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BACKGROUND: The traditional Chinese medicine (TCM) Xiaoliu Pingyi recipe (XLPYR) has been clinically used for several decades, demonstrating favorable therapeutic effects. However, the underlying regulatory mechanisms remain unclear. The aim of this study was to explore the anti-tumor effects of XLPYR and its regulatory role in the vascular microenvironment through in vivo and in vitro experiment. MATERIALS AND METHODS: In the in vivo study, a C57BL/6J mouse model of lung adenocarcinoma (LUAD) allografts was established, and various interventions were administered for 14 days (Model group: administered normal saline via oral gavage; Pemetrexed (PEM) group: intraperitoneally injected with a solution of pemetrexed, once every 3d; XLPYR group: administered XLPYR via oral gavage; Combination (COMBI) group: received XLPYR via oral gavage simultaneously with intraperitoneal injection of pemetrexed solution). Tumor volume and weight were then compared among the groups. The impact of XLPYR on the tumor vascular microenvironment was assessed using immunohistochemistry staining. In the in vitro study, XLPYR-containing serum was prepared by oral administration to SD rats. The CCK-8 assay evaluated the effect of the serum on the proliferation of normal lung epithelial BEAS-2B cells and LUAD A549 cells, determining the optimal intervention concentrations. The cell migration and invasion abilities were evaluated using the wound-healing assay and Transwell assay, respectively. Finally, ELISA assay measured VEGF secretion levels in the LUAD cell supernatant, and RT-qPCR and Western Blot were employed to detect differences in HIF-1α, VEGFA, Ang-2, and PI3K/Akt mRNA and protein expression levels in both in vivo and in vitro experiments. RESULTS: In the in vivo study, XLPYR significantly inhibited the growth of mice LUAD allografts, with enhanced anti-tumor effects observed with prolonged drug intervention. Immunohistochemistry staining revealed reduced MVD and increased pericyte coverage in all intervention groups. Regarding vascular function, FITC-Dextran extravasation in the tumor tissues of the Model group was significantly higher than in the intervention groups, particularly with lower extravasation in the COMBI group compared to the PEM group. In the in vitro study, XLPYR demonstrated a time- and concentration-dependent inhibitory effect on LUAD cells, and with greater sensitivity in inhibiting LUAD cells compared to BEAS-2B cells. The wound-healing assay and Transwell assay confirmed that XLPYR significantly suppressed the migration and invasion abilities of LUAD cells. ELISA experiments further revealed a significant decrease in VEGF expression in the supernatant of each intervention group. RT-qPCR and Western Blot results showed consistent findings between the in vivo and in vitro experiments. HIF-1α, VEGFA, and Ang-2 mRNA and protein expression levels were significantly downregulated in the PEM group, XLPYR group, and COMBI group. There were no significant differences in the expression of PI3K and Akt mRNA and total protein, but the expression levels of phosphorylated p-PI3K and p-Akt were notably downregulated. CONCLUSION: XLPYR significantly inhibited C57BL/6J mouse LUAD allograft growth and improved the vascular microenvironment, thereby intervening in tumor angiogenesis and inducing vascular normalization. It suppressed LUAD cell proliferation, migration, and invasion, while reducing VEGF concentration in the cell supernatant. The regulatory mechanism may involve inhibiting PI3K/Akt protein phosphorylation and downregulating angiogenesis-related factors, such as HIF-1α, VEGF, and Ang-2.
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Adenocarcinoma del Pulmón , Medicamentos Herbarios Chinos , Neoplasias Pulmonares , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Medicamentos Herbarios Chinos/farmacología , Microambiente Tumoral/efectos de los fármacos , Ratones , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Humanos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Masculino , Pemetrexed/farmacología , Neovascularización Patológica/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Medicina Tradicional China/métodosRESUMEN
Vascular disease is the leading health problem worldwide. Vascular microenvironment encompasses diverse cell types, including those within the vascular wall, blood cells, stromal cells, and immune cells. Initiation of the inflammatory state of the vascular microenvironment and changes in its mechanics can profoundly affect vascular homeostasis. Biomedical materials play a crucial role in modern medicine, hydrogels, characterized by their high-water content, have been increasingly utilized as a three-dimensional interaction network. In recent times, the remarkable progress in utilizing hydrogels and understanding vascular microenvironment have enabled the treatment of vascular diseases. In this review, we give an emphasis on the utilization of hydrogels and their advantages in the various vascular diseases including atherosclerosis, aneurysm, vascular ulcers of the lower limbs and myocardial infarction. Further, we highlight the importance and advantages of hydrogels as artificial microenvironments.
