital of Jilin University. The analysis focused on the characteristics of the patients, the treatment regimen, and the prognosis. Results Of 733 patients with advanced breast cancer, 33 patients were identified with BMM. All patients showed a hemoglobin decrease, and 25 (75.75%) presented with a fever of unknown origin. As for the metastasis breast cancer subtype, 25 (75.75%) were hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative, three (9.09%) had HER2 overexpression, and five (15.15%) were triple negative. The BMM patients had a median progression-free survival (PFS) of 7 months (1-21 months) and a median overall survival (OS) of 18 months (2-108 months). Among 25 HR+/HER2- BMM patients treated with different modalities, the median OS of the endocrine therapy (ET) group was 23 months, compared with 5 months in the chemotherapy group. Cox proportional hazards models suggested that higher Eastern Cooperative Oncology Group (ECOG) scores and old age were associated with shorter survival. Conclusion When breast cancer patients present with anemia and fever of unknown origin, BMM should be considered. For HR+/HER2- patients with good physical status and can receive active treatment, CDK4/6 inhibitors combined with ET can be used to control disease progression, improve quality of life, and prolong survival.
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Affiliation(s)
| | | | | | - Zheng Lv
- *Correspondence: Zheng Lv, ; Jiuwei Cui,
| | - Jiuwei Cui
- *Correspondence: Zheng Lv, ; Jiuwei Cui,
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11
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Ferrer AI, Einstein E, Morelli SS. Bone Marrow-Derived Cells in Endometrial Cancer Pathogenesis: Insights from Breast Cancer. Cells 2022; 11:cells11040714. [PMID: 35203363 PMCID: PMC8869947 DOI: 10.3390/cells11040714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/08/2022] [Accepted: 02/13/2022] [Indexed: 02/04/2023] Open
Abstract
Endometrial cancer is the most common gynecological cancer, representing 3.5% of all new cancer cases in the United States. Abnormal stem cell-like cells, referred to as cancer stem cells (CSCs), reside in the endometrium and possess the capacity to self-renew and differentiate into cancer progenitors, leading to tumor progression. Herein we review the role of the endometrial microenvironment and sex hormone signaling in sustaining EC progenitors and potentially promoting dormancy, a cellular state characterized by cell cycle quiescence and resistance to conventional treatments. We offer perspective on mechanisms by which bone marrow-derived cells (BMDCs) within the endometrial microenvironment could promote endometrial CSC (eCSC) survival and/or dormancy. Our perspective relies on the well-established example of another sex hormone-driven cancer, breast cancer, in which the BM microenvironment plays a crucial role in acquisition of CSC phenotype and dormancy. Our previous studies demonstrate that BMDCs migrate to the endometrium and express sex hormone (estrogen and progesterone) receptors. Whether the BM is a source of eCSCs is unknown; alternatively, crosstalk between BMDCs and CSCs within the endometrial microenvironment could be an additional mechanism supporting eCSCs and tumorigenesis. Elucidating these mechanisms will provide avenues to develop novel therapeutic interventions for EC.
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Affiliation(s)
- Alejandra I. Ferrer
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; (A.I.F.); (E.E.)
- School of Graduate Studies Newark, Rutgers University, Newark, NJ 07103, USA
| | - Ella Einstein
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; (A.I.F.); (E.E.)
| | - Sara S. Morelli
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Correspondence:
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Khoogar R, Li F, Chen Y, Ignatius M, Lawlor ER, Kitagawa K, Huang THM, Phelps DA, Houghton PJ. Single-cell RNA profiling identifies diverse cellular responses to EWSR1/FLI1 downregulation in Ewing sarcoma cells. Cell Oncol (Dordr) 2022; 45:19-40. [PMID: 34997546 PMCID: PMC10959445 DOI: 10.1007/s13402-021-00640-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The EWSR1/FLI1 gene fusion is the most common rearrangement leading to cell transformation in Ewing sarcoma (ES). Previous studies have indicated that expression at the cellular level is heterogeneous, and that levels of expression may oscillate, conferring different cellular characteristics. In ES the role of EWSR1/FLI1 in regulating subpopulation dynamics is currently unknown. METHODS We used siRNA to transiently suppress EWSR1/FLI1 expression and followed population dynamics using both single cell expression profiling, CyTOF and functional assays to define characteristics of exponentially growing ES cells and of ES cells in which EWSR1/FLI1 had been downregulated. Novel transcriptional states with distinct features were assigned using random forest feature selection in combination with machine learning. Cells isolated from ES xenografts in immune-deficient mice were interrogated to determine whether characteristics of specific subpopulations of cells in vitro could be identified. Stem-like characteristics were assessed by primary and secondary spheroid formation in vitro, and invasion/motility was determined for each identified subpopulation. Autophagy was determined by expression profiling, cell sorting and immunohistochemical staining. RESULTS We defined a workflow to study EWSR1/FLI1 driven transcriptional states and phenotypes. We tracked EWSR1/FLI1 dependent proliferative activity over time to discover sources of intra-tumoral diversity. Single-cell RNA profiling was used to compare expression profiles in exponentially growing populations (si-Control) or in two dormant populations (D1, D2) in which EWSR1/FLI1 had been suppressed. Three distinct transcriptional states were uncovered contributing to ES intra-heterogeneity. Our predictive model identified ~1% cells in a dormant-like state and ~ 2-4% cells with stem-like and neural stem-like features in an exponentially proliferating ES cell line and in ES xenografts. Following EWSR1/FLI1 knockdown, cells re-entering the proliferative cycle exhibited greater stem-like properties, whereas for those cells remaining quiescent, FAM134B-dependent dormancy may provide a survival mechanism. CONCLUSIONS We show that time-dependent changes induced by suppression of oncogenic EWSR1/FLI1 expression induces dormancy, with different subpopulation dynamics. Cells re-entering the proliferative cycle show enhanced stem-like characteristics, whereas those remaining dormant for prolonged periods appear to survive through autophagy. Cells with these characteristics identified in exponentially growing cell populations and in tumor xenografts may confer drug resistance and could potentially contribute to metastasis.
