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Timely and effective interventions after tracheal mucosal injury are lack in clinical practices, which elevate the risks of airway infection, tracheal cartilage deterioration, and even asphyxiated death. Herein, we proposed a biomaterial-based strategy for the repair of injured tracheal mucosal based on a copper hydrogen phosphate nanosheets (CuHP NSs) functionalized commercial hydrogel (polyethylene glycol disuccinimidyl succinate-human serum albumin, PH). Such CuHP/PH hydrogel achieved favorable injectability, stable gelation, and excellent adhesiveness within the tracheal lumen. Moreover, CuHP NSs within the CuHP/PH hydrogel effectively stimulate the proliferation and migration of endothelial/epithelial cells, enhancing angiogenesis and demonstrating excellent tissue regenerative potential. Additionally, it exhibited significant inhibitory effects on both bacteria and bacterial biofilms. More importantly, when injected injured site of tracheal mucosa under fiberoptic bronchoscopy guidance, our results demonstrated CuHP/PH hydrogel adhered tightly to the tracheal mucosa. The therapeutic effects of the CuHP/PH hydrogel were further confirmed, which significantly improved survival rates, vascular and mucosal regeneration, reduced occurrences of intraluminal infections, tracheal stenosis, and cartilage damage complications. This research presents an initial proposition outlining a strategy employing biomaterials to mitigate tracheal mucosal injury, offering novel perspectives on the treatment of mucosal injuries and other tracheal diseases.

ObjectiveCell-based outer vocal fold replacement (COVR) offers a potential treatment for severe vocal fold scarring or cancer reconstruction. Previous work in rabbits using human adipose-derived stem cells (ASC) in fibrin suggested that a hybrid structure emerged within 2 months, containing both implanted and host cells. This project uses immunocytochemistry to better define the phenotypic fate of implanted cells and features of the extracellular environment.MethodsImmunocytochemistry was performed on sections collected from rabbits 2 months after COVR implantation or scar surgery. Cellular targets included human leukocyte antigen (HLA), CD31, and smooth muscle actin (SMA).ResultsHLA was present in all implanted sections and was used to identify human cells. In adjacent sections, HLA-positive cells were identified expressing CD31. SMA was not identified in the same cells as HLA. These markers were also present in injured vocal folds not receiving COVR. SMA protein content did not differ according to treatment.ConclusionsImplanted human ASC persist in rabbit vocal folds. Some appear to express CD31, an endothelial marker. Smooth muscle actin, a marker of myofibroblast phenotype, was present in all sections regardless of treatment, and was not identified in hASC. Host cells also infiltrate the structure, producing a hybrid host-graft vocal fold.

The review article titled CD39 Transforming Cancer Therapy by Modulating Tumor Microenvironment published in June 2024 in Cancer Letters provides a comprehensive overview of CD39's multifaceted roles in cancer, particularly its influence on immunoregulation, angiogenesis, and metabolic reprogramming within the tumor microenvironment (TME). This commentary builds on that foundation by incorporating recent advancements in CD39 research, highlighting unresolved issues, and proposing future research directions. We delve into the therapeutic potential of targeting CD39, addressing clinical translation challenges, and exploring the integration of CD39-based strategies into precision oncology.

Glioblastoma is a highly aggressive neoplasm and the most common primary malignant brain tumor. Endothelial tissue plays a critical role in glioblastoma growth and progression, facilitating angiogenesis, cellular communication, and tumorigenesis. In this review, we present an up-to-date and comprehensive summary of the role of endothelial cells in glioblastomas, along with an overview of recent developments in glioblastoma therapies and tumor endothelial marker identification.

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

BACKGROUND: Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive. METHOD: AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples. RESULT: Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1-/- mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues. CONCLUSION: AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

IntroductionThis study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC).Patients and methodsSingle institution investigator-initiated phase 1 study using 3+3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed.ResultsFifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%.ConclusionThe combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC.ClinicaltrialsGOV: NCT04868773.

Thrombospondin-4 (TSP-4) belongs to the extracellular matrix glycoprotein family of thrombospondins (TSPs). The multidomain, pentameric structure of TSP-4 allows its interactions with numerous extracellular matrix components, proteins and signaling molecules that enable its modulation to various physiological and pathological processes. Characterization of TSP-4 expression under development and pathogenesis of disorders has yielded important insights into mechanisms underlying the unique role of TSP-4 in mediating various processes including cell-cell, cell-extracellular matrix interactions, cell migration, proliferation, tissue remodeling, angiogenesis, and synaptogenesis. Maladaptation of these processes in response to pathological insults and stress can accelerate the development of disorders including skeletal dysplasia, osteoporosis, degenerative joint disease, cardiovascular diseases, tumor progression/metastasis and neurological disorders. Overall, the diverse functions of TSP-4 suggest that it may be a potential marker or therapeutic target for prognosis, diagnosis, and treatment of various pathological conditions upon further investigations. This review article highlights recent findings on the role of TSP-4 in both physiological and pathological conditions with a focus on what sets it apart from other TSPs.

