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Soria B, Escacena N, Gonzaga A, Soria-Juan B, Andreu E, Hmadcha A, Gutierrez-Vilchez AM, Cahuana G, Tejedo JR, De la Cuesta A, Miralles M, García-Gómez S, Hernández-Blasco L. Cell Therapy of Vascular and Neuropathic Complications of Diabetes: Can We Avoid Limb Amputation? Int J Mol Sci 2023; 24:17512. [PMID: 38139339 PMCID: PMC10743405 DOI: 10.3390/ijms242417512] [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: 10/27/2023] [Revised: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
Globally, a leg is amputated approximately every 30 seconds, with an estimated 85 percent of these amputations being attributed to complications arising from diabetic foot ulcers (DFU), as stated by the American Diabetes Association. Peripheral arterial disease (PAD) is a risk factor resulting in DFU and can, either independently or in conjunction with diabetes, lead to recurring, slow-healing ulcers and amputations. According to guidelines amputation is the recommended treatment for patients with no-option critical ischemia of the limb (CTLI). In this article we propose cell therapy as an alternative strategy for those patients. We also suggest the optimal time-frame for an effective therapy, such as implanting autologous mononuclear cells (MNCs), autologous and allogeneic mesenchymal stromal cells (MSC) as these treatments induce neuropathy relief, regeneration of the blood vessels and tissues, with accelerated ulcer healing, with no serious side effects, proving that advanced therapy medicinal product (ATMPs) application is safe and effective and, hence, can significantly prevent limb amputation.
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Affiliation(s)
- Bernat Soria
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
| | - Natalia Escacena
- Fresci Consultants, Human Health Innovation, 08025 Barcelona, Spain
| | - Aitor Gonzaga
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
| | - Barbara Soria-Juan
- Reseaux Hôpitalieres Neuchatelois et du Jura, 2000 Neuchâtel, Switzerland
| | - Etelvina Andreu
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Department of Applied Physics, University Miguel Hernández Elche, 03202 Elche, Spain
| | - Abdelkrim Hmadcha
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), 46002 Valencia, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Ana Maria Gutierrez-Vilchez
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- Department of Pharmacology, Pediatrics and Organic Chemistry, University Miguel Hernández, 03202 Elche, Spain
| | - Gladys Cahuana
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Juan R. Tejedo
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | | | - Manuel Miralles
- University and Polytechnic Hospital La Fe, 46026 Valencia, Spain
| | | | - Luis Hernández-Blasco
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
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Current Status of Cell-Based Therapy in Patients with Critical Limb Ischemia. Int J Mol Sci 2020; 21:ijms21238999. [PMID: 33256237 PMCID: PMC7731417 DOI: 10.3390/ijms21238999] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
(1) Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. (2) Aims: The aim of this narrative review was to provide an up-to-date critical overview of the knowledge and evidence-based medicine data on the position of cell therapy in the treatment of PAD. The current evidence on the cell-based therapy is summarized and future perspectives outlined, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. (3) Methods: Cochrane and PubMed databases were searched for keywords “critical limb ischemia and cell therapy”. In total, 589 papers were identified, 11 of which were reviews and 11 were meta-analyses. These were used as the primary source of information, using cross-referencing for identification of additional papers. (4) Results: Meta-analyses focusing on cell therapy in PAD treatment confirm significantly greater odds of limb salvage in the first year after the cell therapy administration. Reported odds ratio estimates of preventing amputation being mostly in the region 1.6–3, although with a prolonged observation period, it seems that the odds ratio can grow even further. The odds of wound healing were at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. (5) Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective.
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3
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Rahbari NN, Schölch S, Bork U, Kahlert C, Schneider M, Rahbari M, Büchler MW, Weitz J, Reissfelder C. Prognostic value of circulating endothelial cells in metastatic colorectal cancer. Oncotarget 2018; 8:37491-37501. [PMID: 28415583 PMCID: PMC5514924 DOI: 10.18632/oncotarget.16397] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 03/01/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND There is urgent need for improved staging in patients with metastatic colorectal cancer (mCRC). In this study, we evaluated the prognostic value of circulating endothelial cells (CEC) in comparison with circulating tumor cells (CTC) in patients with mCRC amenable for potentially curative surgery. METHODS A total of 140 patients were enrolled prospectively. CTC and CEC were measured with the CellSearch System (Veridex, NJ, USA). Cut-off values were determined using ROC analyses. Prognostic factors were identified by Cox proportional hazards models. RESULTS ROC analyses revealed ≥ 21 CEC as cut-off levels for detection, which was present in 68 (49%). CEC detection was associated with female gender (p = 0.03) only, whereas CTC detection was associated with presence of the primary tumor (p = 0.007), metastasis size (p < 0.001), bilobar liver metastases (p = 0.02), CEA (p < 0.001) and CA 19-9 levels (p < 0.001). On multivariate analysis only CEC detection (HR 1.81; p = 0.03) and preoperative CA19-9 levels (HR 2.28, p = 0.005) were revealed as independent predictors of poor survival. CONCLUSIONS CEC are of stronger prognostic value than CTC. Further studies are required to validate these results and to evaluate CEC as predictive biomarker for systemic therapy alone as well as in combination with other markers such as CA19-9.
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Affiliation(s)
- Nuh N Rahbari
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany
| | - Sebastian Schölch
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany
| | - Ulrich Bork
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany
| | - Christoph Kahlert
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Mohammad Rahbari
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany
| | - Markus W Büchler
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany
| | - Christoph Reissfelder
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany
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Yoder MC. Endothelial stem and progenitor cells (stem cells): (2017 Grover Conference Series). Pulm Circ 2018; 8:2045893217743950. [PMID: 29099663 PMCID: PMC5731724 DOI: 10.1177/2045893217743950] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 10/31/2017] [Indexed: 12/11/2022] Open
Abstract
The capacity of existing blood vessels to give rise to new blood vessels via endothelial cell sprouting is called angiogenesis and is a well-studied biologic process. In contrast, little is known about the mechanisms for endothelial cell replacement or regeneration within established blood vessels. Since clear definitions exist for identifying cells with stem and progenitor cell properties in many tissues and organs of the body, several groups have begun to accumulate evidence that endothelial stem and progenitor cells exist within the endothelial intima of existing blood vessels. This paper will review stem and progenitor cell definitions and highlight several recent papers purporting to have identified resident vascular endothelial stem and progenitor cells.
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Affiliation(s)
- Mervin C. Yoder
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
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5
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Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 2017; 20:409-426. [PMID: 28660302 DOI: 10.1007/s10456-017-9562-9] [Citation(s) in RCA: 1003] [Impact Index Per Article: 125.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 06/21/2017] [Indexed: 12/27/2022]
Abstract
Tumor blood vessels are a key target for cancer therapeutic management. Tumor cells secrete high levels of pro-angiogenic factors which contribute to the creation of an abnormal vascular network characterized by disorganized, immature and permeable blood vessels, resulting in poorly perfused tumors. The hypoxic microenvironment created by impaired tumor perfusion can promote the selection of more invasive and aggressive tumor cells and can also impede the tumor-killing action of immune cells. Furthermore, abnormal tumor perfusion also reduces the diffusion of chemotherapeutic drugs and radiotherapy efficiency. To fight against this defective phenotype, the normalization of the tumor vasculature has emerged as a new therapeutic strategy. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. In this review, we investigate the mechanisms involved in tumor angiogenesis and describe strategies used to achieve vascular normalization.
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Das SK, Yuan YF, Li MQ. An Overview on Current Issues and Challenges of Endothelial Progenitor Cell-Based Neovascularization in Patients with Diabetic Foot Ulcer. Cell Reprogram 2017; 19:75-87. [PMID: 28266867 DOI: 10.1089/cell.2016.0050] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Diabetic foot ulcer's impaired wound healing, which leads to the development of chronic non-healing wounds and ultimately amputation, is a major problem worldwide. Although recently endothelial progenitor cell-derived cell therapy has been used as a therapeutic intervention to treat diabetic wounds, thereby promoting neovascularization, the results, however, are not satisfactory. In this article, we have discussed the several steps that are involved in the neovascularization process, which might be impaired during diabetes. In addition, we have also discussed the reported possible interventions to correct these impairments. Thus, we have summarized neovascularization as a process with a coordinated sequence of multiple steps and thus, there is the need of a combined therapeutic approach to achieve better treatment outcomes.