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Affiliation(s)
- Roxane Khoogar
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA
| | - Fuyang Li
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA
| | - Yidong Chen
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Myron Ignatius
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA
| | - Elizabeth R Lawlor
- Seattle Children's Research Institute, University of Washington Medical School, Washington, DC, USA
| | - Katsumi Kitagawa
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA
| | - Tim H-M Huang
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Doris A Phelps
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA
| | - Peter J Houghton
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA.
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13
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Moore CA, Ferrer AI, Alonso S, Pamarthi SH, Sandiford OA, Rameshwar P. Exosomes in the Healthy and Malignant Bone Marrow Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1350:67-89. [PMID: 34888844 DOI: 10.1007/978-3-030-83282-7_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The bone marrow (BM) is a complex organ that sustains hematopoiesis via mechanisms involving the microenvironment. The microenvironment includes several cell types, neurotransmitters from innervated fibers, growth factors, extracellular matrix proteins, and extracellular vesicles. The main function of the BM is to regulate hematopoietic function to sustain the production of blood and immune cells. However, the BM microenvironment can also accommodate the survival of malignant cells. A major mechanism by which the cancer cells communicate with cells of the BM microenvironment is through the exchange of exosomes, a subset of extracellular vesicles that deliver molecular signals bidirectionally between malignant and healthy cells. The field of exosomes is an active area of investigation since an understanding of how the exosomal packaging, cargo, and production can be leveraged therapeutically to deter cancer progression and sensitize malignant cells to other therapies. Altogether, this chapter discusses the crucial role of exosomes in the development and progression of BM-associated cancers, such as hematologic malignancies and marrow-metastatic breast cancer. Exosome-based therapeutic strategies and their limitations are also considered.
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Affiliation(s)
- Caitlyn A Moore
- Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, United States
- Rutgers School of Graduate Studies at New Jersey Medical School, Rutgers University, Newark, NJ, United States
| | - Alejandra I Ferrer
- Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, United States
- Rutgers School of Graduate Studies at New Jersey Medical School, Rutgers University, Newark, NJ, United States
| | - Sara Alonso
- Rutgers School of Graduate Studies at New Jersey Medical School, Rutgers University, Newark, NJ, United States
| | - Sri Harika Pamarthi
- Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, United States
| | - Oleta A Sandiford
- Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, United States
- Rutgers School of Graduate Studies at New Jersey Medical School, Rutgers University, Newark, NJ, United States
| | - Pranela Rameshwar
- Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, United States.
- Rutgers School of Graduate Studies at New Jersey Medical School, Rutgers University, Newark, NJ, United States.
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14
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Zhao L, Zhang K, He H, Yang Y, Li W, Liu T, Li J. The Relationship Between Mesenchymal Stem Cells and Tumor Dormancy. Front Cell Dev Biol 2021; 9:731393. [PMID: 34712663 PMCID: PMC8545891 DOI: 10.3389/fcell.2021.731393] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor dormancy, a state of tumor, is clinically undetectable and the outgrowth of dormant tumor cells into overt metastases is responsible for cancer-associated deaths. However, the dormancy-related molecular mechanism has not been clearly described. Some researchers have proposed that cancer stem cells (CSCs) and disseminated tumor cells (DTCs) can be seen as progenitor cells of tumor dormancy, both of which can remain dormant in a non-permissive soil/niche. Nowadays, research interest in the cancer biology field is skyrocketing as mesenchymal stem cells (MSCs) are capable of regulating tumor dormancy, which will provide a unique therapeutic window to cure cancer. Although the influence of MSCs on tumor dormancy has been investigated in previous studies, there is no thorough review on the relationship between MSCs and tumor dormancy. In this paper, the root of tumor dormancy is analyzed and dormancy-related molecular mechanisms are summarized. With an emphasis on the role of the MSCs during tumor dormancy, new therapeutic strategies to prevent metastatic disease are proposed, whose clinical application potentials are discussed, and some challenges and prospects of the studies of tumor dormancy are also described.
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Affiliation(s)
- Linxian Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hongyu He
- Operating Theater and Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Yongping Yang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Wei Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Tongjun Liu
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
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15
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Lk Wong B, Wei Chern Gan R, Adabavazeh B, Jose J. Bone marrow metastasis/carcinomatosis in head and neck squamous cell carcinoma. J Oral Pathol Med 2021; 50:955-961. [PMID: 33818835 DOI: 10.1111/jop.13184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 03/31/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Literature on bone marrow carcinomatosis in head and neck squamous cell carcinoma (HNSCC) is sparse. This work aims to augment understanding on its characteristic features, clinical presentation, investigations, treatment and outcomes. METHODS Comprehensive literature review of all published cases of metastasis of HNSCC to the bone marrow with regard to clinical presentation, diagnosis, treatment and survival outcomes of this disease. Each of these factors is discussed forming an up-to-date review on the subject. RESULTS Eight case reports were identified, seven males and one female with an age range of 35-64 years. Primary sites were from the oral cavity (n = 4), oropharynx (n = 3) and supraglottis (n = 1). Six were stage four disease with nodal involvement, one case stage two and one case with unknown staging. Two of the oropharyngeal cancers were p16 positive, and one p16 status was not documented. Five patients presented with back pain, two patients had ecchymoses with bleeding, and one presented with sepsis and thrombocytopaenia. Three patients had proven disseminated intravascular coagulation. Four patients were treated with palliative chemoradiotherapy, one had palliative radiotherapy, one had radiotherapy and dendritic cell vaccine immunotherapy, and two died from the disease prior to any treatment. Various facets of presentation and management are discussed. CONCLUSION Bone marrow carcinomatosis from HNSCC is rare. It can present with a variety of non-specific symptoms, and a high index of suspicion is required to be able to diagnose the condition promptly. Aggressive chemotherapy is the treatment of choice but prognosis remains poor.