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Hidrogeles , Enfermedades Vasculares , Humanos , Hidrogeles/metabolismo , Materiales Biocompatibles/metabolismoRESUMEN
The vascular microenvironment is the scale at which microvascular transport, interstitial tissue properties and cell metabolism interact. The vascular microenvironment has been widely studied by means of quantitative approaches, including multi-physics mathematical models as it is a central system for the pathophysiology of many diseases, such as cancer. The microvascular architecture is a key factor for fluid balance and mass transfer in the vascular microenvironment, together with the physical parameters characterizing the vascular wall and the interstitial tissue. The scientific literature of this field has witnessed a long debate about which factor of this multifaceted system is the most relevant. The purpose of this work is to combine the interpretative power of an advanced multi-physics model of the vascular microenvironment with state of the art and robust sensitivity analysis methods, in order to determine the factors that most significantly impact quantities of interest, related in particular to cancer treatment. We are particularly interested in comparing the factors related to the microvascular architecture with the ones affecting the physics of microvascular transport. Ultimately, this work will provide further insight into how the vascular microenvironment affects cancer therapies, such as chemotherapy, radiotherapy or immunotherapy.
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Neoplasias , Humanos , Neoplasias/terapia , Modelos Teóricos , Física , Microambiente TumoralRESUMEN
Iron-, magnesium-, or zinc-based metal vessel stents support vessel expansion at the period early after implantation and degrade away after vascular reconstruction, eliminating the side effects due to the long stay of stent implants in the body and the risks of restenosis and neoatherosclerosis. However, emerging evidence has indicated that their degradation alters the vascular microenvironment and induces adaptive responses of surrounding vessel cells, especially vascular smooth muscle cells (VSMCs). VSMCs are highly flexible cells that actively alter their phenotype in response to the stenting, similarly to what they do during all stages of atherosclerosis pathology, which significantly influences stent performance. This Review discusses how biodegradable metal stents modify vascular conditions and how VSMCs respond to various chemical, biological, and physical signals attributable to stent implantation. The focus is placed on the phenotypic adaptation of VSMCs and the clinical complications, which highlight the importance of VSMC transformation in future stent design.
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Músculo Liso Vascular , Stents , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Stents/efectos adversosRESUMEN
Leukemia stem cells in acute myeloid leukemia (AML) can persist within unique bone marrow niches similar to those of healthy hematopoietic stem cells and resist chemotherapy. In the context of AML, endothelial cells (ECs) are crucial components of these niches that appear to promote malignant expansion despite treatment. To better understand these interactions, we developed a real-time cell cycle-tracking mouse model of AML (Fucci-MA9) with an aim of unraveling why quiescent leukemia cells are more resistant to chemotherapy than cycling cells and proliferate during disease relapse. We found that quiescent leukemia cells were more prone to escape chemotherapy than cycling cells, leading to relapse and proliferation. Importantly, post-chemotherapy resting leukemia cells tended to localize closer to blood vessels. Mechanistically, after chemotherapy, resting leukemia cells interacted with ECs, promoting their adhesion and anti-apoptotic capacity. Further, expression analysis of ECs and leukemia cells during AML, after chemotherapy, and after relapse revealed the potential of suppressing the post-chemotherapy inflammatory response to regulate the functions of leukemia cells and ECs. These findings highlight the role of leukemia cells in evading chemotherapy by seeking refuge near blood vessels and provide important insights and directions for future AML research and treatment.
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Vascularization is a crucial step during musculoskeletal tissue regeneration via bioengineered constructs or grafts. Functional vasculature provides oxygen and nutrients to the graft microenvironment, facilitates wound healing, enhances graft integration with host tissue, and ensures the long-term survival of regenerating tissue. Therefore, imaging de novo vascularization (i.e., angiogenesis), changes in microvascular morphology, and the establishment and maintenance of perfusion within the graft site (i.e., vascular microenvironment or VME) can provide essential insights into engraftment, wound healing, as well as inform the design of tissue engineering (TE) constructs. In this review, we focus on state-of-the-art imaging approaches for monitoring the VME in craniofacial TE applications, as well as future advances in this field. We describe how cutting-edge in vivo and ex vivo imaging methods can yield invaluable information regarding VME parameters that can help characterize the effectiveness of different TE constructs and iteratively inform their design for enhanced craniofacial bone regeneration. Finally, we explicate how the integration of novel TE constructs, preclinical model systems, imaging techniques, and systems biology approaches could usher in an era of "image-based tissue engineering."
