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Brocco D, Simeone P, Marino PD, De Bellis D, D’Ascanio F, Colasante G, Grassadonia A, De Tursi M, Florio R, Di Ianni M, Cama A, Tinari N, Lanuti P. Low Phosphatidylserine+ Cells Within the CD34+/CD45dim/CD117(c-kit)+ Subpopulation Are Associated with Poor Outcomes in Metastatic Colorectal Cancer. Cancers (Basel) 2025; 17:499. [PMID: 39941866 PMCID: PMC11816280 DOI: 10.3390/cancers17030499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Colorectal cancer is among the most prevalent causes of tumor-related deaths worldwide. Antiangiogenic therapy represents a cornerstone of metastatic CRC treatment, and biomarkers are advocated for the optimization of this therapeutic strategy. METHODS In this observational prospective study, we employed an optimized flow cytometry protocol to investigate the prognostic and predictive potential of blood circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPCs), and related subsets in a cohort of patients with metastatic colorectal cancer (n = 40). RESULTS Computational FC analysis revealed a differential enrichment of blood cell clusters with a CD34+/CD45dim/CD117(c-kit)+ phenotype between responders and non-responders both to antiangiogenic and non-antiangiogenic treatments. Intriguingly, our results show that a high percentage of annexin V-negative cells in a putative circulating progenitor population with a CD34+/CD45dim/CD117+ phenotype was correlated with a reduced response to systemic anticancer treatments (p = 0.015) and worse overall survival (log-rank p = 0.03). In addition, we observed increased blood concentrations of CD34+/CD45dim/CD117+/annexin V- cells in patients with a higher number of metastatic sites (p = 0.03). CONCLUSIONS Overall, these findings hold promise for the identification of novel circulating biomarkers to develop more personalized treatment approaches in patients with metastatic colorectal cancer.
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Affiliation(s)
- Davide Brocco
- Department of Medical, Oral & Biotechnological Sciences, University "G. D’Annunzio", 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio”, 66100 Chieti, Italy; (P.S.); (D.D.B.); (F.D.); (G.C.); (P.L.)
| | - Pasquale Simeone
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio”, 66100 Chieti, Italy; (P.S.); (D.D.B.); (F.D.); (G.C.); (P.L.)
- Department of Medicine and Aging Sciences, University “G. D’Annunzio”, 66100 Chieti, Italy
| | - Pietro Di Marino
- Clinical Oncology Unit, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Domenico De Bellis
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio”, 66100 Chieti, Italy; (P.S.); (D.D.B.); (F.D.); (G.C.); (P.L.)
- Department of Medicine and Aging Sciences, University “G. D’Annunzio”, 66100 Chieti, Italy
| | - Francesca D’Ascanio
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio”, 66100 Chieti, Italy; (P.S.); (D.D.B.); (F.D.); (G.C.); (P.L.)
- Department of Medicine and Aging Sciences, University “G. D’Annunzio”, 66100 Chieti, Italy
- Department of Humanities, Law and Economics, “Leonardo da Vinci” University, 66010 Torrevecchia Teatina, Italy
| | - Giulia Colasante
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio”, 66100 Chieti, Italy; (P.S.); (D.D.B.); (F.D.); (G.C.); (P.L.)
- Department of Medicine and Aging Sciences, University “G. D’Annunzio”, 66100 Chieti, Italy
| | - Antonino Grassadonia
- Department of Innovative Technologies in Medicine and Dentistry, University “G. D’Annunzio” 66100 Chieti, Italy; (A.G.); (M.D.T.)
| | - Michele De Tursi
- Department of Innovative Technologies in Medicine and Dentistry, University “G. D’Annunzio” 66100 Chieti, Italy; (A.G.); (M.D.T.)
| | - Rosalba Florio
- Department of Pharmacy, University “G. D’Annunzio”, 66100 Chieti, Italy;
| | - Mauro Di Ianni
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio”, 66100 Chieti, Italy; (P.S.); (D.D.B.); (F.D.); (G.C.); (P.L.)
- Department of Medicine and Aging Sciences, University “G. D’Annunzio”, 66100 Chieti, Italy
| | - Alessandro Cama
- Department of Pharmacy, University “G. D’Annunzio”, 66100 Chieti, Italy;
| | - Nicola Tinari
- Department of Medical, Oral & Biotechnological Sciences, University "G. D’Annunzio", 66100 Chieti, Italy;
| | - Paola Lanuti
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio”, 66100 Chieti, Italy; (P.S.); (D.D.B.); (F.D.); (G.C.); (P.L.)
- Department of Medicine and Aging Sciences, University “G. D’Annunzio”, 66100 Chieti, Italy
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Asante DB, Tierno D, Woode M, Scaggiante B. Angiogenesis and Ovarian Cancer: What Potential Do Different Subtypes of Circulating Endothelial Cells Have for Clinical Application? Int J Mol Sci 2024; 25:6283. [PMID: 38892471 PMCID: PMC11172689 DOI: 10.3390/ijms25116283] [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: 05/01/2024] [Revised: 05/29/2024] [Accepted: 06/05/2024] [Indexed: 06/21/2024] Open
Abstract
Ovarian cancer (OC) remains the most fatal disease of gynaecologic malignant tumours. The neovasculature in the tumour microenvironment principally comprises endothelial cells. Haematogenous cancer metastases are significantly impacted by tumour neovascularisation, which predominantly depends on the tumour-derived endothelial vasculogenesis. There is an urgent need for biomarkers for the diagnosis, prognosis and prediction of drug response. Endothelial cells play a key role in angiogenesis and other forms of tumour vascularisation. Subtypes of circulating endothelial cells may provide interesting non-invasive biomarkers of advanced OC that might have the potential to be included in clinical analysis for patients' stratification and therapeutic management. In this review, we summarise the reported studies on circulating endothelial subtypes in OC, detailing their isolation methods as well as their potential diagnostic, prognostic, predictive and therapeutic utility for clinical application. We highlight key biomarkers for the identification of circulating endothelial cell subtypes and their targets for therapies and critically point out future challenges.