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Affiliation(s)
- Billy Lk Wong
- Ear, Nose and Throat Department, Broomfield Hospital, Broomfield, UK
| | - Richard Wei Chern Gan
- Ear, Nose and Throat Department, Hull University Teaching Hospitals NHS Trust, Hull, UK
| | - Babak Adabavazeh
- Ear, Nose and Throat Department, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Jemy Jose
- Ear, Nose and Throat Department, Hull University Teaching Hospitals NHS Trust, Hull, UK
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16
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Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer. Cells 2021; 10:cells10020344. [PMID: 33562088 PMCID: PMC7914642 DOI: 10.3390/cells10020344] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/25/2021] [Accepted: 02/03/2021] [Indexed: 01/16/2023] Open
Abstract
Researchers have developed several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids with increased properties of cancer stem cells (CSCs), also called cancer-initiating cells (CICs). Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anti-cancer drugs have been reported using 2D culture systems, whereas 3D cultured tumoroids have many advantages for assessing drug sensitivity and resistance. Here, we aimed to investigate whether Cisplatin (a DNA crosslinker), Imatinib (a multiple tyrosine kinase inhibitor), and 5-Fluorouracil (5-FU: an antimetabolite) alter the tumoroid growth of metastatic colorectal cancer (mCRC). Gene expression signatures of highly metastatic aggregative CRC (LuM1 cells) vs. low-metastatic, non-aggregative CRC (Colon26 and NM11 cells) were analyzed using microarray. To establish a 3D culture-based multiplexing reporter assay system, LuM1 was stably transfected with the Mmp9 promoter-driven ZsGreen fluorescence reporter gene, which was designated as LuM1/m9 cells and cultured in NanoCulture Plate®, a gel-free 3D culture device. LuM1 cells highly expressed mRNA encoding ABCG2 (a drug resistance pump, i.e., CSC/CIC marker), other CSC/CIC markers (DLL1, EpCAM, podoplanin, STAT3/5), pluripotent stem cell markers (Sox4/7, N-myc, GATA3, Nanog), and metastatic markers (MMPs, Integrins, EGFR), compared to the other two cell types. Hoechst efflux stem cell-like side population was increased in LuM1 (7.8%) compared with Colon26 (2.9%), both of which were markedly reduced by verapamil treatment, an ABCG2 inhibitor. Smaller cell aggregates of LuM1 were more sensitive to Cisplatin (at 10 μM), whereas larger tumoroids with increased ABCG2 expression were insensitive. Notably, Cisplatin (2 μM) and Imatinib (10 μM) at low concentrations significantly promoted tumoroid formation (cell aggregation) and increased Mmp9 promoter activity in mCRC LuM1/m9, while not cytotoxic to them. On the other hand, 5-FU significantly inhibited tumoroid growth, although not completely. Thus, drug resistance in cancer with increased stem cell properties was modeled using the gel-free 3D cultured tumoroid system. The tumoroid culture is useful and easily accessible for the assessment of drug sensitivity and resistance.
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17
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Yuan W, Hai B, Ren X, Zhu J, Zhang C, Guan Z, Jia J, Wang H, Cao B, Song C. Single-dose local intraosseous injection of simvastatin suppresses breast cancer with tumor vascular normalization. Transl Oncol 2020; 13:100867. [PMID: 32950929 PMCID: PMC7509234 DOI: 10.1016/j.tranon.2020.100867] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/23/2022] Open
Abstract
Tumor vessels play important roles in cancer development and angiogenesis has been characterized as an essential process for tumor cell tumor growth. Our previous studies found that a single-dose local intraosseous simvastatin injection rapidly and long-termly mobilized bone marrow-derived endothelial progenitor cells to peripheral blood, promoting angiogenesis and ameliorating ischemia injury. However, whether intraosseous injection of simvastatin participates in cancer progression and the role of angiogenesis enhancement in this process remain unknown. In this study, we found that intraosseous injection of simvastatin improves tumor vascular structure, along with increasing the percentage of pericyte coverage on tumor vessels, and reducing vascular permeability, tumor hypoxia and tumor necrosis. Further, we demonstrate that a single-dose local intraosseous simvastatin injection suppresses tumor growth, facilitates sensitivity of chemotherapy and prolongs survival in breast cancer-bearing mice. In addition, oral application, intravenous, subcutaneous and intraperitoneal injection of simvastatin do not show these effects. Taken together, these results demonstrate that intraosseous injection of simvastatin suppresses breast cancer with tumor vascular normalization, which might be a promising strategy for cancer treatment.