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Affiliation(s)
- Sushant Kumar Das
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, Tongji University , Shanghai, People's Republic of China
| | - Yi Feng Yuan
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, Tongji University , Shanghai, People's Republic of China
| | - Mao Quan Li
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, Tongji University , Shanghai, People's Republic of China
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7
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Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature. Clin Transl Oncol 2016; 19:125-133. [PMID: 27188167 DOI: 10.1007/s12094-016-1515-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 04/19/2016] [Indexed: 10/21/2022]
Abstract
PURPOSE Tumor expansion is dependent on neovascularization, a process that requires sustained new vessel formation. Although the critical role of angiogenesis by endothelial sprouting in this process, controversy still prevails on whether angiogenesis involving bone marrow-derived endothelial cells, does contribute to this process. This study aims to evaluate the recruitment of bone marrow-derived cells by the melanoma tumor, including endothelial cells, and if they contribute to angiogenesis. METHODS A chimeric mouse model of GFP bone marrow was used to induce melanoma tumors derived from murine B16-F10 cell line. These tumors were evaluated for the presence of myeloid cells (CD11b), T lymphocytes (CD3, CD4 and CD8) and endothelial cells (VEGFR2 and CD31) derived from bone marrow. RESULTS Mice transplanted with GFP+ cells showed significant bone marrow chimerism (90.9 ± 0.87 %) when compared to the GFP transgenic mice (90.66 ± 2.1 %, p = 0.83) demonstrating successful engraftment of donor bone marrow stem/progenitor cells. Analysis of the murine melanoma tumor showed the presence of donor cells in the tumors (3.5 ± 1.7 %) and interestingly, these cells represent endothelial cells (CD31+ cells; 11.5 ± 6.85 %) and myeloid cells (CD11b+ cells; 80 ± 21 %), but also tumor-infiltrating lymphocytes (CD8+ T cells, 13.31 ± 0.2 %; CD4+ T-cells, 2.1 ± 1.2 %). Examination of the tumor endothelium by confocal microscopy suggests the presence of donor CD31+/GFP+ cells in the wall of some blood vessels. CONCLUSION This study demonstrates that bone marrow-derived cells are recruited by the murine melanoma tumor, with myeloid cells and CD4 and CD8 T lymphocytes migrating as antitumor immune response, and endothelial cells participating of the tumor blood vessels formation.
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Endothelial progenitor cells support tumour growth and metastatisation: implications for the resistance to anti-angiogenic therapy. Tumour Biol 2015; 36:6603-14. [DOI: 10.1007/s13277-015-3823-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/20/2015] [Indexed: 12/15/2022] Open
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9
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Klein D, Meissner N, Kleff V, Jastrow H, Yamaguchi M, Ergün S, Jendrossek V. Nestin(+) tissue-resident multipotent stem cells contribute to tumor progression by differentiating into pericytes and smooth muscle cells resulting in blood vessel remodeling. Front Oncol 2014; 4:169. [PMID: 25019063 PMCID: PMC4072089 DOI: 10.3389/fonc.2014.00169] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 06/11/2014] [Indexed: 12/14/2022] Open
Abstract
Tumor vessels with resistance to anti-angiogenic therapy are characterized by the normalization of the vascular structures through integration of mature pericytes and smooth muscle cells (SMC) into the vessel wall, a process termed vessel stabilization. Unfortunately, stabilization-associated vascular remodeling can result in reduced sensitivity to subsequent anti-angiogenic therapy. We show here that blockade of VEGF by bevacizumab induces stabilization of angiogenic tumor blood vessels in human tumor specimen by recruiting Nestin-positive cells, whereas mature vessels down-regulated Nestin-expression. Using xenograft tumors growing on bone-marrow (BM) chimera of C57Bl/6 wildtype and Nestin-GFP transgenic mice, we show for first time that Nestin(+) cells inducing the maturation of tumor vessels do not originate from the BM but presumably reside within the adventitia of adult blood vessels. Complementary ex vivo experiments using explants of murine aortas revealed that Nestin(+) multipotent stem cells (MPSCs) are mobilized from their niche and differentiated into pericytes and SMC through the influence of tumor-cell-secreted factors. We conclude that tissue-resident Nestin(+) cells are more relevant than BM-derived cells for vessel stabilization and therefore have to be considered in future strategies for anti-angiogenic therapy. The identification of proteins mediating recruitment or differentiation of local Nestin(+) cells with potential stem cell character to angiogenic blood vessels may allow the definition of new therapeutic targets to reduce tumor resistance against anti-angiogenic drugs.
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Affiliation(s)
- Diana Klein
- Institute for Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Nicole Meissner
- Institute for Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Veronika Kleff
- Institute of Anatomy, University Hospital, University of Duisburg-Essen , Essen , Germany
| | - Holger Jastrow
- Institute of Anatomy, University Hospital, University of Duisburg-Essen , Essen , Germany
| | - Masahiro Yamaguchi
- Department of Physiology, Graduate School of Medicine, University of Tokyo , Tokyo , Japan
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, University of Würzburg , Würzburg , Germany
| | - Verena Jendrossek
- Institute for Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen , Essen , Germany
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Yu P, Ge YZ, Zhao Y, Wu JP, Wu R, Zhou LH, Jia RP. Identification and significance of mobilized endothelial progenitor cells in tumor neovascularization of renal cell carcinoma. Tumour Biol 2014; 35:9331-41. [PMID: 24943683 DOI: 10.1007/s13277-014-2205-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 06/06/2014] [Indexed: 12/12/2022] Open
Abstract
Neovascularization is a key role of renal cell carcinoma (RCC) and the status of neovascularization in RCC is closely correlated with the tumor development and patient prognosis. Endothelial progenitor cells (EPCs) are considered as important building blocks for neovascularization. However, the role of mobilized EPCs in RCC remains unknown. In this study, the orthotopic RCC model was established to investigate the distribution, frequency, and significance of mobilized EPCs. We found that circulating endothelial progenitor cell (CEPC) levels and plasma angiogenic factors (vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were higher in peripheral blood (PB) of the RCC than those in the normal group and positively correlated with each other. EPC levels in adjacent nonmalignant kidney tissue (AT) were significantly higher than those in tumor tissue (TT) and normal kidney tissue (NT), which were positively correlated with CEPC levels. VEGF, VEGF receptor-2 (Flk), and SDF-1 and its SDF-1 receptor (CXCR4) expression in AT was significantly higher than that in TT and NT. Levels of these angiogenic factors in AT were positively correlated with those in PB. Mean microvessel density (MVD) was higher in AT than in TT, and that in TT was slightly lower than that in NT. Our findings propose that mobilized EPCs play an important role in RCC neovascularization. EPCs in PB and AT can be used as a biomarker for predicting RCC progression.
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Affiliation(s)
- Peng Yu
- Department of Urology and Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, People's Republic of China
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Florczyk U, Jazwa A, Maleszewska M, Mendel M, Szade K, Kozakowska M, Grochot-Przeczek A, Viscardi M, Czauderna S, Bukowska-Strakova K, Kotlinowski J, Jozkowicz A, Loboda A, Dulak J. Nrf2 regulates angiogenesis: effect on endothelial cells, bone marrow-derived proangiogenic cells and hind limb ischemia. Antioxid Redox Signal 2014; 20:1693-708. [PMID: 24053644 PMCID: PMC3961841 DOI: 10.1089/ars.2013.5219] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
AIMS Nuclear factor E2-related factor 2 (Nrf2), a key cytoprotective transcription factor, regulates also proangiogenic mediators, interleukin-8 and heme oxygenase-1 (HO-1). However, hitherto its role in blood vessel formation was modestly examined. Particularly, although Nrf2 was shown to affect hematopoietic stem cells, it was not tested in bone marrow-derived proangiogenic cells (PACs). Here we investigated angiogenic properties of Nrf2 in PACs, endothelial cells, and inflammation-related revascularization. RESULTS Treatment of endothelial cells with angiogenic cytokines increased nuclear localization of Nrf2 and induced expression of HO-1. Nrf2 activation stimulated a tube network formation, while its inhibition decreased angiogenic response of human endothelial cells, the latter effect reversed by overexpression of HO-1. Moreover, lack of Nrf2 attenuated survival, proliferation, migration, and angiogenic potential of murine PACs and affected angiogenic transcriptome in vitro. Additionally, angiogenic capacity of PAC Nrf2(-/-) in in vivo Matrigel assay and PAC mobilization in response to hind limb ischemia of Nrf2(-/-) mice were impaired. Despite that, restoration of blood flow in Nrf2-deficient ischemic muscles was better and accompanied by increased oxidative stress and inflammatory response. Accordingly, the anti-inflammatory agent etodolac tended to diminish blood flow in the Nrf2(-/-) mice. INNOVATION Identification of a novel role of Nrf2 in angiogenic signaling of endothelial cells and PACs. CONCLUSION Nrf2 contributes to angiogenic potential of both endothelial cells and PACs; however, its deficiency increases muscle blood flow under tissue ischemia. This might suggest a proangiogenic role of inflammation in the absence of Nrf2 in vivo, concomitantly undermining the role of PACs in such conditions.