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Affiliation(s)
- Du-Bois Asante
- Department of Biomedical and Forensic Sciences, University of Cape Coast, Cape Coast P.O. Box CCLN 33, Ghana; (D.-B.A.); (M.W.)
| | - Domenico Tierno
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume 447, I-34149 Trieste, Italy;
| | - Michael Woode
- Department of Biomedical and Forensic Sciences, University of Cape Coast, Cape Coast P.O. Box CCLN 33, Ghana; (D.-B.A.); (M.W.)
| | - Bruna Scaggiante
- Department of Life Sciences, University of Trieste, Via Valerio 28, I-34127 Trieste, Italy
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D’Urso S, Hwang LD. New Insights into Polygenic Score-Lifestyle Interactions for Cardiometabolic Risk Factors from Genome-Wide Interaction Analyses. Nutrients 2023; 15:4815. [PMID: 38004209 PMCID: PMC10675788 DOI: 10.3390/nu15224815] [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: 10/11/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
The relationship between lifestyles and cardiometabolic outcomes varies between individuals. In 382,275 UK Biobank Europeans, we investigate how lifestyles interact with polygenic scores (PGS) of cardiometabolic risk factors. We identify six interactions (PGS for body mass index with meat diet, physical activity, sedentary behaviour and insomnia; PGS for high-density lipoprotein cholesterol with sedentary behaviour; PGS for triglycerides with meat diet) in multivariable linear regression models including an interaction term and show stronger associations between lifestyles and cardiometabolic risk factors among individuals with high PGSs than those with low PGSs. Genome-wide interaction analyses pinpoint three genetic variants (FTO rs72805613 for BMI; CETP rs56228609 for high-density lipoprotein cholesterol; TRIB2 rs4336630 for triglycerides; PInteraction < 5 × 10-8). The associations between lifestyles and cardiometabolic risk factors differ between individuals grouped by the genotype of these variants, with the degree of differences being similar to that between individuals with high and low values for the corresponding PGSs. This study demonstrates that associations between lifestyles and cardiometabolic risk factors can differ between individuals based upon their genetic profiles. It further suggests that genetic variants with interaction effects contribute more to such differences compared to those without interaction effects, which has potential implications for developing PGSs for personalised intervention.
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Affiliation(s)
| | - Liang-Dar Hwang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4067, Australia;
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Fang Y, Chen L, Imoukhuede PI. Toward Blood-Based Precision Medicine: Identifying Age-Sex-Specific Vascular Biomarker Quantities on Circulating Vascular Cells. Cell Mol Bioeng 2023; 16:189-204. [PMID: 37456786 PMCID: PMC10338416 DOI: 10.1007/s12195-023-00771-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/20/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Abnormal angiogenesis is central to vascular disease and cancer, and noninvasive biomarkers of vascular origin are needed to evaluate patients and therapies. Vascular endothelial growth factor receptors (VEGFRs) are often dysregulated in these diseases, making them promising biomarkers, but the need for an invasive biopsy has limited biomarker research on VEGFRs. Here, we pioneer a blood biopsy approach to quantify VEGFR plasma membrane localization on two circulating vascular proxies: circulating endothelial cells (cECs) and circulating progenitor cells (cPCs). Methods Using quantitative flow cytometry, we examined VEGFR expression on cECs and cPCs in four age-sex groups: peri/premenopausal females (aged < 50 years), menopausal/postmenopausal females (≥ 50 years), and younger and older males with the same age cut-off (50 years). Results cECs in peri/premenopausal females consisted of two VEGFR populations: VEGFR-low (~ 55% of population: population medians ~ 3000 VEGFR1 and 3000 VEGFR2/cell) and VEGFR-high (~ 45%: 138,000 VEGFR1 and 39,000-236,000 VEGFR2/cell), while the menopausal/postmenopausal group only possessed the VEGFR-low cEC population; and 27% of cECs in males exhibited high plasma membrane VEGFR expression (206,000 VEGFR1 and 155,000 VEGFR2/cell). The absence of VEGFR-high cEC subpopulations in menopausal/postmenopausal females suggests that their high-VEGFR cECs are associated with menstruation and could be noninvasive proxies for studying the intersection of age-sex in angiogenesis. VEGFR1 plasma membrane localization in cPCs was detected only in menopausal/postmenopausal females, suggesting a menopause-specific regenerative mechanism. Conclusions Overall, our quantitative, noninvasive approach targeting cECs and cPCs has provided the first insights into how sex and age influence VEGFR plasma membrane localization in vascular cells. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-023-00771-1.
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Affiliation(s)
- Yingye Fang
- Department of Bioengineering, University of Washington, Seattle, WA USA
| | - Ling Chen
- Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO USA
| | - P. I. Imoukhuede
- Department of Bioengineering, University of Washington, Seattle, WA USA
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Di Paolo V, Colletti M, Ferruzzi V, Russo I, Galardi A, Alessi I, Milano GM, Di Giannatale A. Circulating Biomarkers for Tumor Angiogenesis: Where Are We? Curr Med Chem 2020; 27:2361-2380. [PMID: 30129403 DOI: 10.2174/0929867325666180821151409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 01/26/2023]
Abstract
BACKGROUND In recent years, several anti-angiogenic drugs have been developed and their addition to standard treatment has been associated with clinical benefits. However, the response to anti-angiogenic therapy is characterized by considerable variability. In this context, the development of dynamic non-invasive biomarkers would be helpful to elucidate the emergence of anti-angiogenic resistance as well as to correctly address the treatment. OBJECTIVES The purpose of this review is to describe current reports on circulating diagnostic and prognostic biomarkers related to angiogenesis. We further discuss how this non-invasive strategy could improve the monitoring of tumor treatment and help clinical strategy. RESULTS We discuss the latest evidence in the literature regarding circulating anti-angiogenic markers. Besides growth factor proteins, different circulating miRNAs could exert a pro- or anti-angiogenic activity so as to represent suitable candidates for a non-invasive strategy. Recent reports indicate that tumor-derived exosomes, which are small membrane vesicles abundant in biological fluids, also have an impact on vascular remodeling. CONCLUSION Numerous circulating biomarkers related to angiogenesis have been recently identified. Their use will allow identifying patients who are more likely to benefit from a specific anti-angiogenic treatment, as well as detecting those who will develop resistance and/or adverse effects. Nonetheless, further studies are required to elucidate the role of these biomarkers in clinical settings.