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Affiliation(s)
- Wanqiong Yuan
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China.
| | - Bao Hai
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China.
| | - Xiaoqing Ren
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
| | - Junxiong Zhu
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China.
| | - Chenggui Zhang
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China.
| | - Zhiyuan Guan
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China.
| | - Jialin Jia
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China.
| | - Hong Wang
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China
| | - Baoshan Cao
- Department of Tumor Chemotherapy and Radiation Sickness, Peking University Third Hospital, Beijing, China
| | - Chunli Song
- Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China.
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18
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Anastasio A, Gergues M, Lebhar MS, Rameshwar P, Fernandez-Moure J. Isolation and characterization of mesenchymal stem cells in orthopaedics and the emergence of compact bone mesenchymal stem cells as a promising surgical adjunct. World J Stem Cells 2020; 12:1341-1353. [PMID: 33312402 PMCID: PMC7705465 DOI: 10.4252/wjsc.v12.i11.1341] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 09/26/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
The potential clinical and economic impact of mesenchymal stem cell (MSC) therapy is immense. MSCs act through multiple pathways: (1) as “trophic” cells, secreting various factors that are immunomodulatory, anti-inflammatory, anti-apoptotic, proangiogenic, proliferative, and chemoattractive; (2) in conjunction with cells native to the tissue they reside in to enhance differentiation of surrounding cells to facilitate tissue regrowth. Researchers have developed methods for the extraction and expansion of MSCs from animal and human tissues. While many sources of MSCs exist, including adipose tissue and iliac crest bone graft, compact bone (CB) MSCs have shown great potential for use in orthopaedic surgery. CB MSCs exert powerful immunomodulatory effects in addition to demonstrating excellent regenerative capacity for use in filling boney defects. CB MSCs have been shown to have enhanced response to hypoxic conditions when compared with other forms of MSCs. More work is needed to continue to characterize the potential applications for CB MSCs in orthopaedic trauma.
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Affiliation(s)
- Albert Anastasio
- Department of Orthopedic Surgery, Duke University Health System, Durham, NC 27710, United States
| | - Marina Gergues
- Department of Medicine, Hematology/Oncology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, United States
| | - Michael S Lebhar
- School of Medicine, Duke University School of Medicine, Durham, NC 27710, United States
| | - Pranela Rameshwar
- Department of Medicine-Hematology/Oncology, Rutgers School of Biomedical Health Science, Newark, NJ 07103, United States
| | - Joseph Fernandez-Moure
- Department of Surgery, Division of Trauma, Acute, and Critical Care Surgery, Duke University School of Medicine, Durham, NC 27710, United States
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19
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Sinha G, Ferrer AI, Moore CA, Naaldijk Y, Rameshwar P. Gap Junctions and Breast Cancer Dormancy. Trends Cancer 2020; 6:348-357. [PMID: 32209448 DOI: 10.1016/j.trecan.2020.01.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 12/21/2022]
Abstract
Breast cancer (BC) relapse, despite clinical advancement, remains one of the biggest issues in the field. Intercellular communication, specifically via connexin (Cx)-mediated gap junctions (GJs), play a key role in the long-term survival of these, treatment-resistant breast cancer stem cells (CSCs), allowing for relapse. Both basic and clinical evidence reveal dual roles for GJs, in tumor suppression, generally referred to as dormancy, and progression and metastasis. GJ intercellular communication (GJIC) can be mediated by multiple types of Cxs, depending on the organ to which the BC cells metastasize. This review expands on the differential expression of Cx-mediated GJIC between CSCs and niche cells within a given microenvironment.
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Affiliation(s)
- Garima Sinha
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA; Department of Medicine - Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Alejandra I Ferrer
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA; Department of Medicine - Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Caitlyn A Moore
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA; Department of Medicine - Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Yahaira Naaldijk
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA
| | - Pranela Rameshwar
- Department of Medicine - Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA.
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20
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Flüh C, Mafael V, Adamski V, Synowitz M, Held-Feindt J. Dormancy and NKG2D system in brain metastases: Analysis of immunogenicity. Int J Mol Med 2019; 45:298-314. [PMID: 31894267 PMCID: PMC6984787 DOI: 10.3892/ijmm.2019.4449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022] Open
Abstract
Patients with breast cancer (BC) and lung cancer (LC) are prone to developing brain metastases, which are associated with devastating prognoses. Dormant tumor cells, a population of non-apoptotic quiescent cells and immunological escape mechanisms, including the Natural Killer Group 2 member D (NKG2D) receptor-ligand system, represent potential mechanisms of tumor recurrence. To date, the immunological characteristics of dormant tumor cells concerning the NKG2D system in cerebral malignancies are mostly unknown. In the present study, an extensive characterization of dormant and NKG2D ligand (NKG2DL)+ cells in cerebral metastases was performed. The expression profiles and localization patterns of various NKG2DL and several dormancy markers were analyzed in solid human brain metastases from patients with BC and LC using immunostaining and reverse transcription-quantitative polymerase chain reaction analyses. Statistical analysis was performed using Student's t-test and Bravais-Pearson correlation analysis. Not only 'peripheral', but also 'central' dormancy markers, which had been previously described in primary brain tumors, were identified in all cerebral metastases at detectable levels at protein and mRNA levels. Notably, the majority of NKG2DL+ cells were also positive for 'central' dormancy markers, but not 'peripheral' dormancy markers in both patient groups. This cell population may represent a promising future therapeutic target.