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Affiliation(s)
- Urszula Florczyk
- 1 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Krakow, Poland
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Fadini GP. A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications. Diabetologia 2014; 57:4-15. [PMID: 24173366 DOI: 10.1007/s00125-013-3087-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 10/01/2013] [Indexed: 01/10/2023]
Abstract
Traditionally, the development of diabetic complications has been attributed to the biochemical pathways driving hyperglycaemic cell damage, while reparatory mechanisms have been long overlooked. A more comprehensive view of the balance between damage and repair suggests that an impaired regenerative capacity of bone marrow (BM)-derived cells strongly contributes to defective re-endothelisation and neoangiogenesis in diabetes. Although recent technological advances have redefined the biology and function of endothelial progenitor cells (EPCs), interest in BM-derived vasculotropic cells in the setting of diabetes and its complications remains high. Several circulating cell types of haematopoietic and non-haematopoietic origin are affected by diabetes and are potentially involved in the pathobiology of chronic complications. In addition to classical EPCs, these include circulating (pro-)angiogenic cells, polarised monocytes/macrophages (M1 and M2), myeloid calcifying cells and smooth muscle progenitor cells, having disparate roles in vascular biology. In parallel with the study of elusive progenitor cell phenotypes, it has been recognised that diabetes induces a profound remodelling of the BM stem cell niche. The alteration of circulating (progenitor) cells in the BM is now believed to be the link among distant end-organ complications. The field is rapidly evolving and interest is shifting from specific cell populations to the complex network of interactions that orchestrate trafficking of circulating vasculotropic cells.
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Affiliation(s)
- G P Fadini
- Department of Medicine, University Hospital of Padova, University of Padova, Via Giustiniani, 2, 35100, Padova, Italy,
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Reeves F, Sapre N, Corcoran N, Hovens C. Tumor vascularity in prostate cancer: an update on circulating endothelial cells and platelets as noninvasive biomarkers. Biomark Med 2013; 7:879-91. [PMID: 24266820 DOI: 10.2217/bmm.13.100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
In order to individually tailor prostate cancer (PCa) treatment, clinicians need better tools to predict prognosis and treatment response. Given the relationship between angiogenesis and cancer progression, circulating endothelial cells (CECs) and their progenitors have logically been proposed as potential biomarkers. The utility of their baseline levels and kinetics has been investigated for years. However, owing to a lack of standardization and validation of CEC and circulating endothelial progenitors enumeration protocols, results have been inconsistent in prostate and other cancers. Similarly, platelets play a significant part in cancer progression, yet the role of platelet-related biomarkers in PCa is unclear. While there have been a number of theoretically interesting platelet-related markers proposed, limited research has been conducted in PCa patients. Currently, CECs and platelets do not have a clear role as biomarkers in routine PCa care. Given the theoretical merits of these cells, prospective trials are warranted.
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Affiliation(s)
- Fairleigh Reeves
- Department of Urology & Surgery, University of Melbourne, Level 3 Centre, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
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Hepatic ischemia-reperfusion increases circulating bone marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases. J Surg Res 2013; 184:888-97. [PMID: 23726239 DOI: 10.1016/j.jss.2013.04.069] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 04/09/2013] [Accepted: 04/26/2013] [Indexed: 01/22/2023]
Abstract
BACKGROUND Hepatic pedicle clamping is often required to reduce blood loss and transfusion during liver resection. However, the question remains whether use of hepatic pedicle clamping promotes tumor growth. Endothelial progenitor cells (EPCs) are mobilized from bone marrow in response to tissue ischemia, which allows neovascularization of ischemic tissue. It has been suggested that EPCs are involved in tumor progression. We hypothesized that hepatic ischemia reperfusion (I/R)-induced mobilization of EPCs could enhance growth of microscopic tumor, therefore promoting liver metastasis in a mouse model of colorectal cancer. MATERIALS AND METHODS We used mouse models of hepatic I/R and hind limb ischemia. For comparison, we studied mice that underwent limb ischemia as positive controls of EPC mobilization. At day 0, we divided 40 mice into four groups: hepatic I/R, hind limb ischemia, combined hepatic I/R and hind limb ischemia, and control (sham midline incision laparotomy). At day 2, we induced liver metastasis in all mice by injecting CT-26 cells into the spleen. Time-dependent circulating EPCs were determined by flow cytometry. We evaluated liver metastasis and microvascular density on day 21. RESULTS The number of circulating progenitor cells increased rapidly in the ischemic groups compared with the control group. Hepatic I/R significantly increased tumor outgrowth compared with the control group. Increased tumor growth was associated with enhanced CD31-positive microvascular density in liver tissue. CONCLUSIONS Hepatic I/R leads to mobilization of bone marrow-derived EPCs and enhanced intra-hepatic angiogenesis, which is associated with increased tumor burden in an animal model of colorectal liver metastasis.
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HUANG SHUAI, PENG LONGYUN, TANG YUBO, ZHANG LONGJUAN, GUO WEI, ZOU XUENONG, PENG XINSHENG. Hypoxia of PC-3 prostate cancer cells enhances migration and vasculogenesis in vitro of bone marrow-derived endothelial progenitor cells by secretion of cytokines. Oncol Rep 2013; 29:2369-77. [DOI: 10.3892/or.2013.2363] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 02/22/2013] [Indexed: 11/06/2022] Open
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Yoder MC. Endothelial progenitor cell: a blood cell by many other names may serve similar functions. J Mol Med (Berl) 2013; 91:285-95. [PMID: 23371317 PMCID: PMC3704045 DOI: 10.1007/s00109-013-1002-8] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 01/13/2013] [Indexed: 12/15/2022]
Abstract
The first reports of circulating cells that displayed the capacity to repair and regenerate damaged vascular endothelial cells as progenitor cells for the endothelial lineage (EPC) were met with great enthusiasm. However, the cell surface antigens and colony assays used to identify the putative EPC were soon found to overlap with those of the hematopoietic lineage. Over the past decade, it has become clear that specific hematopoietic subsets play important roles in vascular repair and regeneration. This review will provide some overview of the hematopoietic hierarchy and methods to segregate distinct subsets that may provide clarity in identifying the proangiogenic hematopoietic cells. This review will not discuss those circulating viable endothelial cells that play a role as EPC and are called endothelia colony-forming cells. The review will conclude with identification of some roadblocks to progress in the field of identification of circulating cells that participate in vascular repair and regeneration.
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Affiliation(s)
- Mervin C Yoder
- Hermann B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Generation of functional blood vessels from a single c-kit+ adult vascular endothelial stem cell. PLoS Biol 2012; 10:e1001407. [PMID: 23091420 PMCID: PMC3473016 DOI: 10.1371/journal.pbio.1001407] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 09/05/2012] [Indexed: 12/22/2022] Open
Abstract
Adult vascular endothelial stem cells are shown to reside in the blood vessel wall endothelium. When isolated, these cells are capable of clonal expansion and generate functional blood vessels in vivo. In adults, the growth of blood vessels, a process known as angiogenesis, is essential for organ growth and repair. In many disorders including cancer, angiogenesis becomes excessive. The cellular origin of new vascular endothelial cells (ECs) during blood vessel growth in angiogenic situations has remained unknown. Here, we provide evidence for adult vascular endothelial stem cells (VESCs) that reside in the blood vessel wall endothelium. VESCs constitute a small subpopulation within CD117+ (c-kit+) ECs capable of undergoing clonal expansion while other ECs have a very limited proliferative capacity. Isolated VESCs can produce tens of millions of endothelial daughter cells in vitro. A single transplanted c-kit-expressing VESC by the phenotype lin−CD31+CD105+Sca1+CD117+ can generate in vivo functional blood vessels that connect to host circulation. VESCs also have long-term self-renewal capacity, a defining functional property of adult stem cells. To provide functional verification on the role of c-kit in VESCs, we show that a genetic deficit in endothelial c-kit expression markedly decreases total colony-forming VESCs. In vivo, c-kit expression deficit resulted in impaired EC proliferation and angiogenesis and retardation of tumor growth. Isolated VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization after ischemic events. VESCs also provide a novel cellular target to block pathological angiogenesis and cancer growth. Angiogenesis—the growth of blood vessels—is essential for organ growth and repair, but also occurs during tumorigenesis and in certain inflammatory disorders. All blood vessels are lined by endothelial cells (ECs)—thin, flattened cells that form a continuous monolayer throughout the entire circulatory system. The cellular origin of new vascular ECs during blood vessel growth in angiogenic situations in adults is a matter of debate. New ECs could develop, in principle, from as yet undiscovered stem cells, as is well documented for the differentiated cells of skin or epithelia, or by the duplication of existing differentiated ECs. Here, we provide evidence for the existence of vascular endothelial stem cells (VESCs) that reside in the adult blood vessel wall endothelium. VESCs constitute a small subpopulation of ECs capable of clonal expansion, while other ECs have a very limited proliferative capacity. When isolated, these VESCs can produce tens of millions of endothelial daughter cells, and a single transplanted VESC can generate in vivo functional blood vessels that connect to host blood circulation. Isolated VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization following ischemia and could also be pursued as a novel cellular target of inhibition to block pathological angiogenesis, for example during tumor growth.