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Affiliation(s)
- Virginia Di Paolo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Marta Colletti
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Valentina Ferruzzi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Ida Russo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Angela Galardi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Iside Alessi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Giuseppe Maria Milano
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Angela Di Giannatale
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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Insights into Endothelial Progenitor Cells: Origin, Classification, Potentials, and Prospects. Stem Cells Int 2018; 2018:9847015. [PMID: 30581475 PMCID: PMC6276490 DOI: 10.1155/2018/9847015] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/27/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023] Open
Abstract
With the discovery of endothelial progenitor cells (EPCs) in the late 1990s, a paradigm shift in the concept of neoangiogenesis occurred. The identification of circulating EPCs in peripheral blood marked the beginning of a new era with enormous potential in the rapidly transforming regenerative field. Overwhelmed with the revelation, researchers across the globe focused on isolating, defining, and interpreting the role of EPCs in various physiological and pathological conditions. Consequently, controversies emerged regarding the isolation techniques and classification of EPCs. Nevertheless, the potential of using EPCs in tissue engineering as an angiogenic source has been extensively explored. Concomitantly, the impact of EPCs on various diseases, such as diabetes, cancer, and cardiovascular diseases, has been studied. Within the limitations of the current knowledge, this review attempts to delineate the concept of EPCs in a sequential manner from the speculative history to a definitive presence (origin, sources of EPCs, isolation, and identification) and significance of these EPCs. Additionally, this review is aimed at serving as a guide for investigators, identifying potential research gaps, and summarizing our current and future prospects regarding EPCs.
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Li Y, Liu J, Zhao Z, Wen L, Li H, Ren J, Liu H. Correlation between circulating endothelial progenitor cells and serum carcinoembryonic antigen level in colorectal cancer. Acta Biochim Biophys Sin (Shanghai) 2018; 50:307-312. [PMID: 29377980 DOI: 10.1093/abbs/gmx147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Indexed: 12/13/2022] Open
Abstract
Circulating endothelial progenitor cells (cEPCs) play an important role in cancer development. Previous studies showed that serum carcinoembryonic antigen (CEA) levels and the number of circulating endothelial progenitor cells (cEPCs) in the peripheral blood are both involved in tumor neoangiogenesis, and can be used for monitoring tumor progression, recurrence, metastasis, and therapeutic responses. However, the clinical relevance of these biomarkers remains unknown. In this study, 40 colorectal cancer (CRC) patients and 17 healthy volunteers were recruited and the amount of cEPCs in the peripheral blood was measured by flow cytometry. The serum CEA level was determined by CEA-RIACT assay. Results showed that cEPC level positively correlated with the stage of the disease, but not with the age and gender of the patients. Moreover, patients with higher serum CEA levels had higher cEPC levels. These results provide clinical evidence for a correlation between two commonly used biomarkers. Further understanding the role of serum CEA in cEPC-mediated tumor vascularization may improve clinical CRC diagnosis and provide useful insights into the design of therapeutic interventions that target tumor vasculature.
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Affiliation(s)
- Yuanxiang Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jingwen Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zheyan Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lu Wen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huili Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jinghua Ren
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hongli Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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El Bairi K, Amrani M, Kandhro AH, Afqir S. Prediction of therapy response in ovarian cancer: Where are we now? Crit Rev Clin Lab Sci 2017; 54:233-266. [PMID: 28443762 DOI: 10.1080/10408363.2017.1313190] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Therapy resistance is a major challenge in the management of ovarian cancer (OC). Advances in detection and new technology validation have led to the emergence of biomarkers that can predict responses to available therapies. It is important to identify predictive biomarkers to select resistant and sensitive patients in order to reduce important toxicities, to reduce costs and to increase survival. The discovery of predictive and prognostic biomarkers for monitoring therapy is a developing field and provides promising perspectives in the era of personalized medicine. This review article will discuss the biology of OC with a focus on targetable pathways; current therapies; mechanisms of resistance; predictive biomarkers for chemotherapy, antiangiogenic and DNA-targeted therapies, and optimal cytoreductive surgery; and the emergence of liquid biopsy using recent studies from the Medline database and ClinicalTrials.gov.
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Affiliation(s)
- Khalid El Bairi
- a Faculty of Medicine and Pharmacy , Mohamed Ist University , Oujda , Morocco
| | - Mariam Amrani
- b Equipe de Recherche ONCOGYMA, Faculty of Medicine, Pathology Department , National Institute of Oncology, Université Mohamed V , Rabat , Morocco
| | - Abdul Hafeez Kandhro
- c Department of Biochemistry , Healthcare Molecular and Diagnostic Laboratory , Hyderabad , Pakistan
| | - Said Afqir
- d Department of Medical Oncology , Mohamed VI University Hospital , Oujda , Morocco
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Danova M, Comolli G, Manzoni M, Torchio M, Mazzini G. Flow cytometric analysis of circulating endothelial cells and endothelial progenitors for clinical purposes in oncology: A critical evaluation. Mol Clin Oncol 2016; 4:909-917. [PMID: 27284422 DOI: 10.3892/mco.2016.823] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 12/11/2015] [Indexed: 12/19/2022] Open
Abstract
Malignant tumors are characterized by uncontrolled cell growth and metastatic spread, with a pivotal importance of the phenomenon of angiogenesis. For this reason, research has focused on the development of agents targeting the vascular component of the tumor microenvironment and regulating the angiogenic switch. As a result, the therapeutic inhibition of angiogenesis has become an important component of anticancer treatment, however, its utility is partly limited by the lack of an established methodology to assess its efficacy in vivo. Circulating endothelial cells (CECs), which are rare in healthy subjects and significantly increased in different tumor types, represent a promising tool for monitoring the tumor clinical outcome and the treatment response. A cell population circulating into the blood also able to form endothelial colonies in vitro and to promote vasculogenesis is represented by endothelial progenitor cells (EPCs). The number of both of these cell types is extremely low and they cannot be identified using a single marker, therefore, in absence of a definite consensus on their phenotype, require discrimination using combinations of antigens. Multiparameter flow cytometry (FCM) is ideal for rapid processing of high numbers of cells per second and is commonly utilized to quantify CECs and EPCs, however, remains technically challenging since there is as yet no standardized protocol for the identification and enumeration of these rare events. Methodology in studies on CECs and/or EPCs as clinical biomarkers in oncology is heterogeneous and data have been obtained from different studies leading to conflicting conclusions. The present review presented a critical review of the issues that limit the comparability of results of the most significant studies employing FCM for CEC and/or EPC detection in patients with cancer.