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Affiliation(s)
- Charlotte Flüh
- Department of Neurosurgery, University Medical Center Schleswig‑Holstein, Campus Kiel, D‑24105 Kiel, Germany
| | - Victor Mafael
- Department of Neurosurgery, University Medical Center Schleswig‑Holstein, Campus Kiel, D‑24105 Kiel, Germany
| | - Vivian Adamski
- Department of Neurosurgery, University Medical Center Schleswig‑Holstein, Campus Kiel, D‑24105 Kiel, Germany
| | - Michael Synowitz
- Department of Neurosurgery, University Medical Center Schleswig‑Holstein, Campus Kiel, D‑24105 Kiel, Germany
| | - Janka Held-Feindt
- Department of Neurosurgery, University Medical Center Schleswig‑Holstein, Campus Kiel, D‑24105 Kiel, Germany
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Herrmann M, Jakob F. Bone Marrow Niches for Skeletal Progenitor Cells and their Inhabitants in Health and Disease. Curr Stem Cell Res Ther 2019; 14:305-319. [PMID: 30674266 DOI: 10.2174/1574888x14666190123161447] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 12/04/2018] [Accepted: 01/02/2019] [Indexed: 12/19/2022]
Abstract
The bone marrow hosts skeletal progenitor cells which have most widely been referred to as Mesenchymal Stem or Stromal Cells (MSCs), a heterogeneous population of adult stem cells possessing the potential for self-renewal and multilineage differentiation. A consensus agreement on minimal criteria has been suggested to define MSCs in vitro, including adhesion to plastic, expression of typical surface markers and the ability to differentiate towards the adipogenic, osteogenic and chondrogenic lineages but they are critically discussed since the differentiation capability of cells could not always be confirmed by stringent assays in vivo. However, these in vitro characteristics have led to the notion that progenitor cell populations, similar to MSCs in bone marrow, reside in various tissues. MSCs are in the focus of numerous (pre)clinical studies on tissue regeneration and repair. Recent advances in terms of genetic animal models enabled a couple of studies targeting skeletal progenitor cells in vivo. Accordingly, different skeletal progenitor cell populations could be identified by the expression of surface markers including nestin and leptin receptor. While there are still issues with the identity of, and the overlap between different cell populations, these studies suggested that specific microenvironments, referred to as niches, host and maintain skeletal progenitor cells in the bone marrow. Dynamic mutual interactions through biological and physical cues between niche constituting cells and niche inhabitants control dormancy, symmetric and asymmetric cell division and lineage commitment. Niche constituting cells, inhabitant cells and their extracellular matrix are subject to influences of aging and disease e.g. via cellular modulators. Protective niches can be hijacked and abused by metastasizing tumor cells, and may even be adapted via mutual education. Here, we summarize the current knowledge on bone marrow skeletal progenitor cell niches in physiology and pathophysiology. We discuss the plasticity and dynamics of bone marrow niches as well as future perspectives of targeting niches for therapeutic strategies.
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Affiliation(s)
- Marietta Herrmann
- IZKF Group Tissue Regeneration in Musculoskeletal Diseases, University Clinics Wuerzburg, Wuerzburg, Germany.,Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Franz Jakob
- Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
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22
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Leto G. Current status and future directions in the treatment of bone metastases from breast cancer. Clin Exp Pharmacol Physiol 2019; 46:968-971. [DOI: 10.1111/1440-1681.13139] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/02/2019] [Accepted: 07/15/2019] [Indexed: 11/27/2022]
Affiliation(s)
- Gaetano Leto
- Laboratory of Experimental Pharmacology Department of Health Promotion Sciences School of Medicine University of Palermo 90127 Palermo Italy
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23
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Wang H, Jia R, Zhao T, Li X, Lang M, Lan C, Wang H, Li Z, Zhou B, Wu L, Sun Y, Wang X, Ren H, Hao J. RETRACTED: HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma. Cancer Lett 2019; 453:10-20. [PMID: 30922919 DOI: 10.1016/j.canlet.2019.03.036] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/15/2019] [Accepted: 03/21/2019] [Indexed: 10/27/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Authors. Following concerns raised in the public domain, the authors contacted the journal to request the retraction of the article. Sections of panels from various figures appear similar to each other, particularly panels from Figures 3G and 5B, 3G and 5F, 3F, S4D, S5D, S5C and S10C, as well as S10E.
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Affiliation(s)
- Haotian Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Rujiang Jia
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Tiansuo Zhao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Xin Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Mingxiao Lang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Chungen Lan
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Hongwei Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Zengxun Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Bodong Zhou
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Liangliang Wu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Yan Sun
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China
| | - Xiuchao Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China.
| | - He Ren
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China.
| | - Jihui Hao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, China.
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Tandon I, Sharma NK. Macrophage Flipping from Foe to Friend: A Matter of Interest in Breast Carcinoma Heterogeneity Driving Drug Resistance. Curr Cancer Drug Targets 2019; 19:189-198. [PMID: 29952260 DOI: 10.2174/1568009618666180628102247] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 05/09/2018] [Accepted: 06/13/2018] [Indexed: 02/06/2023]
Abstract
Tumor heterogeneity within various cancer types including breast carcinoma is pivotal in the manifestations of tumor hallmarks. Tumor heterogeneity is seen as a common landscape where intra-tumoral components including cellular and non-cellular factors create an interface with outside environment that leads to the unique identity of a specific cancer type. Among various contributors to tumor heterogeneity, cellular heterogeneity immensely plays a role in drug resistance and relapse of cancer. Within cellular heterogeneity of tumor, tumor-associated macrophages (TAMs) are the pro-tumor type of immune cells that promote growth, metastasis and drug resistance in breast carcinoma and other cancer types. Revealing the molecular aspects of TAMs can provide a breakthrough to remove therapeutics blockade to existing drugs and this understanding in future will pave the way for a new class of cancer immunotherapeutic. This review addresses current understanding of the role of TAMs in breast carcinoma hallmarks and clarifies the current scenario of pre-clinical drugs directed to tame pro-cancer TAMs.