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Huesos , Ingeniería de Tejidos , Humanos , Ingeniería de Tejidos/métodos , Regeneración Ósea , Neovascularización Patológica , Cicatrización de Heridas , Andamios del Tejido , Neovascularización FisiológicaRESUMEN
BACKGROUND: Brain arteriovenous malformations (bAVM) are abnormal vascular lesions characterized by direct connections between arteries and veins without an intervening capillary bed. The primary goal for brain AVM treatment is to prevent rupture and hemorrhage; however, the underlying molecular mechanisms are still unknown. METHODS: We constructed venous hypertension (VH) rat model with end-to-end anastomosis of the proximal left common carotid artery and the left distal external jugular vein. Thirty-eight adult rats were randomly assigned to four groups: the 0-week (n=5), the 1-week VH group (n=12), the 3-week VH group (n=9), and the 6-week VH group (n=12). We measured the hemodynamics and diameter of the arterialized veins. An RNA sequencing of arterialized veins was conducted, followed by comprehensive bioinformatics analysis to identify key genes and biological pathways involved in VH progression. The candidate genes from RNA-Seq were validated by RT-qPCR and immunostaining in human tissues. RESULTS: We observed high-flow and low resistance characteristics in VH models. A total of 317 upregulated and 258 downregulated common genes were consistently differentially expressed during VH progression. Thirteen co-expression modules were obtained by WGCNA analysis, and 4 key modules were identified. Thirteen genes: Adamts8, Adamtsl3, Spon2, Adamtsl2, Chad, Itga7, Comp, Itga8, Bmp6, Fst, Smad6, Smad7, Grem1, and Nog with differential expressions were identified using the density of maximum neighborhood component (DMNC) algorithm in Cytohubba. The expression of five potential genes (Adamts8, Adamtsl3, Spon2, Adamtsl2, Itga8) were increased in RT-qPCR, while in human bAVM tissue, the protein levels of Adamtsl2 and Itga8 were significant elevated and Spon2 and Adamtsl3 were decreased. CONCLUSION: The identified gene networks of Adamtsl3, Spon2, Adamtsl2, and Itga8 provided key genes for further intervention.
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Previously, we showed that mice treated with cyclophosphamide (CTX) 4 days before intravenous injection of breast cancer cells had more cancer cells in the lung at 3 h after cancer injection than control counterparts without CTX. At 4 days after its injection, CTX is already excreted from the mice, allowing this pre-treatment design to reveal how CTX may modify the lung environment to indirectly affect cancer cells. In this study, we tested the hypothesis that the increase in cancer cell abundance at 3 h by CTX is due to an increase in the adhesiveness of vascular wall for cancer cells. Our data from protein array analysis and inhibition approach combined with in vitro and in vivo assays support the following two-prong mechanism. (1) CTX increases vascular permeability, resulting in the exposure of the basement membrane (BM). (2) CTX increases the level of matrix metalloproteinase-2 (MMP-2) in mouse serum, which remodels the BM and is functionally important for CTX to increase cancer abundance at this early stage. The combined effect of these two processes is the increased accessibility of critical protein domains in the BM, resulting in higher vascular adhesiveness for cancer cells to adhere. The critical protein domains in the vascular microenvironment are RGD and YISGR domains, whose known binding partners on cancer cells are integrin dimers and laminin receptor, respectively.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/farmacología , Metaloproteinasa 2 de la Matriz/sangre , Microambiente Tumoral/efectos de los fármacos , Animales , Membrana Basal/efectos de los fármacos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Permeabilidad Capilar/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Integrina beta1/metabolismo , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Noqueados , Dominios Proteicos , Microambiente Tumoral/fisiologíaRESUMEN
BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Camptotecina/uso terapéutico , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/metabolismo , Angiografía por Tomografía Computarizada , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/farmacología , Leucovorina/uso terapéutico , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/uso terapéutico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Onset, development and progression of atherosclerosis are complex multistep processes. Many aspects of atherogenesis are not yet properly known. This study investigates the changes in vasculature that contribute to switching of vascular cells towards atherogenesis, focusing mainly on ageing. METHODS: Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving atherogenesis, vascular homeostasis, aging, gene expression, signaling pathways, angiogenesis, vascular development, vascular cell differentiation and maintenance, vascular stem cells, endothelial and vascular smooth muscle cells. RESULTS: Atherogenesis is a complex multistep process that unfolds in a sequence. It is caused by alterations in: epigenetics and genetics, signaling pathways, cell circuitry, genome stability, heterotypic interactions between multiple cell types and pathologic alterations in vascular microenvironment. Such alterations involve pathological changes in: Shh, Wnt, NOTCH signaling pathways, TGF beta, VEGF, FGF, IGF 1, HGF, AKT/PI3K/ mTOR pathways, EGF, FOXO, CREB, PTEN, several apoptotic pathways, ET - 1, NF-κB, TNF alpha, angiopoietin, EGFR, Bcl - 2, NGF, BDNF, neurotrophins, growth factors, several signaling proteins, MAPK, IFN, TFs, NOs, serum cholesterol, LDL, ephrin, its receptor pathway, HoxA5, Klf3, Klf4, BMPs, TGFs and others.This disruption in vascular homeostasis at cellular, genetic and epigenetic level is involved in switching of the vascular cells towards atherogenesis. All these factors working in pathologic manner, contribute to the development and progression of atherosclerosis. CONCLUSION: The development of atherosclerosis involves the switching of gene expression towards pro-atherogenic genes. This happens because of pathologic alterations in vascular homeostasis. When pathologic alterations in epigenetics, genetics, regulatory genes, microenvironment and vascular cell biology accumulate beyond a specific threshold, then the disease begins to express itself phenotypically. The process of biological ageing is one of the most significant factors in this aspect as it is also involved in the decline in homeostasis, maintenance and integrity.The process of atherogenesis unfolds sequentially (step by step) in an interconnected loop of pathologic changes in vascular biology. Such changes are involved in 'switching' of vascular cells towards atherosclerosis.
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Therapeutically exploiting vascular and metabolic endpoints becomes critical to translational cancer studies because altered vascularity and deregulated metabolism are two important cancer hallmarks. The metabolic and vascular phenotypes of three sibling breast tumor lines with different metastatic potential are investigated in vivo with a newly developed quantitative spectroscopy system. All tumor lines have different metabolic and vascular characteristics compared to normal tissues, and there are strong positive correlations between metabolic (glucose uptake and mitochondrial membrane potential) and vascular (oxygen saturations and hemoglobin concentrations) parameters for metastatic (4T1) tumors but not for micrometastatic (4T07) and nonmetastatic (67NR) tumors. A longitudinal study shows that both vascular and metabolic endpoints of 4T1 tumors increased up to a specific tumor size threshold beyond which these parameters decreased. The synchronous changes between metabolic and vascular parameters, along with the strong positive correlations between these endpoints suggest that 4T1 tumors rely on strong oxidative phosphorylation in addition to glycolysis. This study illustrates the great potential of our optical technique to provide valuable dynamic information about the interplay between the metabolic and vascular status of tumors, with important implications for translational cancer investigations.
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Determinación de Punto Final , Neoplasias Mamarias Experimentales/metabolismo , Neovascularización Patológica , Fenómenos Ópticos , Animales , Línea Celular Tumoral , Femenino , Glucólisis , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/fisiopatología , Ratones , Metástasis de la Neoplasia , Fosforilación Oxidativa , Carga TumoralRESUMEN
OBJECTIVE: Squamous cell carcinoma is often associated with the deletion or mutation of zinc finger protein 750 (ZNF750), its deletion or mutation is associated with squamous epithelial malignant biological characteristics. The present study is to explore the mechanism of ZNF750 to suppress the tumor malignant process by regulation tumor microenvironment. METHODS: To evaluate the changes of tumor microenvironment in oral squamous cells carcinoma cell line CAL-27 cell, the expression of angiogenin, vascular endothelial growth factor (VEGF), prolyl hydroxylase 2 (PHD2), G protein signal regulated protein 5 (RGS5), integrin A5 (ITGA5), integrin B1 (ITGB1) and CD44 were detected by Western-blot. The changes of platelet derived growth factor (PDGFB) and tumor vascular marker CD105 (Endoglin) mRNA were estimated by qPCR. The effect of over-expressed ZNF750 on cell viability and lateral migration capacity was investigated by CCK-8 and cell scratch assay in three oral squamous cells carcinoma. RESULTS: ZNF750 could effectively inhibit the protein or mRNA expression of angiogenin, VEGF, RGS5 and CD105, repressed the cell adhesion molecules ITGA5, ITGB1 and CD44, but up-regulate the protein or mRNA expression of PHD2 and PDGFB. The cell viability and lateral migration ability of three oral squamous cells carcinoma were reduced by over-expression of ZNF750. CONCLUSION: ZNF750 could modulate the tumor vascular microenvironment to inhibit the oral squamous cells carcinoma malignant progression.