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Affiliation(s)
- Marco Danova
- Internal Medicine and Medical Oncology, Vigevano Hospital, ASST Pavia, I-27029 Vigevano, Italy
| | - Giuditta Comolli
- Microbiology and Virology, Biotechnology Laboratories, IRCCS San Matteo Foundation, I-27100 Pavia, Italy
| | | | - Martina Torchio
- Internal Medicine and Medical Oncology, Vigevano Hospital, ASST Pavia, I-27029 Vigevano, Italy
| | - Giuliano Mazzini
- Molecular Genetics Institute, National Research Council and Biology and Biotechnology Department 'L. Spallanzani', University of Pavia, I-27100 Pavia, Italy
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Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition. Cancer Metastasis Rev 2015; 33:17-39. [PMID: 24357056 DOI: 10.1007/s10555-013-9456-2] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ovarian adenocarcinoma is characterized by a late detection, dissemination of cancer cells into the whole peritoneum, and the frequent acquisition of chemoresistance. If these particularities can be explained in part by intrinsic properties of ovarian cancer cells, an increased number of studies show the importance of the tumor microenvironment in tumor progression. Ovarian cancer cells can regulate the composition of their stroma in promoting the formation of ascitic fluid, rich in cytokines and bioactive lipids, and in stimulating the differentiation of stromal cells into a pro-tumoral phenotype. In return, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, tumor-associated macrophages, or other peritoneal cells, such as adipocytes and mesothelial cells can regulate tumor growth, angiogenesis, dissemination, and chemoresistance. This review focuses on the current knowledge about the roles of stromal cells and the associated secreted factors on tumor progression. We also summarize the different studies showing that targeting the microenvironment represents a great potential for improving the prognosis of patients with ovarian adenocarcinoma.
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11
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Circulating endothelial progenitor cell: a promising biomarker in clinical oncology. Med Oncol 2014; 32:332. [PMID: 25428376 DOI: 10.1007/s12032-014-0332-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 11/06/2014] [Indexed: 12/11/2022]
Abstract
Human cancers are endowed with sustained vascularization capability, and their growth, invasion, and metastasis are vascularization dependent. Recently, accumulated body of evidence suggests that endothelial progenitor cells (EPCs) can support vasculogenesis and induce angiogenesis through paracrine mechanisms. In addition, numerous clinical studies have revealed the increase in the number of EPCs in the peripheral blood of cancer patients and demonstrated the correlation of circulating EPCs (CEPCs) with the clinical outcomes. This review highlights current enrichment procedures and methods for the detection of CEPCs and different biomarkers to identify CEPCs as well as the functions of EPCs in tumor vascularization. Furthermore, we systematically review available studies on the clinical relevance of CEPCs in cancer patients to explore the potential diagnostic and prognostic values of CEPCs. Although several contrasting results exist, CEPCs can conceivably serve as a promising biomarker for the early diagnosis, prognosis prediction, and treatment response indication in the future. Additionally, further well-designed clinical studies with larger sample size and unique, specific enumeration procedures are warranted to achieve further insight into the clinical implications of CEPCs.
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Moschetta M, Mishima Y, Sahin I, Manier S, Glavey S, Vacca A, Roccaro AM, Ghobrial IM. Role of endothelial progenitor cells in cancer progression. Biochim Biophys Acta Rev Cancer 2014; 1846:26-39. [PMID: 24709008 DOI: 10.1016/j.bbcan.2014.03.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/19/2014] [Accepted: 03/27/2014] [Indexed: 12/12/2022]
Abstract
Tumor-associated neovasculature is a critical therapeutic target; however, despite significant progress made in the clinical efficacy of anti-vessel drugs, the effect of these agents remains transient: over time, most patients develop resistance, which inevitably leads to tumor progression. To develop more effective treatments, it is imperative that we better understand the mechanisms involved in tumor vessel formation, how they participate to the tumor progression and metastasis, and the best way to target them. Several mechanisms contribute to the formation of tumor-associated vasculature: i) neoangiogenesis; ii) vascular co-option; iii) mosaicism; iv) vasculogenic mimicry, and v) postnatal vasculogenesis. These mechanisms can also play a role in the development of resistance to anti-angiogenic drugs, and could serve as targets for designing new anti-vascular molecules to treat solid as well as hematological malignancies. Bone marrow-derived endothelial progenitor cell (EPC)-mediated vasculogenesis represents an important new target, especially at the early stage of tumor growth (when EPCs are critical for promoting the "angiogenic switch"), and during metastasis, when EPCs promote the transition from micro- to macro-metastases. In hematologic malignancies, the EPC population could be related to the neoplastic clone, and both may share a common ontogeny. Thus, characterization of tumor-associated EPCs in blood cancers may provide clues for more specific anti-vascular therapy that has both direct and indirect anti-tumor effects. Here, we review the role of vasculogenesis, mediated by bone marrow-derived EPCs, in the progression of cancer, with a particular focus on the role of these cells in promoting progression of hematological malignancies.