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Affiliation(s)
- Ishita Tandon
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra 411033, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra 411033, India
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25
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Pradhan S, Sperduto JL, Farino CJ, Slater JH. Engineered In Vitro Models of Tumor Dormancy and Reactivation. J Biol Eng 2018; 12:37. [PMID: 30603045 PMCID: PMC6307145 DOI: 10.1186/s13036-018-0120-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 11/16/2018] [Indexed: 12/23/2022] Open
Abstract
Metastatic recurrence is a major hurdle to overcome for successful control of cancer-associated death. Residual tumor cells in the primary site, or disseminated tumor cells in secondary sites, can lie in a dormant state for long time periods, years to decades, before being reactivated into a proliferative growth state. The microenvironmental signals and biological mechanisms that mediate the fate of disseminated cancer cells with respect to cell death, single cell dormancy, tumor mass dormancy and metastatic growth, as well as the factors that induce reactivation, are discussed in this review. Emphasis is placed on engineered, in vitro, biomaterial-based approaches to model tumor dormancy and subsequent reactivation, with a focus on the roles of extracellular matrix, secondary cell types, biochemical signaling and drug treatment. A brief perspective of molecular targets and treatment approaches for dormant tumors is also presented. Advances in tissue-engineered platforms to induce, model, and monitor tumor dormancy and reactivation may provide much needed insight into the regulation of these processes and serve as drug discovery and testing platforms.
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Affiliation(s)
- Shantanu Pradhan
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
| | - John L. Sperduto
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
| | - Cindy J. Farino
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
| | - John H. Slater
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
- Delaware Biotechnology Institute, 15 Innovation Way, Newark, DE 19711 USA
- Department of Materials Science and Engineering, University of Delaware, 201 DuPont Hall, Newark, DE 19716 USA
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26
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Casson J, Davies OG, Smith CA, Dalby MJ, Berry CC. Mesenchymal stem cell-derived extracellular vesicles may promote breast cancer cell dormancy. J Tissue Eng 2018; 9:2041731418810093. [PMID: 30627418 PMCID: PMC6311537 DOI: 10.1177/2041731418810093] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 10/10/2018] [Indexed: 12/28/2022] Open
Abstract
Disseminated breast cancer cells have the capacity to metastasise to the bone marrow and reside in a dormant state within the mesenchymal stem cell niche. Research has focussed on paracrine signalling factors, such as soluble proteins, within the microenvironment. However, it is now clear extracellular vesicles secreted by resident mesenchymal stem cells into this microenvironment also play a key role in the initiation of dormancy. Dormancy encourages reduced cell proliferation and migration, while upregulating cell adhesion, thus retaining the cancer cells within the bone marrow microenvironment. Here, MCF7 breast cancer cells were treated with mesenchymal stem cell-derived extracellular vesicles, resulting in reduced migration in two-dimensional and three-dimensional culture, with reduced cell proliferation and enhanced adhesion, collectively supporting cancer cell dormancy.
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Affiliation(s)
- Jake Casson
- Centre for Cell Engineering, Institute of Molecular, Cell and Systems Biology (IMCSB), The University of Glasgow, Glasgow, UK
| | - Owen G Davies
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Carol-Anne Smith
- Centre for Cell Engineering, Institute of Molecular, Cell and Systems Biology (IMCSB), The University of Glasgow, Glasgow, UK
| | - Matthew J Dalby
- Centre for Cell Engineering, Institute of Molecular, Cell and Systems Biology (IMCSB), The University of Glasgow, Glasgow, UK
| | - Catherine C Berry
- Centre for Cell Engineering, Institute of Molecular, Cell and Systems Biology (IMCSB), The University of Glasgow, Glasgow, UK
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27
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Emerging and Established Models of Bone Metastasis. Cancers (Basel) 2018; 10:cancers10060176. [PMID: 29865211 PMCID: PMC6024970 DOI: 10.3390/cancers10060176] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 05/30/2018] [Accepted: 05/30/2018] [Indexed: 02/07/2023] Open
Abstract
Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as healthcare costs. Bone is the primary site of metastasis for several cancers—breast and prostate cancers in particular. Efforts to treat bone metastases have been stymied by a lack of models to study the progression, cellular players, and signaling pathways driving bone metastasis. In this review, we examine newly described and classic models of bone metastasis. Through the use of current in vivo, microfluidic, and in silico computational bone metastasis models we may eventually understand how cells escape the primary tumor and how these circulating tumor cells then home to and colonize the bone marrow. Further, future models may uncover how cells enter and then escape dormancy to develop into overt metastases. Recreating the metastatic process will lead to the discovery of therapeutic targets for disrupting and treating bone metastasis.