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Zhu H, Shao Q, Sun X, Deng Z, Yuan X, Yu D, Zhou X, Ding Y. The mobilization, recruitment and contribution of bone marrow-derived endothelial progenitor cells to the tumor neovascularization occur at an early stage and throughout the entire process of hepatocellular carcinoma growth. Oncol Rep 2012; 28:1217-1224. [PMID: 22858892 DOI: 10.3892/or.2012.1944] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 05/11/2012] [Indexed: 01/17/2023] Open
Abstract
Obvious neovascularization is a key feature of hepatocellular carcinoma (HCC) and the status of neovascularization in HCC is closely correlated with the tumor growth and patient prognosis. The actual effect of current antivascular treatment including embolization to HCC is not satisfactory. Compensatory angiogenesis is one of the primary causes responsible for failure of antiangiogenic therapy. Bone marrow-derived endothelial progenitor cells (BM-EPCs) are considered as important building blocks for adult neovascularization. However, the role of mobilized BM-EPCs in HCC remains unknown. In this study, GFP+-BM orthotropic HCC mice were established to investigate whether BM-EPCs are involved in HCC-induced neovascularization. We found that a large number of BM-EPCs were mobilized into the circulation with the development of HCC, recruited into the HCC region and incorporated into the vascular endothelium directly by differentiation into vascular endothelial cells, including sinus, capillary vessels and great vessels. Dynamic observation revealed that the mobilization and the incorporation of BM-EPCs into different types of vessels were present in early phases and throughout the whole process of HCC growth. The proportion of BM-EPCs in vessels increased gradually, from 17 to 21% with tumor growth. Moreover, injected GFP+-EPCs also specifically homed to tumor tissue and incorporated into tumor vessels directly. In this initial study, we demonstrated that BM-EPCs play a prominent role in HCC neovascularization. Blockade of BM-EPC-mediated vasculogenesis may improve the efficacy of current anti-vascularization therapy for patients with HCC.
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MESH Headings
- AC133 Antigen
- Animals
- Antigens, CD/metabolism
- Antigens, CD34/metabolism
- Blood Circulation
- Bone Marrow/pathology
- Capillaries/pathology
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Endothelial Cells/pathology
- Glycoproteins/metabolism
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Intercellular Adhesion Molecule-1/metabolism
- Liver Neoplasms/blood supply
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Peptides/metabolism
- Up-Regulation
- Vascular Cell Adhesion Molecule-1/metabolism
- Vascular Endothelial Growth Factor A/metabolism
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Affiliation(s)
- Haitao Zhu
- Institute of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Affiliated DrumTower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, PR China
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Sun XT, Yuan XW, Zhu HT, Deng ZM, Yu DC, Zhou X, Ding YT. Endothelial precursor cells promote angiogenesis in hepatocellular carcinoma. World J Gastroenterol 2012; 18:4925-4933. [PMID: 23002366 PMCID: PMC3447276 DOI: 10.3748/wjg.v18.i35.4925] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Revised: 05/16/2012] [Accepted: 05/26/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of bone marrow-derived endothelial progenitor cells (EPCs) in the angiogenesis of hepatocellular carcinoma (HCC). METHODS The bone marrow of HCC mice was reconstructed by transplanting green fluorescent protein (GFP) + bone marrow cells. The concentration of circulating EPCs was determined by colony-forming assays and fluorescence-activated cell sorting. Serum and tissue levels of vascular endothelial growth factor (VEGF) and colony-stimulating factor (CSF) were quantified by enzyme-linked immunosorbent assay. The distribution of EPCs in tumor and tumor-free tissues was detected by immunohistochemistry and real-time polymerase chain reaction. The incorporation of EPCs into hepatic vessels was examined by immunofluorescence and immunohistochemistry. The proportion of EPCs in vessels was then calculated. RESULTS The HCC model was successful established. The flow cytometry analysis showed the mean percentage of CD133CD34 and CD133VEGFR2 double positive cells in HCC mice was 0.45% ± 0.16% and 0.20% ± 0.09% respectively. These values are much higher than in the sham-operation group (0.11% ± 0.13%, 0.05% ± 0.11%, n = 9) at 14 d after modeling. At 21 d, the mean percentage of circulating CD133CD34 and CD133VEGFR2 cells is 0.23% ± 0.19%, 0.25% ± 0.15% in HCC model vs 0.05% ± 0.04%, 0.12% ± 0.11% in control. Compared to the transient increase observed in controls, the higher level of circulating EPCs were induced by HCC. In addition, the level of serum VEGF and CSF increased gradually in HCC, reaching its peak 14 d after modeling, then slowly decreased. Consecutive sections stained for the CD133 and CD34 antigens showed that the CD133+ and CD34+ VEGFR2 cells were mostly recruited to HCC tissue and concentrated in tumor microvessels. Under fluorescence microscopy, the bone-marrow (BM)-derived cells labeled with GFP were concentrated in the same area. The relative levels of CD133 and CD34 gene expression were elevated in tumors, around 5.0 and 3.8 times that of the tumor free area. In frozen liver sections from HCC mice, cells co-expressing CD133 and VEGFR2 were identified by immunohistochemical staining using anti-CD133 and VEGFR2 antibodies. In tumor tissue, the double-positive cells were incorporated into vessel walls. In immunofluorescent staining. These CD31 and GFP double positive cells are direct evidence that tumor vascular endothelial cells (VECs) come partly from BM-derived EPCs. The proportion of GFP CD31 double positive VECs (out of all VECs) on day 21 was around 35.3% ± 21.2%. This is much higher than the value recorded on day 7 group (17.1% ± 8.9%). The expression of intercellular adhesion molecule 1, vascular adhesion molecule 1, and VEGF was higher in tumor areas than in tumor-free tissues. CONCLUSION Mobilized EPCs were found to participate in tumor vasculogenesis of HCC. Inhibiting EPC mobilization or recruitment to tumor tissue may be an efficient strategy for treating HCC.
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MESH Headings
- AC133 Antigen
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, CD34/genetics
- Antigens, CD34/metabolism
- Bone Marrow Transplantation
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Movement
- Cell Separation/methods
- Colony-Forming Units Assay
- Colony-Stimulating Factors/blood
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelial Cells/transplantation
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Fluorescent Antibody Technique
- Glycoproteins/genetics
- Glycoproteins/metabolism
- Green Fluorescent Proteins/biosynthesis
- Green Fluorescent Proteins/genetics
- Immunohistochemistry
- Intercellular Adhesion Molecule-1/metabolism
- Liver Neoplasms/blood supply
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neovascularization, Pathologic
- Peptides/genetics
- Peptides/metabolism
- Real-Time Polymerase Chain Reaction
- Stem Cell Transplantation
- Stem Cells/metabolism
- Stem Cells/pathology
- Time Factors
- Vascular Cell Adhesion Molecule-1/metabolism
- Vascular Endothelial Growth Factor A/blood
- Vascular Endothelial Growth Factor Receptor-2/metabolism
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Nowak K, Jachol N, Rafat N, Joas E, Beck GC, Hohenberger P. Alterations of circulating bone marrow-derived VEGFR-2+ progenitor cells in isolated limb perfusion with or without rhTNF-α. Ann Surg Oncol 2012; 20:3694-701. [PMID: 22948772 PMCID: PMC3764318 DOI: 10.1245/s10434-012-2637-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Circulating endothelial progenitor cells (cEPCs) as recruited to the angiogenic vascular system of malignant tumors have been proposed as a biomarker in malignancies. The effect of antitumor chemotherapy on cEPCs is not fully understood. We examined the level of cEPCs, vascular endothelial growth factor (VEGF), and angiopoietin-2 in the blood of sarcoma and melanoma patients before and after isolated limb perfusion (ILP) with or without recombinant human tumor necrosis factor-α (rhTNF-α). METHODS Twenty-two patients, 11 each with soft tissue sarcoma or recurrent melanoma of the limb, were recruited. ILP was performed with rhTNF-α/melphalan (TNF) or melphalan only (no TNF). Fifteen healthy volunteers served as control subjects. Blood was sampled before and up to 6 weeks after ILP. Peripheral blood mononuclear cells were isolated by density gradient centrifugation, and annexin V-negative cells were characterized as cEPCs by triple staining for CD133(+), CD34, and VEGFR-2(+). RESULTS Before treatment, cEPC numbers were significantly increased in sarcoma (0.179 ± 0.190 %) and melanoma patients (0.110 ± 0.073 %) versus healthy controls (0.025 ± 0.018 %; P < 0.01), but did not differ significantly between sarcoma and melanoma patients. cEPC decreased significantly after ILP in patients with no TNF compared to pretreatment values (P < 0.05) and were significantly lower at 4 h, 48 h, and 1 week compared to ILP with TNF (P < 0.05). Values 6 weeks after ILP were significantly lower than before ILP in both investigated groups (P < 0.01). CONCLUSIONS ILP with TNF results in activation of bone marrow-derived EPCs compared to ILP without TNF. Alteration of cEPCs and angiopoietin-2 by rhTNF-α might account for the cytotoxicity and hemorrhagic effects on tumor vessels during limb perfusion procedures.