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Affiliation(s)
- Michele Moschetta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; University of Bari Medical School, Department of Biomedical Sciences and Human Oncology (DIMO), Section of Internal Medicine and Clinical Oncology, Bari, Italy
| | - Yuji Mishima
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ilyas Sahin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Salomon Manier
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Siobhan Glavey
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Angelo Vacca
- University of Bari Medical School, Department of Biomedical Sciences and Human Oncology (DIMO), Section of Internal Medicine and Clinical Oncology, Bari, Italy
| | - Aldo M Roccaro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Irene M Ghobrial
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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Ha XQ, Zhao M, Li XY, Peng JH, Dong JZ, Deng ZY, Zhao HB, Zhao Y, Zhang YY. Distribution of endothelial progenitor cells in tissues from patients with gastric cancer. Oncol Lett 2014; 7:1695-1700. [PMID: 24765203 PMCID: PMC3997668 DOI: 10.3892/ol.2014.1944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Accepted: 01/27/2014] [Indexed: 01/04/2023] Open
Abstract
It is accepted that endothelial progenitor cells (EPCs) are recruited into tumor sites and take part in the neovascularization of tumors. However, few articles have discussed the specific distribution of EPCs in vivo in tissues of gastric cancer patients. For this reason, the present study sought to elucidate EPC distribution in vivo in tissues of patients with gastric cancer. Fresh tumor tissues were collected from 26 newly diagnosed patients with histologically confirmed gastric cancer (mean age, 51 years; range, 21–81 years; 7 females, 19 males). All patients were treated surgically with curative intent. One portion of the fresh tissues was prepared for flow cytometric analysis and another was immediately snap frozen in liquid nitrogen and stored at −80°C for later use in quantitative polymerase chain reaction. The analysis was based on two groups of tissues, namely the cancer group and cancer-adjacent group. The presence of CD34/CD133 double-positive cells was determined in cancer-adjacent and cancer tissues by flow cytometry. The analysis revealed that the total number of EPCs in cancer tissue was slightly greater than the number in the cancer-adjacent tissue, but not to the point of statistical significance. The number of EPCs in cancer-adjacent and cancer tissues of patients with early-stage gastric cancer was higher than the EPC count in late-stage gastric cancer patients, and significant differences were identified in the number of EPCs in cancer tissue between patients of different tumor stages. Levels of cluster of differentiation (CD)34, CD133 and vascular endothelial growth factor receptor 2 were not significantly different in cancer-adjacent tissue compared with cancer tissue. These results suggest that cancer-adjacent and cancer tissue of gastric cancer patients may be used as a reference index in the clinical and pathological staging of tumors.
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Affiliation(s)
- Xiao-Qin Ha
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Man Zhao
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Xiao-Yun Li
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Jun-Hua Peng
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Ju-Zi Dong
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Zhi-Yun Deng
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Hong-Bin Zhao
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Yong Zhao
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
| | - Yuan-Yuan Zhang
- Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army; Key Laboratory of Stem Cell and Gene Medicine of Gansu Province, Lanzhou, Gansu 730050, P.R. China
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Grigoras D, Pirtea L, Ceausu RA. Endothelial progenitor cells contribute to the development of ovarian carcinoma tumor blood vessels. Oncol Lett 2014; 7:1511-1514. [PMID: 24765167 PMCID: PMC3997705 DOI: 10.3892/ol.2014.1917] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 02/07/2014] [Indexed: 11/17/2022] Open
Abstract
Only a few studies in the literature have reported the contribution of endothelial progenitor cells (EPCs) in ovarian tumors, and with regard to malignant tumors, the data on the pre-existing endothelium insertion rate and the extent to which these cells contribute to tumor angiogenesis is controversial. The present study demonstrated the existence of EPCs and evaluated the expression of two markers, AC133 (also known as cluster of differentiation 133 or prominin) and tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2), signaling the presence of EPCs in the pre-existing endothelium. In total, 62 female patients who were diagnosed with ovarian tumors were retrospectively selected over a four-year period. Immunohistochemical analyses used Tie2 and AC133 as primary antibodies. In total, 27.4% of ovarian tumor cases expressed AC133 and Tie2 in blood vessel endothelial cells. The expression of these two markers did not correlate with the clinicopathological prognostic parameters, histological type, vascular microdensity or vessel type. The expression of AC133 and Tie2 in blood vessel endothelial cells contributes to angiogenesis progression in cases where the budding process is reduced or absent, as shown by the inverse correlation with the rate of proliferation of the endothelial cells.
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Affiliation(s)
- Dorin Grigoras
- Department of Obstetrics and Gynecology, 'Victor Babeş' University of Medicine and Pharmacy, Timişoara 300041, Romania
| | - Laurenţiu Pirtea
- Department of Obstetrics and Gynecology, 'Victor Babeş' University of Medicine and Pharmacy, Timişoara 300041, Romania
| | - Raluca Amalia Ceausu
- Department of Microscopic Morphology, Angiogenesis Research Center, 'Victor Babeş' University of Medicine and Pharmacy, Timişoara 300041, Romania
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Parmaksız G, Czabanka M, Vinci M, Vajkoczy P. Antiangiogenic Therapy Inhibits the Recruitment of Vascular Accessory Cells to the Perivascular Niche in Glioma Angiogenesis. J Vasc Res 2014; 51:102-9. [DOI: 10.1159/000357620] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 11/23/2013] [Indexed: 11/19/2022] Open
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Qiu H, Cao L, Wang D, Xu H, Liang Z. High levels of circulating CD34+/VEGFR3+ lymphatic/vascular endothelial progenitor cells is correlated with lymph node metastasis in patients with epithelial ovarian cancer. J Obstet Gynaecol Res 2013; 39:1268-75. [PMID: 23803010 DOI: 10.1111/jog.12047] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 12/12/2012] [Indexed: 11/28/2022]
Abstract
AIM Lymph node metastasis is one of the predictive factors associated with poor prognosis of epithelial ovarian cancer. To clarify the role of CD34 and vascular endothelial growth factor receptor-3-positive (CD34+/VEGFR3+) lymphatic/vascular endothelial progenitor cells (LVEPC) in patients with lymph node metastasis and epithelial ovarian cancer progression, the levels of circulating CD34+/VEGFR3+ LVEPC in epithelial ovarian cancer patients were detected. We also tested the plasma protein levels of VEGF and stromal cell-derived factor to find out their possible relationships with lymph node metastasis in our epithelial ovarian cancer cohort. MATERIAL AND METHODS Peripheral blood samples were collected from 54 patients diagnosed as epithelial ovarian cancer, and 31 normal samples as control. The circulating levels of LVEPC were carried out by flow cytometry, and blood protein levels of biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS The level of circulating LVEPC was significantly higher in patients with ovarian cancer compared with that of healthy controls. There was also a statistically significant correlation between LVEPC levels and surgical staging of epithelial ovarian cancer (P < 0.01). CONCLUSION The circulating levels of bone marrow-derived LVEPC are significantly increased in epithelial ovarian cancer patients and these levels correlate with lymph node metastasis too.