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28
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Graham N, Qian BZ. Mesenchymal Stromal Cells: Emerging Roles in Bone Metastasis. Int J Mol Sci 2018; 19:E1121. [PMID: 29642534 PMCID: PMC5979535 DOI: 10.3390/ijms19041121] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/25/2018] [Accepted: 03/29/2018] [Indexed: 12/13/2022] Open
Abstract
Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. The establishment of metastasis within the bone is a multistep process. To ensure survival within the bone marrow, tumor cells must initially colonize a niche in which they can enter dormancy. Subsequently, reactivation permits the proliferation and growth of the tumor cells, giving rise to a macro-metastasis displayed clinically as a bone metastatic lesion. Here, we review the evidences that suggest mesenchymal stromal cells play an important role in each of these steps throughout the development of bone metastasis. Similarities between the molecular mechanisms implicated in these processes and those involved in the homeostasis of the bone indicate that the metastatic cells may exploit the homeostatic processes to their own advantage. Identifying the molecular interactions between the mesenchymal stromal cells and tumor cells that promote tumor development may offer insight into potential therapeutic targets that could be utilized to treat bone metastasis.
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Affiliation(s)
- Nicola Graham
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
| | - Bin-Zhi Qian
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
- Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh EH4 2XR, UK.
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29
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Wassmer G, Hmitti Z, Voisin L, Perfettini JL. [Eating and sleeping, two vital tumor activities favoring anticancer treatment failure]. Med Sci (Paris) 2018; 34:37-40. [PMID: 29384094 DOI: 10.1051/medsci/20183401011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
| | - Zohra Hmitti
- M1 Biologie Santé, Université Paris-Saclay, 91405 Orsay, France
| | - Laurent Voisin
- Unité de radiothérapie moléculaire, Inserm U1030, Université Paris-Sud, Institut Gustave Roussy, 94800 Villejuif, France
| | - Jean-Luc Perfettini
- Unité de radiothérapie moléculaire, Inserm U1030, Université Paris-Sud, Institut Gustave Roussy, 94800 Villejuif, France
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30
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Sandiford OA, Moore CA, Du J, Boulad M, Gergues M, Eltouky H, Rameshwar P. Human Aging and Cancer: Role of miRNA in Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1056:137-152. [PMID: 29754179 DOI: 10.1007/978-3-319-74470-4_9] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human aging is an inevitable and complex phenomenon characterized by a progressive, gradual degradation of physiological and cellular processes that leads from vulnerability to death. Mammalian somatic cells display limited proliferative properties in vitro that results in a process of permanent cell cycle arrest commonly known as senescence. Events leading to cellular senescence are complex but may be due to the increase in tumor suppressor genes, caused by lifetime somatic mutations. Cumulative mutation leaves an imprint on the genome of the cell, an important risk factor for the occurrence of cancer. Adults over the age of 65+ are vulnerable to age related diseases such as cancers but such changes may begin at middle age. MicroRNAs (miRNAs), which are small non-coding RNA, can regulate cancer progression, recurrence and metastasis. This chapter discusses the role of miRNA in tumor microenvironment, consequent to aging.
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Affiliation(s)
- Oleta A Sandiford
- Division of Hematology/Oncology, Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA
| | - Caitlyn A Moore
- Division of Hematology/Oncology, Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA
| | - Jun Du
- Division of Hematology/Oncology, Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA
| | - Mathieu Boulad
- Division of Hematology/Oncology, Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA
| | - Marina Gergues
- Division of Hematology/Oncology, Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA
| | - Hussam Eltouky
- Division of Hematology/Oncology, Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA
| | - Pranela Rameshwar
- Division of Hematology/Oncology, Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA.
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Kucerova L, Durinikova E, Toro L, Cihova M, Miklikova S, Poturnajova M, Kozovska Z, Matuskova M. Targeted antitumor therapy mediated by prodrug-activating mesenchymal stromal cells. Cancer Lett 2017; 408:1-9. [PMID: 28838843 DOI: 10.1016/j.canlet.2017.08.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 08/09/2017] [Accepted: 08/11/2017] [Indexed: 12/14/2022]
Abstract
Mesenchymal stromal cells (MSCs) were introduced as tumor-targeted vehicles suitable for delivery of the gene-directed enzyme/prodrug therapy more than 10 years ago. Over these years key properties of tumor cells and MSCs, which are crucial for the treatment efficiency, were examined; and there are some critical issues to be considered for the maximum antitumor effect. Moreover, engineered MSCs expressing enzymes capable of activating non-toxic prodrugs achieved long-term curative effect even in metastatic and hard-to-treat tumor types in pre-clinical scenario(s). These gene-modified MSCs are termed prodrug-activating MSCs throughout the text and represent promising approach for further clinical application. This review summarizes major determinants to be considered for the application of the prodrug-activating MSCs in antitumor therapy in order to maximize therapeutic efficiency.
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Affiliation(s)
- Lucia Kucerova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
| | - Erika Durinikova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Lenka Toro
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Marina Cihova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Svetlana Miklikova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Martina Poturnajova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Zuzana Kozovska
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Miroslava Matuskova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
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32
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Bone Marrow Metastasis Is an Early Stage of Bone Metastasis in Breast Cancer Detected Clinically by F18-FDG-PET/CT Imaging. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9852632. [PMID: 28884133 PMCID: PMC5572575 DOI: 10.1155/2017/9852632] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Revised: 06/17/2017] [Accepted: 07/12/2017] [Indexed: 11/24/2022]
Abstract
Objective To determine the value of 18F-FDG PET/CT in detection of bone marrow (BM) metastasis in breast cancer which is considered an early stage of bone metastasis. Patients and Methods Retrospectively, breast cancer patients with bone metastasis were included. BM metastasis was considered if the lesion was PET positive/CT occult while bone metastasis was considered if the lesion was PET positive/ CT positive. BM metastases were observed sequentially on F18-FDG PET/CT. Results We included 35 patients. Eighteen patients (51%) had BM metastases in addition to other bone metastases. BM metastases comprised 24% of all lesions. Posttreatment scan was performed on 26/35 patients. Twenty-three percent of BM metastases had resolved completely without causing bone destruction after treatment. Sixty-five percent of BM metastases had converted into bone metastases after treatment. Twelve percent of BM metastases had persisted after treatment. Conclusion This retrospective study showed clinically by 18F-FDG PET/CT imaging that BM metastasis is an early stage of bone metastasis in breast cancer. Interestingly, 18F-FDG-PET/CT showed that early eradication of individual BM metastasis by systemic treatment precluded development of bone metastasis. However, more research is needed to study the impact of an early diagnosis of BM metastases on treatment outcome.