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Affiliation(s)
- Kai Nowak
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, Mannheim University Medical Center, Heidelberg University, Heidelberg, Germany.
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Korkusuz H, Ulbrich K, Bihrer V, Welzel K, Chernikov V, Knobloch T, Petersen S, Huebner F, Ackermann H, Gelperina S, Korkusuz Y, Kromen W, Hammerstingl R, Haupenthal J, Fiehler J, Zeuzem S, Kreuter J, Vogl TJ, Piiper A. Contrast Enhancement of the Brain by Folate-Conjugated Gadolinium–Diethylenetriaminepentaacetic Acid–Human Serum Albumin Nanoparticles by Magnetic Resonance Imaging. Mol Imaging 2012. [DOI: 10.2310/7290.2011.00047] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Different from regular small molecule contrast agents, nanoparticle-based contrast agents have a longer circulation time and can be modified with ligands to confer tissue-specific contrasting properties. We evaluated the tissue distribution of polymeric nanoparticles (NPs) prepared from human serum albumin (HSA), loaded with gadolinium–diethylenetriaminepentaacetic acid (Gd-DTPA) (Gd-HSA-NP), and coated with folic acid (FA) (Gd-HSA-NP-FA) in mice by magnetic resonance imaging (MRI). FA increases the affinity of the Gd-HSA-NP to FA receptor–expressing cells. Clinical 3 T MRI was used to evaluate the signal intensities in the different organs of mice injected with Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-FA. Signal intensities were measured and standardized by calculating the signal to noise ratios. In general, the NP-based contrast agents provided stronger contrasting than Gd-DTPA. Gd-HSA-NP-FA provided a significant contrast enhancement (CE) in the brain ( p = .0032), whereas Gd-DTPA or Gd-HSA-NP did not. All studied MRI contrast agents showed significant CE in the blood, kidney, and liver ( p < .05). Gd-HSA-NP-FA elicited significantly higher CE in the blood than Gd-HSA-NP ( p = .0069); Gd-HSA-NP and Gd-HSA-NP-FA did not show CE in skeletal muscle and gallbladder; Gd-HSA-NP, but not Gd-HSA-NP-FA, showed CE in the cardiac muscle. Gd-HSA-NP-FA has potential as an MRI contrast agent in the brain.
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Affiliation(s)
- Huedayi Korkusuz
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karsten Ulbrich
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Verena Bihrer
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katerina Welzel
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Valery Chernikov
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Knobloch
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Petersen
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Huebner
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hanns Ackermann
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Svetlana Gelperina
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Yuecel Korkusuz
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Wolfgang Kromen
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Renate Hammerstingl
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jörg Haupenthal
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jens Fiehler
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Zeuzem
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jörg Kreuter
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas J. Vogl
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Albrecht Piiper
- From the Departments of Diagnostic and Interventional Radiology, Medicine I, and Biomathematics, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany; Institute of Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany; Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, Russia; Nanosystem Ltd, Moscow, Russia; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Zhu H, Shao Q, Sun X, Deng Z, Yuan X, Zhou X, Ding Y. Bone marrow cells: Important role on neovascularization of hepatocellular carcinoma. J Gastroenterol Hepatol 2012; 27:1241-51. [PMID: 22142567 DOI: 10.1111/j.1440-1746.2011.07044.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Present antivascular therapies including embolization to hepatocellular carcinoma (HCC) were not as satisfying as expected. The aim was to explore whether or not bone marrow cells (BMCs) played an important role on neovascularization in HCC. METHODS Bone marrow-GFP(+) orthotropic HCC mice model was used. In controls and HCC mice, the dynamic change of circulating BMCs and serum vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) were measured by flow cytometry and enzyme linked immunosorbent assay, respectively. Intrahepatic distribution of BMCs was evaluated using immunofluorescent and realtime polymerase chain reaction protocols. BMCs' intrahepatic differentiation and proportion in vessels was investigated by immunofluorescent methods. Immunohistochemistry and western blotting were performed to examine the expression of adhesion molecule in tumor tissues and tumor free tissues. RESULTS Compared with controls, the frequency of circulating BMCs and serum VEGF, PDGF were much higher in HCC mice. The number of BMCs and the level of CD133 gene in tumor increased significantly relative to the tumor free zone. Since the early stage of HCC, BMCs have been mobilized, recruited into tumor and incorporated into different types of vessels of the liver. Besides into endothelial cells, BMCs also differentiated into vascular fibroblast and hepatic stellate cells. Moreover with tumor growth, the proportion of BMCs in vessels increased gradually. CONCLUSION Mobilized BMCs played an important role in tumor vasculogenesis of HCC. Combined blockading of bone marrow-mediated vasculogenesis may improve the efficacy of current therapy to HCC patients.
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Affiliation(s)
- Haitao Zhu
- Institute of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, the Affiliated DrumTower Hospital, School of Medicine, Nanjing University, NanJing, JiangSu Province, China
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Nakamura DS, Edwards AK, Virani S, Thomas R, Tayade C. Thrombospondin-1 mimetic peptide ABT-898 affects neovascularization and survival of human endometriotic lesions in a mouse model. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:570-82. [PMID: 22727957 DOI: 10.1016/j.ajpath.2012.05.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Revised: 04/04/2012] [Accepted: 05/02/2012] [Indexed: 12/25/2022]
Abstract
Endometriosis is a common cause of pelvic pain and infertility in women, and a common indication for hysterectomy, yet the disease remains poorly diagnosed and ineffectively treated. Because endometriotic lesions require new blood supply for survival, inhibiting angiogenesis could provide a novel therapeutic strategy. ABT-898 mimics the antiangiogenic properties of thrombospondin-1, so we hypothesized that ABT-898 will prevent neovascularization of human endometriotic lesions and that ABT-898 treatment will not affect reproductive outcomes in a mouse model. Endometriosis was induced in BALB/c-Rag2(-/-)Il2rg(-/-) mice by surgical implantation of human endometrial fragments in the peritoneal cavity. Mice received daily injections of ABT-898 for 21 days. Flow cytometry was performed to measure circulating endothelial progenitor cells in peripheral blood. Cytokines were measured in plasma samples. Half of the ABT-898-treated and control mice were euthanized to assess neovascularization of endometriotic lesions, using CD31(+) immunofluorescence. The remaining mice were mated and euthanized at gestation day 12. Endometriotic lesions increased circulating endothelial progenitor cells 13 days after engraftment, relative to baseline. Endometriotic lesions from ABT-898-treated mice exhibited reduced neovascularization, compared with controls, and lesions had fewer CD31(+) microvessels. Chronic treatment with ABT-898 did not lead to any fetal anomalies or affect litter size at gestation day 12, compared with controls. Our results suggest that ABT-898 inhibits neovascularization of human endometriotic lesions without affecting mouse fecundity.
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Affiliation(s)
- Diane S Nakamura
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
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Du F, Zhou J, Gong R, Huang X, Pansuria M, Virtue A, Li X, Wang H, Yang XF. Endothelial progenitor cells in atherosclerosis. Front Biosci (Landmark Ed) 2012; 17:2327-49. [PMID: 22652782 DOI: 10.2741/4055] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Endothelial progenitor cells (EPCs) are involved in the maintenance of endothelial homoeostasis and in the process of new vessel formation. Experimental and clinical studies have shown that atherosclerosis is associated with reduced numbers and dysfunction of EPCs; and that medications alone are able to partially reverse the impairment of EPCs in patients with atherosclerosis. Therefore, novel EPC-based therapies may provide enhancement in restoring EPCs' population and improvement of vascular function. Here, for a better understanding of the molecular mechanisms underlying EPC impairment in atherosclerosis, we provide a comprehensive overview on EPC characteristics, phenotypes, and the signaling pathways underlying EPC impairment in atherosclerosis.