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Affiliation(s)
- Huiling Qiu
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China
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17
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Feng G, Jiang F, Pan C, Pu C, Huang H, Li G. Quantification of peripheral blood CD133 mRNA in identifying metastasis and in predicting recurrence of patients with clear cell renal cell carcinoma. Urol Oncol 2013; 32:44.e9-14. [PMID: 24054866 DOI: 10.1016/j.urolonc.2013.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Revised: 06/06/2013] [Accepted: 06/11/2013] [Indexed: 12/16/2022]
Abstract
OBJECTIVES To investigate whether CD133 messenger ribonucleic acid (mRNA) could provide useful information to identify metastasis or predict recurrence in patients with clear cell renal cell carcinoma (cRCC). METHODS AND MATERIALS This study included 86 patients with cRCC and 30 healthy controls. Real-time reverse transcriptase-polymerase chain reaction was used to quantify CD133 mRNA in peripheral blood mononuclear cells before nephrectomy. RESULTS The average CD133 mRNA in patients with metastatic cRCC (1.546 ± 0.291) was significantly higher than that in those with localized cRCC (1.034 ± 0.316, P = 0.022) or in controls (0.042 ± 0.028, P = 0.001). Metastasis could be identified with a sensitivity of 82.6% at specificity of 69.8% by CD133 mRNA. Among patients with localized cRCC, there was a significant difference in CD133 mRNA between the patients with recurrence (1.136 ± 0.127) and without recurrence (1.010 ± 0.091, P = 0.047). Recurrence could be identified with a sensitivity of 75.0% at specificity of 61.8%. Patients with a higher CD133 mRNA had a significantly higher recurrence rate than those with a low CD133 mRNA (P = 0.019). CONCLUSIONS CD133 mRNA can be useful for identifying metastasis, predicting recurrence, and stratifying the patients into different risk groups for possible adjuvant treatment.
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Affiliation(s)
- Gang Feng
- Clinical Genetics Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Feng Jiang
- Department of Ultrasound, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Caiming Pan
- Department of Urology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Chun Pu
- Clinical Genetics Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Houbao Huang
- Department of Urology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China.
| | - Guorong Li
- Department of Urology, North Hospital, CHU of Saint-Etienne, Saint-Etienne, France
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Perroud HA, Rico MJ, Alasino CM, Queralt F, Mainetti LE, Pezzotto SM, Rozados VR, Scharovsky OG. Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients. Future Oncol 2013; 9:451-62. [PMID: 23469980 DOI: 10.2217/fon.12.196] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Metronomic chemotherapy (MCT), the chronic administration, at regular intervals, of low doses of chemotherapeutic drugs without extended rest periods, allows chronic treatment with therapeutic efficacy and low toxicity. Our preclinical results suggested that combined MCT with cyclophosphamide and celecoxib could inhibit breast cancer growth. The aim of this study was to determine the toxicity, safety and efficacy of oral MCT with cyclophosphamide 50 mg per orem daily and celecoxib 400 mg (200 mg per orem two-times a day) in advanced breast cancer patients. During the first stage of the study, the therapeutic response consisted of prolonged stable disease for ≥24 weeks in six out of 15 (40%) patients with a median duration of 37.5 weeks and a partial response in one out of 15 (response rate: 6.7%) patients lasting 6 weeks. The overall clinical benefit rate was 46.7%. The median time to progression was 14 weeks. Progression-free survival at 24 weeks was 40% and the 1-year overall survival rate was 46.7%. The adverse events were mild (gastric, grade 1; and hematologic, grade 1 or 2). No grade 3 or 4 toxicities were associated with the treatment. Evaluation of patients' quality of life showed no changes during the response period. MCT with cyclophosphamide plus celecoxib is safe and shows a therapeutic effect in advanced breast cancer patients.