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Carcinoma de Células Escamosas/genética , Genes Supresores de Tumor , Neoplasias de la Boca/genética , Neovascularización Patológica/genética , Factores de Transcripción/genética , Microambiente Tumoral/genética , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia Celular/genética , Células HEK293 , Humanos , Neoplasias de la Boca/irrigación sanguínea , Neoplasias de la Boca/patología , Ribonucleasa Pancreática/genética , Proteínas Supresoras de Tumor , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Recently, compelling evidence shows that cancer stem-like cells (CSLC) are thought to be critical for initiation and propagation of many types of cancers. Most of CSLC are dependent upon the vascular microenvironments that promote their long-term growth and self-renewal. However, it is not known if when we disrupted their vascular microenvironments, CSLC would be eliminated. Considering these possibilities, we have investigated the influence of different chemotherapy regimens on the CSLC population of hepatocarcinoma xenografts model. The mouse models of hepatocarcinoma were treated with different therapeutic regimens: low-dose metronomic (LDM) regimens, combination therapies of Bolus dose and low-dose metronomic regimens, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose (MTD) chemotherapy using gemcitabine (GEM). All therapies produced a significant tumor growth delay. LDM GEM and Bolus+LDM GEM significantly reduced the tumor spheres, whereas MTD GEM had no effect on the tumor spheres. Furthermore, Bolus+LDM GEM could more significantly decrease both the population of CSLC and the levels of viable endothelial progenitor cells (EPC). Overall, our data indicate that Bolus+LDM GEM is a potent treatment regimen for inhibiting angiogenesis, attacking the tumor vascular microenvironments, and decreasing the population of CSLC. Targeting the unique microenvironment of CSLC may be the key to effective cancer therapy, and shows great promise for the clinical practice.
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Carcinoma Hepatocelular/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Hepáticas/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Antígeno AC133 , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Antígenos CD/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Desoxicitidina/administración & dosificación , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Glicoproteínas/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neovascularización Patológica/patología , Péptidos/genética , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Prolonged isolated thrombocytopenia (PT) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, it remains unclear whether abnormalities of the bone marrow (BM) microenvironment are involved in the pathogenesis of PT. This prospective, nested case-control study included 20 patients with PT, 40 matched patients with good graft function (GGF) after allo-HSCT, and 16 healthy donors (HDs). Cellular elements of the BM microenvironment, including BM endothelial cells (BMECs), perivascular cells, and endosteal cells, were analyzed via flow cytometry and via hematoxylin-eosin and immunohistochemical staining in situ. Moreover, stromal-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) were measured in the plasma of BM via an enzyme-linked immunosorbent assay. No significant differences in endosteal cells (15 per high-power field [hpf] versus 16 per hpf versus 20 per hpf, P > .05) were demonstrated among the patients with PT, GGF, and the HDs. The PT patients exhibited remarkable decreases in cellular elements of the vascular microenvironment, including BMECs (.01% versus .18% versus .20%, P < .0001) and perivascular cells (.01% versus .12% versus .13%, P < .0001), compared with the GGF allo-HSCT recipients and the HDs, respectively. Moreover, significantly lower levels of SDF-1 (3163 pg/mL versus 3928 pg/mL, P = .0002) and VEGF (56 pg/mL versus 123 pg/mL, P < .0001) were found in the BM plasma of the PT patients compared with the BM of the GGF patients. A multivariate analysis revealed that BMECs (odds ratio [OR] = 171.57, P = .002) and cytomegalovirus infection after HSCT (OR = 4.35, P = .009) were independent risk factors for PT. Our data suggested that an impaired BM vascular microenvironment and megakaryocyte-active factors may contribute to the occurrence of PT after HSCT.