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Affiliation(s)
- Fuyong Du
- Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA
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25
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Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 2012; 110:624-37. [PMID: 22343557 DOI: 10.1161/circresaha.111.243386] [Citation(s) in RCA: 510] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diverse subsets of endothelial progenitor cells (EPCs) are used for the treatment of ischemic diseases in clinical trials, and circulating EPCs levels are considered as biomarkers for coronary and peripheral artery disease. However, despite significant steps forward in defining their potential for both therapeutic and diagnostic purposes, further progress has been mired by unresolved questions around the definition and the mechanism of action of EPCs. Diverse culturing methods and detection of various combinations of different surface antigens were used to enrich and identify EPCs. These attempts were particularly challenged by the close relationship and overlapping markers of the endothelial and hematopoietic lineages. This article will critically review the most commonly used protocols to define EPCs by culture assays or by fluorescence-activated cell sorter in the context of their therapeutic or diagnostic use. We also delineate new research avenues to move forward our knowledge on EPC biology.
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Affiliation(s)
- Gian Paolo Fadini
- Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt, Germany
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Benoit E, O'Donnell TF, Patel AN. Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transplant 2012; 22:545-62. [PMID: 22490340 DOI: 10.3727/096368912x636777] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Researchers have accumulated a decade of experience with autologous cell therapy in the treatment of critical limb ischemia (CLI). We conducted a systematic review of clinical trials in the literature to determine the safety and efficacy of cell therapy in CLI. We searched the literature for clinical trials of autologous cell therapy in CLI, including observational series of five or more patients to accrue a large pool of patients for safety analysis. Safety analysis included evaluation of death, cancer, unregulated angiogenesis, and procedural adverse events such as bleeding. Efficacy analysis included the clinical endpoints amputation and death as well as functional and surrogate endpoints. We identified 45 clinical trials, including seven RCTs, and 1,272 patients who received cell therapy. The overall adverse event rate was low (4.2%). Cell therapy patients did not have a higher mortality rate than control patients and demonstrated no increase in cancer incidence when analyzed against population rates. With regard to efficacy, cell therapy patients had a significantly lower amputation rate than control patients (OR 0.36, p = 0.0004). Cell therapy also demonstrated efficacy in a variety of functional and surrogate outcomes. Clinical trials differed in the proportion of patients with risk factors for clinical outcomes, and these influenced rates of amputation and death. Cell therapy presents a favorable safety profile with a low adverse event rate and no increase in severe events such as mortality and cancer and treatment with cell therapy decreases the risk of amputation. Cell therapy has a positive benefit-to-risk ratio in CLI and may be a valuable treatment option, particularly for those challenging patients who cannot undergo arterial reconstruction.
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Affiliation(s)
- Eric Benoit
- Department of Surgery, Tufts Medical Center, Boston, MA, USA
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Schlosser S, Dennler C, Schweizer R, Eberli D, Stein JV, Enzmann V, Giovanoli P, Erni D, Plock JA. Paracrine effects of mesenchymal stem cells enhance vascular regeneration in ischemic murine skin. Microvasc Res 2012; 83:267-75. [PMID: 22391452 DOI: 10.1016/j.mvr.2012.02.011] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Revised: 02/08/2012] [Accepted: 02/19/2012] [Indexed: 02/07/2023]
Abstract
New theories on the regeneration of ischemic vasculature have emerged indicating a pivotal role of adult stem cells. The aim of this study was to investigate homing and hemodynamic effects of circulating bone marrow-derived mesenchymal stem cells (MSCs) in a critically ischemic murine skin flap model. Bone marrow-derived mesenchymal stem cells (Lin(-)CD105(+)) were harvested from GFP(+)-donor mice and transferred to wildtype C57BL/6 mice. Animals receiving GFP(+)-fibroblasts served as a control group. Laser scanning confocal microscopy and intravital fluorescence microscopy were used for morphological analysis, monitoring and quantitative assessment of the stem cell homing and microhemodynamics over two weeks. Immunohistochemical staining was performed for GFP, eNOS, iNOS, VEGF. Tissue viability was analyzed by TUNEL-assay. We were able to visualize perivascular homing of MSCs in vivo. After 4 days, MSCs aligned along the vascular wall without undergoing endothelial or smooth muscle cell differentiation during the observation period. The gradual increase in arterial vascular resistance observed in the control group was abolished after MSC administration (P<0.01). At capillary level, a strong angiogenic response was found from day 7 onwards. Functional capillary density was raised in the MSC group to 197% compared to 132% in the control group (P<0.01). Paracrine expression of VEGF and iNOS, but not eNOS could be shown in the MSC group but not in the controls. In conclusion, we demonstrated that circulating bone marrow-derived MSCs home to perivascular sites in critically ischemic tissue, exhibits paracrine function and augment microhemodynamics. These effects were mediated through arteriogenesis and angiogenesis, which contributed to vascular regeneration.
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Affiliation(s)
- Stefan Schlosser
- Department of Clinical Research, University of Bern, Switzerland
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28
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Mustafa DAM, Dekker LJ, Stingl C, Kremer A, Stoop M, Sillevis Smitt PAE, Kros JM, Luider TM. A proteome comparison between physiological angiogenesis and angiogenesis in glioblastoma. Mol Cell Proteomics 2012; 11:M111.008466. [PMID: 22278369 DOI: 10.1074/mcp.m111.008466] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The molecular pathways involved in neovascularization of regenerating tissues and tumor angiogenesis resemble each other. However, the regulatory mechanisms of neovascularization under neoplastic circumstances are unbalanced leading to abnormal protein expression patterns resulting in the formation of defective and often abortive tumor vessels. Because gliomas are among the most vascularized tumors, we compared the protein expression profiles of proliferating vessels in glioblastoma with those in tissues in which physiological angiogenesis takes place. By using a combination of laser microdissection and LTQ Orbitrap mass spectrometry comparisons of protein profiles were made. The approach yielded 29 and 12 differentially expressed proteins for glioblastoma and endometrium blood vessels, respectively. The aberrant expression of five proteins, i.e. periostin, tenascin-C, TGF-beta induced protein, integrin alpha-V, and laminin subunit beta-2 were validated by immunohistochemistry. In addition, pathway analysis of the differentially expressed proteins was performed and significant differences in the usage of angiogenic pathways were found. We conclude that there are essential differences in protein expression profiles between tumor and normal physiological angiogenesis.
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Affiliation(s)
- Dana A M Mustafa
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
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29
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Exploiting extracellular matrix-stem cell interactions: A review of natural materials for therapeutic muscle regeneration. Biomaterials 2012; 33:428-43. [DOI: 10.1016/j.biomaterials.2011.09.078] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 09/28/2011] [Indexed: 02/07/2023]
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Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J Vasc Surg 2011; 54:1650-8. [DOI: 10.1016/j.jvs.2011.06.118] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Revised: 06/28/2011] [Accepted: 06/30/2011] [Indexed: 11/23/2022]
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31
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Grapensparr L, Olerud J, Vasylovska S, Carlsson PO. The therapeutic role of endothelial progenitor cells in Type 1 diabetes mellitus. Regen Med 2011; 6:599-605. [DOI: 10.2217/rme.11.45] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pancreatic β-cells sense and adjust the blood glucose level by secretion of insulin. In Type 1 diabetes mellitus, these insulin-producing cells are destroyed, leaving the patients incapable of regulating blood glucose homeostasis. At the time of diagnosis, most patients still have 20–30% of their original β-cell mass remaining. These residual β-cells are targets for intervention therapies aimed at preventing further autoimmune destruction, in addition to increasing the number of existing β-cells. Such a therapeutic option is highly desirable since it may lead to a full recovery of newly diagnosed patients, with no need for further treatment with immunosuppressant drugs or exogenous insulin administration. In this article, we propose that endothelial progenitor cells, a cell type known to promote and support neovascularization following endothelial injury, may be used as part of a combinational stem cell therapy aimed to improve the vascularization, survival and proliferation of β-cells.