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Affiliation(s)
- Herman A Perroud
- Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Argentina
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19
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Ha X, Zhao M, Zhao H, Peng J, Deng Z, Dong J, Yang X, Zhao Y, Ju J. Identification and clinical significance of circulating endothelial progenitor cells in gastric cancer. Biomarkers 2013; 18:487-92. [DOI: 10.3109/1354750x.2013.810666] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Su Y, Gao L, Teng L, Wang Y, Cui J, Peng S, Fu S. Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways. J Transl Med 2013; 11:132. [PMID: 23714001 PMCID: PMC3687679 DOI: 10.1186/1479-5876-11-132] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 05/22/2013] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) contribute to tumor angiogenesis and growth. We previously reported that over-expression of an inhibitor of DNA binding/differentiation 1 (Id1) in EPCs can enhance EPC proliferation, migration, and adhesion. In this study, we investigated the role of Id1 in EPC angiogenesis in patients with ovarian cancer and the underlying signaling pathway. METHODS Circulating EPCs from 22 patients with ovarian cancer and 15 healthy control subjects were cultured. Id1 and matrix metalloproteinase-2 (MMP-2) expression were analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. EPC angiogenesis was detected by tube formation assays. Double-stranded DNA containing the interference sequences was synthesized according to the structure of a pGCSIL-GFP viral vector and then inserted into a linearized vector. Positive clones were identified as lentiviral vectors that expressed human Id1 short hairpin RNA (shRNA). RESULTS Id1 and MMP-2 expression were increased in EPCs freshly isolated from ovarian cancer patients compared to those obtained from healthy subjects. shRNA-mediated Id1 down-regulation substantially reduced EPC angiogenesis and MMP-2 expression. Importantly, transfection of EPCs with Id1 in vitro induced phosphorylation of Akt (p-Akt) via phosphoinositide 3-kinase and increased the expression of MMP-2 via NF-κB. Blockage of both pathways by specific inhibitors (LY294002 and PDTC, respectively) abrogated Id1-enhanced EPC angiogenesis. CONCLUSIONS Id1 can enhance EPC angiogenesis in ovarian cancer, which is mainly mediated by the PI3K/Akt and NF-κB/MMP-2 signaling pathways. Id1 and its downstream effectors are potential targets for treatment of ovarian cancer because of their contribution to angiogenesis.
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Affiliation(s)
- Yajuan Su
- Department of clinical laboratory, the affiliated tumor hospital, Harbin Medical University, Harbin, China
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21
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Jiang Q, Gong Z, Ding S. Endothelial progenitor cells may participate in stress-induced tumour angiogenesis. Med Hypotheses 2013; 80:778-80. [PMID: 23578361 DOI: 10.1016/j.mehy.2013.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 03/07/2013] [Accepted: 03/09/2013] [Indexed: 01/23/2023]
Abstract
Epidemiological and animal studies have suggested that chronic stress promotes tumourigenesis by promoting tumour angiogenesis. However, underlying mechanisms have not been fully elucidated. Endothelial progenitor cells (EPCs) are a group of bone marrow-derived cells that have an important function in neovascularisation of various tumour growths. In this study, chronic stress was hypothesised to increase tumour angiogenesis via sympathetic neurotransmitter-induced activation of EPCs through α1 adrenoreceptor (AR)-extracellular regulated protein kinases and β2 AR-endothelial nitric oxide synthase signal pathways. This hypothesis should be tested in several clinical and animal studies. Results may have implications on the development of new anti-tumour drugs.
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Affiliation(s)
- Qijun Jiang
- Department of Cardiology, Wuhan General Hospital of Guangzhou Military, 627 Wuluo Road, Wuhan 430070, China
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22
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Zheng PP, van der Weiden M, van der Spek PJ, Vincent AJ, Kros JM. Intratumoral, not circulating, endothelial progenitor cells share genetic aberrations with glial tumor cells. J Cell Physiol 2013; 228:1383-90. [DOI: 10.1002/jcp.24309] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 12/07/2012] [Indexed: 12/26/2022]
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Kim YB, Chung YW, Bae HS, Lee JK, Lee NW, Lee KW, Song JY. Circulating endothelial progenitor cells in gynaecological cancer. J Int Med Res 2013; 41:293-9. [DOI: 10.1177/0300060513476999] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Objectives To compare the frequency and absolute numbers of circulating endothelial progenitor cells (EPCs) in healthy control subjects and patients with gynaecological cancer, and to test the hypothesis that cancer treatment lowers EPC numbers. Methods Patients with cervical or ovarian cancer and healthy control subjects provided peripheral blood samples for the isolation of mononuclear cells. EPCs were identified by quadruple immunofluorescence staining and flow cytometry as CD45–/CD34+/CD133+/vascular endothelial growth factor receptor 2 (VEGFR2)+ cells. Results In total, 28 participants were enrolled. Circulating EPCs were present at higher frequencies (and in greater absolute numbers) in patients with cervical or ovarian cancer ( n = 14) than in controls ( n = 14). Concurrent chemoradiation therapy or surgery significantly reduced the frequency and number of EPCs in patients with gynaecological cancer, compared with pretreatment levels. Conclusions EPC levels decline throughout cancer treatment; their measurement may therefore be a useful surrogate marker to monitor treatment response.
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Affiliation(s)
- Yoon Byoung Kim
- Department of Obstetrics and Gynaecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ye Won Chung
- Department of Obstetrics and Gynaecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hyo Sook Bae
- Department of Obstetrics and Gynaecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jae Kwan Lee
- Department of Obstetrics and Gynaecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Nak Woo Lee
- Department of Obstetrics and Gynaecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Kyu Wan Lee
- Department of Obstetrics and Gynaecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jae Yun Song
- Department of Obstetrics and Gynaecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
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Yuan XW, Ge XQ, Sun XT, Ding YT. Intravenous administration of endothelial progenitor cells transfected with the TRAIL gene inhibits the growth of tumors derived from H22 cells in nude mice. Shijie Huaren Xiaohua Zazhi 2012; 20:2986-2991. [DOI: 10.11569/wcjd.v20.i31.2986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of intravenous administration of endothelial progenitor cells (EPCs) transfected with the TRAIL gene on the growth of tumors derived from subcutaneously inoculated H22 cells in nude mice to provide a theoretical basis for the treatment of liver cancer.
METHODS: The TRAIL gene was amplified by PCR, cloned into the pcDNA3.1 vector, and transfected into EPCs. The expression of TRAIL protein was detected by Western blot. Mice were inoculated subcutaneously with H22 cells to induce tumor formation. Tumor-bearing mice were randomly divided into three groups and injected via the tail vein with EPCs transfected with the recombinant adenoviral vector carrying the TRAIL gene, the empty vector, and normal saline, respectively.
RESULTS: Restriction enzyme digestion and DNA sequencing analyses indicate that the recombinant plasmid was constructed successfully. TRAIL expression was detected in EPCs transfected with the recombinant adenoviral vector by Western blot. The rate of reduced tumor growth was 47.77% in mice administered with EPCs carrying the TRAIL gene. Tumor volume and weight in the experimental group (0.791 cm3 ± 0.119 cm3, 0.29 g ± 0.04 g) were significantly lower than those in the two control groups (all P < 0.05).