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33
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Single cell time-lapse analysis reveals that podoplanin enhances cell survival and colony formation capacity of squamous cell carcinoma cells. Sci Rep 2017; 7:39971. [PMID: 28059107 PMCID: PMC5216406 DOI: 10.1038/srep39971] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/30/2016] [Indexed: 01/04/2023] Open
Abstract
Tumor initiating cells (TICs) are characterized by high clonal expansion capacity. We previously reported that podoplanin is a TIC-specific marker for the human squamous cell carcinoma cell line A431. The aim of this study is to explore the molecular mechanism underlying the high clonal expansion potential of podoplanin-positive A431cells using Fucci imaging. Single podoplanin-positive cells created large colonies at a significantly higher frequency than single podoplanin-negative cells, whereas no difference was observed between the two types of cells with respect to cell cycle status. Conversely, the cell death ratio of progenies derived from podoplanin-positive single cell was significantly lower than that of cells derived from podoplanin-negative cells. Single A431 cells, whose podoplanin expression was suppressed by RNA interference, exhibited increased cell death ratios and decreased frequency of large colony forming. Moreover, the frequency of large colony forming decreased significantly when podoplanin-positive single cells was treated with a ROCK (Rho-associated coiled-coil kinase) inhibitor, whereas no difference was observed in single podoplanin-negative cells. Our current study cleared that high clonal expansion capacity of podoplanin-positive TICs populations was the result of reduced cell death by podoplanin-mediated signaling. Therefore, podoplanin activity may be a therapeutic target in the treatment of squamous cell carcinomas.
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34
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Bartosh TJ. Cancer cell cannibalism and the SASP: Ripples in the murky waters of tumor dormancy. Mol Cell Oncol 2016; 4:e1263715. [PMID: 28197538 DOI: 10.1080/23723556.2016.1263715] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 11/13/2016] [Accepted: 11/15/2016] [Indexed: 10/20/2022]
Abstract
Relapse in cancer patients following an apparent cure and a prolonged latency period, known as tumor dormancy, remains an unrelenting clinical crisis. Here, I expand on our recent findings that potentially link cancer cell cannibalism of bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) to the senescence-associated secretory phenotype (SASP) and tumor dormancy.
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Affiliation(s)
- Thomas J Bartosh
- Medical Physiology, College of Medicine, Texas A&M University System Health Science Center, Temple, TX, USA; Institute for Regenerative Medicine, College of Medicine, Texas A&M University System Health Science Center, Temple, TX, USA
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35
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Matsumoto Y, Kano M, Akutsu Y, Hanari N, Hoshino I, Murakami K, Usui A, Suito H, Takahashi M, Otsuka R, Xin H, Komatsu A, Iida K, Matsubara H. Quantification of plasma exosome is a potential prognostic marker for esophageal squamous cell carcinoma. Oncol Rep 2016; 36:2535-2543. [PMID: 27599779 PMCID: PMC5055211 DOI: 10.3892/or.2016.5066] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 07/25/2016] [Indexed: 12/14/2022] Open
Abstract
Exosomes play important roles in cancer progression. Although its contents (e.g., proteins and microRNAs) have been focused on in cancer research, particularly as potential diagnostic markers, the exosome behavior and methods for exosome quantification remain unclear. In the present study, we analyzed the tumor-derived exosome behavior and assessed the quantification of exosomes in patient plasma as a biomarker for esophageal squamous cell carcinoma (ESCC). A CD63-GFP expressing human ESCC cell line (TE2-CD63-GFP) was made by transfection, and mouse subcutaneous tumor models were established. Fluorescence imaging was performed on tumors and plasma exosomes harvested from mice. GFP-positive small vesicles were confirmed in the plasma obtained from TE2-CD63-GFP tumor-bearing mice. Patient plasma was collected in Chiba University Hospital (n=86). Exosomes were extracted from 100 µl of the plasma and quantified by acetylcholinesterase (AChE) activity. The relationship between exosome quantification and the patient clinical characteristics was assessed. The quantification of exosomes isolated from the patient plasma revealed that esophageal cancer patients (n=66) expressed higher exosome levels than non-malignant patients (n=20) (P=0.0002). Although there was no correlation between the tumor progression and the exosome levels, exosome number was the independent prognostic marker and low levels of exosome predicted a poor prognosis (P=0.03). In conclusion, exosome levels may be useful as an independent prognostic factor for ESCC patients.
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Affiliation(s)
- Yasunori Matsumoto
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yasunori Akutsu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Naoyuki Hanari
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Isamu Hoshino
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kentaro Murakami
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Akihiro Usui
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiroshi Suito
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Masahiko Takahashi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Ryota Otsuka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hu Xin
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Aki Komatsu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Keiko Iida
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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36
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Human Bone Xenografts: from Preclinical Testing for Regenerative Medicine to Modeling of Diseases. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/s40610-016-0044-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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