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Affiliation(s)
- Liza Grapensparr
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Johan Olerud
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Svitlana Vasylovska
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Per-Ola Carlsson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Fang J, Wang S, Chen J, Zhang Y, Zhang B, Liang H, Zhang W. The effects of magnetically labeled rat spleen-originated endothelial progenitor cells on growth of glioma in vivo an experimental study. Acad Radiol 2011; 18:892-901. [PMID: 21543240 DOI: 10.1016/j.acra.2011.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 02/22/2011] [Accepted: 02/23/2011] [Indexed: 12/01/2022]
Abstract
RATIONALE AND OBJECTIVES The aim of this study was to investigate the effects of exogenous endothelial progenitor cells (EPCs) on the growth and invasiveness of glioma in vivo to provide an experimental basis for the value and safety of using magnetically labeled EPCs as target vectors to detect early infiltration of glioma. MATERIALS AND METHODS EPCs were collected from the spleens of healthy Sprague-Dawley rats, made EPCs conditioned medium after identification. Four models of Sprague-Dawley rat glioma (60 rats in total) were established as a control and three experimental groups (group A, B, and C). In the control group, orthotopic transplantation of C6 glioma cells was performed. Compared to the control group, EPCs conditioned medium was added in group A and P7228-labeled EPCs were added in group B. In group C, P7228-labeled EPCs were transplanted via the tail vein. Magnetic resonance imaging and perfusion-weighted imaging were performed on several days. Tumor microvascular density and vascular endothelial growth factor expression were determined through immunohistochemistry. RESULTS In group C, hypointense areas were detected at the periphery of the tumor on the first day after transplantation of EPCs, and more hypointense areas were found inside the tumor over time. Tumor size in all four groups developed significantly with increasing time (P < .01), but there was no marked difference among these groups at the same time (P > .05). No remarkable differences in microvascular density and cells positive for vascular endothelial growth factor were found at the same time among the four groups (P > .05). CONCLUSIONS Both magnetic resonance imaging and immunohistochemical findings confirmed that exogenous EPCs could not affect the biologic behavior of C6 glioma cells in vivo through a paracrine effect or by direct cellular interaction. Therefore, exogenous EPCs could not exert significant promoting effects on glioma growth.
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Affiliation(s)
- Jingqin Fang
- Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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Preconditioned Endothelial Progenitor Cells Reduce Formation of Melanoma Metastases through SPARC-Driven Cell–Cell Interactions and Endocytosis. Cancer Res 2011; 71:4748-57. [DOI: 10.1158/0008-5472.can-10-2449] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Leite de Oliveira R, Hamm A, Mazzone M. Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies. Mol Aspects Med 2011; 32:71-87. [PMID: 21540050 DOI: 10.1016/j.mam.2011.04.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Accepted: 04/13/2011] [Indexed: 12/17/2022]
Abstract
The establishment of a functional, integrated vascular system is instrumental for tissue growth and homeostasis. Without blood vessels no adequate nutrition and oxygen would be provided to cells, nor could the undesired waste products be efficiently removed. Blood vessels constitute therefore one of the largest and most complex body network whose assembly depends on the precise balance of growth factors acting in a complementary and coordinated manner with cells of several identities. However, the vessels that are crucial for life can also foster death, given their involvement in cancer progression towards malignancy and metastasis. Targeting tumor vasculature has thus arisen as an appealing anti-cancer therapeutic approach. Since the milestone achievements that vascular endothelial growth factor (VEGF) blockade suppressed angiogenesis and tumor growth in mice and prolonged the survival of cancer patients when administered in combination with chemotherapy, the clinical development of anti-VEGF(R) drugs has accelerated remarkably. FDA has approved the use of bevacizumab - a humanized monoclonal antibody against VEGF - in colorectal, lung and metastatic breast cancers in combination with standard chemotherapy. Additional broad-spectrum VEGF receptor tyrosine kinase inhibitors, such as sunitinib and sorafenib, are used in monotherapy for metastatic renal carcinoma, while sunitinib is also approved for imatinib resistant gastrointestinal stromal tumors and sorafenib for advanced stage hepatocellular carcinoma. Nevertheless, the survival benefit offered by VEGF(R) blockers, either as single agents or in combination with chemotherapy, is calculated merely in the order of months. Posterior studies in preclinical models have reported that despite reducing primary tumor growth, the inhibition of VEGF increased tumor invasiveness and metastasis. The clinical implications of these findings urge the need to reconcile these conflicting results. Anti-angiogenic therapy represents a significant step forth in cancer therapy and in our understanding of cancer biology, but it is also clear that we need to learn how to use it. What is the biological consequence of VEGF-blockade? Does VEGF inhibition starve the tumor to death - as initially postulated - or does it rather foster malignancy? Can anti-VEGF(R) therapy favor tumor vessel formation by VEGF-independent means? Tumors are very diverse and plastic entities, able to adapt to the harshest conditions; this is also reflected by the tumor vasculature. Lessons from the bench to the bedside and vice versa have taught us that the diversity of signals underlying tumor vessel growth will likely be responsive (or resistant) to distinct therapeutic approaches. In this review, we propose a reflection of the different strategies tumors use to grow blood vessels and how these can have impact on the (un)success of current anti-angiogenic therapies.
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Affiliation(s)
- Rodrigo Leite de Oliveira
- Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium
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35
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Liang PH, Tian F, Lu Y, Duan B, Stolz DB, Li LY. Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors. Angiogenesis 2011; 14:61-8. [PMID: 21188501 PMCID: PMC3042043 DOI: 10.1007/s10456-010-9195-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 12/08/2010] [Indexed: 12/17/2022]
Abstract
Bone marrow (BM)-derived endothelial progenitor cells (EPC) have a critical role in tumor neovascularization. Vascular endothelial growth inhibitor (VEGI) is a member of the TNF superfamily (TNFSF15). We have shown that recombinant VEGI suppresses tumor angiogenesis by specifically eliminating proliferating endothelial cells (EC). We report here that treatment of tumor bearing mice with recombinant VEGI leads to a significantly decreased population of BM-derived EPC in the tumors. We transplanted whole bone marrow from green fluorescent protein (GFP) transgenic mice into C57BL/6 recipient mice, which were then inoculated with Lewis lung carcinoma (LLC) cells. Intraperitoneal injection of recombinant VEGI led to significant inhibition of tumor growth and decrease of vasculature density compared to vehicle-treated mice. Tumor implantation yielded a decrease of BM-derived EPC in the peripheral blood, while VEGI-treatment resulted in an initial delay of such decrease. Analysis of the whole bone marrow showed a decrease of Lin(-)-c-Kit(+)-Sca-1(+) hematopoietic stem cell (HSC) population in tumor bearing mice; however, VEGI-treatment caused a significant increase of this cell population. In addition, the number of BM-derived EPC in VEGI-treated tumors was notably less than that in the vehicle-treated group, and most of the apoptotic cells in the VEGI-treated tumors were of bone marrow origin. These findings indicate that VEGI inhibits BM-derived EPC mobilization and prevents their incorporation into LLC tumors by inducing apoptosis specifically of BM-derived cells, resulting in the inhibition of EPC-supported tumor vasculogenesis and tumor growth.
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Affiliation(s)
- Paulina H. Liang
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Fang Tian
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Yi Lu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Biyan Duan
- College of Pharmacy, Nankai University, Tianjin, China
| | - Donna B. Stolz
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Lu-Yuan Li
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. College of Pharmacy, Nankai University, Tianjin, China
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36
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Fang S, Salven P. Stem cells in tumor angiogenesis. J Mol Cell Cardiol 2011; 50:290-5. [DOI: 10.1016/j.yjmcc.2010.10.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 10/19/2010] [Accepted: 10/19/2010] [Indexed: 01/01/2023]
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Fleitas T, Martínez-Sales V, Gómez-Codina J, Martín M, Reynés G. Circulating endothelial and endothelial progenitor cells in non-small-cell lung cancer. Clin Transl Oncol 2011; 12:521-5. [PMID: 20709649 DOI: 10.1007/s12094-010-0549-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
New treatments have recently been introduced for treating non-small-cell lung cancer. Chemotherapeutic agents, such as pemetrexed, and targeted therapies, such as bevacizumab, erlotinib or gefitinib, have extended treatment options for selected histological subgroups. Antiangiogenic treatments, either associated with conventional chemotherapeutic drugs or given alone as maintenance therapy, constitute an active clinical research field. However, not all lung cancer patients benefit from antiangiogenic compounds. Moreover, tumour response assessment is often difficult when using these drugs, since targeted therapies generally do not cause rapid and measurable tumour shrinkage but, rather, long stabilisations and slight density changes on imaging tests. The finding of clinical or biological factors that might identify patients who will better benefit from these treatments, as well as identifying surrogate markers of tumour response and prognosis, is an issue of great interest. In that sense, different research lines have investigated the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. Circulating endothelial (CECs) and endothelial progenitor cells (CEPCs) are of prognostic value in different types of cancers, and relevant data are published about their potential usefulness as predictors of response to chemotherapy and antiangiogenic treatments. In this review, we discuss the data available on the role of CECs and CEPCs as prognostic factors and as surrogate markers of treatment response in non-small-cell lung cancer.