CONCLUSION: The recombinant plasmid carrying the TRAIL gene has been successfully constructed. Intravenous administration of endothelial progenitor cells transfected with the TRAIL gene inhibits the growth of tumors derived from H22 cells in nude mice.
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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; 18:4925-33. [PMID: 23002366 PMCID: PMC3447276 DOI: 10.3748/wjg.v18.i35.4925] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [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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Rodrigues MCO, Hernandez-Ontiveros DG, Louis MK, Willing AE, Borlongan CV, Sanberg PR, Voltarelli JC, Garbuzova-Davis S. Neurovascular aspects of amyotrophic lateral sclerosis. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2012; 102:91-106. [PMID: 22748827 DOI: 10.1016/b978-0-12-386986-9.00004-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated and poorly understood pathogenesis. Strong evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models. The present review provides an updated analysis of the microvascular pathology and impaired BBB/BSCB in ALS. Based on experimental and clinical ALS studies, the roles of cellular components, cell interactions, tight junctions, transport systems, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption are discussed. The impact of BBB/BSCB damage in ALS pathogenesis is a novel research topic, and this review will reveal some aspects of microvascular pathology involved in the disease and hopefully engender new therapeutic approaches.
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Affiliation(s)
- Maria Carolina O Rodrigues
- Center of Excellence for Aging & Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
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Abstract
PURPOSE OF REVIEW Since the discovery of endothelial progenitor cells (EPCs), there have been conflicting reports as to the precise phenotypic identity, and thus an accurate description of the function of these cells in disease pathology is lacking. This review will detail the protocols that have been published within 2010 to help decipher the true identity of the various cells that have been reported as EPCs in numerous clinical trials. RECENT FINDINGS Throughout 2010, three protocols have been published alleging to identify EPCs, yet only one provides a true nonhematopoietic origin for a cell that is classified as an EPC. In addition to the protocols published to try to establish a consensus definition, 10 studies involving EPCs across disease pathologies were published with various degrees of correlation to disease phenotype and cellular level. SUMMARY A true phenotypic definition of a circulating EPC capable of becoming an endothelial colony forming cell with proliferative potential has been given. It is now time the EPC field drops this ambiguous term (i.e. EPCs), as many studies purporting to measure EPCs are in fact still quantifying cells of a hematopoietic origin. It is necessary for cross study comparisons that a uniform phenotypic definition be adhered to when using the term EPC.
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Andrusiewicz M, Szczerba A, Wołuń-Cholewa M, Warchoł W, Nowak-Markwitz E, Gąsiorowska E, Adamska K, Jankowska A. CGB and GNRH1 expression analysis as a method of tumor cells metastatic spread detection in patients with gynecological malignances. J Transl Med 2011; 9:130. [PMID: 21827674 PMCID: PMC3173340 DOI: 10.1186/1479-5876-9-130] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Accepted: 08/09/2011] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Metastasis is a common feature of many advanced stage cancers and metastatic spread is thought to be responsible for cancer progression. Most cancer cells are localized in the primary tumor and only a small population of circulating tumor cells (CTC) has metastatic potential. CTC amount reflects the aggressiveness of tumors, therefore their detection can be used to determine the prognosis and treatment of cancer patients.The aim of this study was to evaluate human chorionic gonadotropin beta subunit (CGB) and gonadoliberin type 1 (GNRH1) expression as markers of tumor cells circulating in peripheral blood of gynecological cancer patients, indicating the metastatic spread of tumor. METHODS CGB and GNRH1 expression level in tumor tissue and blood of cancer patients was assessed by real-time RT-PCR. The data was analyzed using the Mann-Whitney U and Spearman tests. In order to distinguish populations with homogeneous genes' expression the maximal likelihood method for one- and multiplied normal distribution was used. RESULT Real time RT-PCR results revealed CGB and GNRH1 genes activity in both tumor tissue and blood of gynecological cancers patients. While the expression of both genes characterized all examined tumor tissues, in case of blood analysis, the transcripts of GNRH1 were found in all cancer patients while CGB were present in 93% of patients. CGB and GNRH1 activity was detected also in control group, which consisted of tissue lacking cancerous changes and blood of healthy volunteers. The log-transformation of raw data fitted to multiplied normal distribution model showed that CGB and GNRH1 expression is heterogeneous and more than one population can be distinguished within defined groups.Based on CGB gene activity a critical value indicating the presence of cancer cells in studied blood was distinguished. In case of GNRH1 this value was not established since the results of the gene expression in blood of cancer patients and healthy volunteers were overlapping. However one subpopulation consists of cancer patient with much higher GNRH1 expression than in control group was found. CONCLUSIONS Assessment of CGB and GNRH1 expression level in cancer patients' blood may be useful for indicating metastatic spread of tumor cells.
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George AL, Bangalore-Prakash P, Rajoria S, Suriano R, Shanmugam A, Mittelman A, Tiwari RK. Endothelial progenitor cell biology in disease and tissue regeneration. J Hematol Oncol 2011; 4:24. [PMID: 21609465 PMCID: PMC3123653 DOI: 10.1186/1756-8722-4-24] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 05/24/2011] [Indexed: 12/20/2022] Open
Abstract
Endothelial progenitor cells are increasingly being studied in various diseases ranging from ischemia, diabetic retinopathy, and in cancer. The discovery that these cells can be mobilized from their bone marrow niche to sites of inflammation and tumor to induce neovasculogenesis has afforded a novel opportunity to understand the tissue microenvironment and specific cell-cell interactive pathways. This review provides a comprehensive up-to-date understanding of the physiological function and therapeutic utility of these cells. The emphasis is on the systemic factors that modulate their differentiation/mobilization and survival and presents the challenges of its potential therapeutic clinical utility as a diagnostic and prognostic reagent.
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Affiliation(s)
- Andrea L George
- Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, USA
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