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Affiliation(s)
- Tania Fleitas
- Medical Oncology Department, La Fe University Hospital, Valencia, Spain.
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Mueller RJ, Stussi G, Puga Yung G, Nikolic M, Soldini D, Halter J, Meyer-Monard S, Gratwohl A, Passweg JR, Odermatt B, Schanz U, Biedermann BC, Seebach JD. Persistence of recipient-type endothelium after allogeneic hematopoietic stem cell transplantation. Haematologica 2010; 96:119-27. [PMID: 20934999 DOI: 10.3324/haematol.2010.030288] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The possibility that allogeneic hematopoietic stem cell transplantation performed across the ABO blood group-barrier is associated with an increase of graft-versus-host disease, in particular endothelial damage, has not been elucidated so far. For this reason, we investigated the level of endothelial cell chimerism after allogeneic hematopoietic stem cell transplantation in order to delineate the role of hematopoietic stem cells in endothelial replacement. DESIGN AND METHODS The frequency of donor-derived endothelial cells was analyzed in 52 hematopoietic stem cell transplant recipients, in 22 normal skin biopsies, in 12 skin samples affected by graft-versus-host disease, various tissues from five autopsies and four secondary solid tumors by ABH immunohistochemistry, XY fluorescence in situ hybridization and short tandem repeat analysis of laser captured endothelial cells. RESULTS Skin biopsies from two patients transplanted with minor ABO-incompatible grafts (i.e. O in A) showed 3.3% and 0.9% H antigen-positive donor-derived endothelial cells by ABH immunohistochemistry. Tumor biopsies from two recipients showed 1.2% and 2.5% donor-derived endothelial cells by combined immunohistochemistry/ fluorescence in situ hybridization. All other skin samples, heart, liver, bone-marrow, and tumor tissues failed to reveal donor-type endothelial cells up to several years after ABO-incompatible hematopoietic stem cell transplantation. CONCLUSIONS Endothelial cell replacement by bone marrow-derived donor cells after allogeneic hematopoietic stem cell transplantation is a rare event. It does not seem to represent a major mechanism of physiological in vivo blood vessel formation, tumor neoangiogenesis, vascular repair after graft-versus-host disease episodes or acceptance of ABO-incompatible grafts.
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Affiliation(s)
- Regula J Mueller
- Laboratory for Transplantation Immunology, University Hospital, Zurich, Switzerland
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Abstract
Diabetes mellitus increases cardiovascular risk through its negative impact on vascular endothelium. Although glucotoxicity and lipotoxicity account for endothelial cell damage, endothelial repair is also affected by diabetes. Endothelial progenitor cells (EPCs) are involved in the maintenance of endothelial homoeostasis and in the process of new vessel formation. For these reasons, EPCs are thought to have a protective impact within the cardiovascular system. In addition, EPCs appear to modulate the functioning of other organs, providing neurotropic signals and promoting repair of the glomerular endothelium. The exact mechanisms by which EPCs provide cardiovascular protection are unknown and the definition of EPCs is not standardized. Notwithstanding these limitations, the literature consistently indicates that EPCs are altered in type 1 and type 2 diabetes and in virtually all diabetic complications. Moreover, experimental models suggest that EPC-based therapies might help prevent or reverse the features of end-organ complications. This identifies EPCs as having a novel pathogenic role in diabetes and being a potential therapeutic target. Several ways of favourably modulating EPCs have been identified, including lifestyle intervention, commonly used medications and cell-based approaches. Herein, we provide a comprehensive overview of EPC pathophysiology and the potential for EPC modulation in diabetes.
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Affiliation(s)
- G P Fadini
- Department of Clinical and Experimental Medicine, Division of Metabolic Diseases, University of Padova, Medical School, Padova, Italy.
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40
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Bone marrow is a reservoir for proangiogenic myelomonocytic cells but not endothelial cells in spontaneous tumors. Blood 2010; 116:3367-71. [PMID: 20453162 DOI: 10.1182/blood-2010-02-271122] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The hypothesis that bone marrow-derived, circulating endothelial cells incorporate into tumor blood vessels is unresolved. We have measured the numbers of bone marrow-derived versus resident endothelial cells in spontaneous prostate cancers during different stages of tumor progression and in age-matched normal prostates. Bone marrow-derived endothelial cells were rare in dysplasia and in well differentiated cancers representing between 0 and 0.04% of the total tumor mass. Instead, approximately 99% of all tumor-associated bone marrow-derived cells were CD45(+) hematopoietic cells, including GR-1(+), F4-80(+), and CD11b(+) myeloid cells. Similar to peripheral blood mononuclear cells, these tumor-associated myeloid cells expressed matrix metalloproteinases (MMPs), consistent with their proposed catalytic role during tumor angiogenesis. Furthermore, freshly isolated CD11b(+) cells stimulated tumor endothelial cell cord formation by 10-fold in an in vitro angiogenesis assay. The bone marrow is, therefore, a reservoir for cells that augment tumor angiogenesis, but the tumor endothelium is derived primarily from the local environment.
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41
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Fadini GP, Avogaro A. Cell-based methods for ex vivo evaluation of human endothelial biology. Cardiovasc Res 2010; 87:12-21. [DOI: 10.1093/cvr/cvq119] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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42
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Watson AR, Pitchford SC, Reynolds LE, Direkze N, Brittan M, Alison MR, Rankin S, Wright NA, Hodivala-Dilke KM. Deficiency of bone marrow beta3-integrin enhances non-functional neovascularization. J Pathol 2010; 220:435-45. [PMID: 19967726 DOI: 10.1002/path.2660] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
beta3-Integrin is a cell surface adhesion and signalling molecule important in the regulation of tumour angiogenesis. Mice with a global deficiency in beta3-integrin show increased pathological angiogenesis, most likely due to increased vascular endothelial growth factor receptor 2 expression on beta3-null endothelial cells. Here we transplanted beta3-null bone marrow (BM) into wild-type (WT) mice to dissect the role of BM beta3-integrin deficiency in pathological angiogenesis. Mice transplanted with beta3-null bone marrow show significantly enhanced angiogenesis in subcutaneous B16F0 melanoma and Lewis lung carcinoma (LLC) cell models and in B16F0 melanoma lung metastasis when compared with tumours grown in mice transplanted with WT bone marrow. The effect of bone marrow beta3-integrin deficiency was also assessed in the RIPTAg mouse model of pancreatic tumour growth. Again, angiogenesis in mice lacking BM beta3-integrin was enhanced. However, tumour weight between the groups was not significantly altered, suggesting that the enhanced blood vessel density in the mice transplanted with beta3-null bone marrow was not functional. Indeed, we demonstrate that in mice transplanted with beta3-null bone marrow a significant proportion of tumour blood vessels are non-functional when compared with tumour blood vessels in WT-transplanted controls. Furthermore, beta3-null-transplanted mice showed an increased angiogenic response to VEGF in vivo when compared with WT-transplanted animals. BM beta3-integrin deficiency affects the mobilization of progenitor cells to the peripheral circulation. We show that VEGF-induced mobilization of endothelial progenitor cells is enhanced in mice transplanted with beta3-null bone marrow when compared with WT-transplanted controls, suggesting a possible mechanism underlying the increased blood vessel density seen in beta3-null-transplanted mice. In conclusion, although BM beta3-integrin is not required for pathological angiogenesis, our studies demonstrate a role for BM beta3-integrin in VEGF-induced mobilization of bone marrow-derived cells to the peripheral circulation and for the functionality of those vessels in which BM-derived cells become incorporated.
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Affiliation(s)
- Alan R Watson
- Histopathology Unit, Cancer Research UK London Research Institute, UK
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Pearson JD. Endothelial progenitor cells--an evolving story. Microvasc Res 2010; 79:162-8. [PMID: 20043930 DOI: 10.1016/j.mvr.2009.12.004] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Accepted: 12/20/2009] [Indexed: 01/06/2023]
Abstract
The first description of endothelial progenitor cells (EPC) in 1997 led rapidly to substantial changes in our understanding of angiogenesis, and within 5 years to the first clinical studies in humans using bone marrow derived EPC to enhance coronary neovascularisation and cardiac function after myocardial ischemia. However, to improve the success of this therapy a clearer understanding of the biology of EPC is needed. This article summarises recent data indicating that most EPC are not, in fact, endothelial progenitors but can be better described as angiogenic monocytes, and explores the implications this has for their future therapeutic use.
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Affiliation(s)
- Jeremy D Pearson
- King's College London, Cardiovascular Division, London SE1 9NH, UK.
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