Myeloid immune cells are abundant in both ruptured and unruptured brain arteriovenous malformations (bAVMs). The role of central nervous system (CNS) resident and circulating monocyte-derived macrophages in bAVM pathogenesis has not been fully understood. We hypothesize that CNS resident macrophages enhance bAVM development and hemorrhage. RNA sequencing using cultured endothelial cells (ECs) and mouse bAVM samples revealed that downregulation of two bAVM causative genes, activin-like kinase 1 (ALK1) or endoglin, increased inflammation and innate immune signaling. To understand the role of CNS resident macrophages in bAVM development and hemorrhage, we administrated a colony-stimulating factor 1 receptor inhibitor to bAVM mice with brain focal Alk1 deletion. Transient depletion of CNS resident macrophages at an early stage of bAVM development mitigated the phenotype severity of bAVM, including a prolonged inhibition of angiogenesis, dysplastic vasculature formation, and infiltration of CNS resident and circulating monocyte-derived macrophages during bAVM development. Transient depletion of CNS resident macrophages increased EC tight junction protein expression, reduced the number of dysplasia vessels and severe hemorrhage in established bAVMs. Thus, EC AVM causative gene mutation can activate CNS resident macrophages promoting bAVM progression. CNS resident macrophage could be a therapeutic target to mitigate the development and severity of bAVMs.

VEGF-A is a key cytokine in tumor angiogenesis and a major therapeutic target for cancer. VEGF165 is the predominant isoform of VEGF-A, and it is the most potent angiogenesis stimulant. VEGFR2/KDR domains 2 and 3 (D2D3) bind to the N-terminal domain (NTD, residues 1-110) of VEGF165. Since removal of the heparin-binding domain (HBD, residues 111-165) markedly reduced the mitogenic activity of the growth factor, it has been proposed that the HBD plays a critical role in the mitogenicity of VEGF165. Here, we report that αvβ3 specifically bound to the isolated VEGF165 HBD but not to VEGF165 NTD. Based on docking simulation and mutagenesis, we identified several critical amino acid residues within the VEGF165 HBD required for αvβ3 binding, i.e., Arg123, Arg124, Lys125, Lys140, Arg145, and Arg149. We discovered that VEGF165 HBD binds to the KDR domain 1 (D1) and identified that Arg123 and Arg124 are critical for KDR D1 binding by mutagenesis, indicating that the KDR D1-binding and αvβ3-binding sites overlap in the HBD. Full-length VEGF165 mutant (R123A/R124A/K125A/K140A/R145A/R149A) defective in αvβ3 and KDR D1 binding failed to induce ERK1/2 phosphorylation, integrin β3 phosphorylation, and KDR phosphorylation and did not support proliferation of endothelial cells, although the mutation did not affect the KDR D2D3 interaction with VEGF165. Since β3-knockout mice are known to show enhanced VEGF165 signaling, we propose that the binding of KDR D1 to the VEGF165 HBD and KDR D2D3 binding to the VEGF165 NTD are critically involved in the potent mitogenicity of VEGF165. We propose that binding competition between KDR and αvβ3 to the VEGF165 HBD endows integrin αvβ3 with regulatory properties to act as a negative regulator of VEGF165 signaling.

Angiogenesis is a morphogenic process resulting in the formation of new blood vessels from pre-existing ones, usually in hypoxic micro-environments. The initial steps of angiogenesis depend on robust differentiation of oligopotent endothelial cells into the Tip and Stalk phenotypic cell fates, controlled by NOTCH-dependent cell-cell communication. The dynamics of spatial patterning of this cell fate specification are only partially understood. Here, by combining a controlled experimental angiogenesis model with mathematical and computational analyses, we find that the regular spatial Tip-Stalk cell patterning can undergo an order-disorder transition at a relatively high input level of a pro-angiogenic factor VEGF. The resulting differentiation is robust but temporally unstable for most cells, with only a subset of presumptive Tip cells leading sprout extensions. We further find that sprouts form in a manner maximizing their mutual distance, consistent with a Turing-like model that may depend on local enrichment and depletion of fibronectin. Together, our data suggest that NOTCH signaling mediates a robust way of cell differentiation enabling but not instructing subsequent steps in angiogenic morphogenesis, which may require additional cues and self-organization mechanisms. This analysis can assist in further understanding of cell plasticity underlying angiogenesis and other complex morphogenic processes.

BACKGROUND: Previous studies showed that extracts of Sambucus adnata Wall. have the ability to promote the proliferation and differentiation of osteoblasts, fracture healing, anti-inflammatory and antioxidant effects, which can effectively alleviate the development of osteoarthritis. Vascular endothelial growth factor, on the other hand, is a biomarker for the evaluation of osteoarthritis severity. OBJECTIVE: To investigate the effect and mechanism of two extracts of Sambucus adnata Wall. (methanol extract SAW-ME and dichloromethane extract SAWDCE) on angiogenesis in osteoarthritis. METHODS: (1) Rat models of osteoarthritis were established using anterior cruciate ligament transection and given SAW-ME and SAW-DCE. A sham group was set as a control. Immunohistochemistry and immunofluorescence were used to detect the changes of articular vascular endothelial growth factor A in joint tissue and vascular endothelial growth factor and “H” type blood vessels in serum of osteoarthritis rats. (2) Vascular endothelial cells EA.hy926 were used as the research object and intervened with SAW-ME and SAW-DCE. Cell proliferation was then detected by MTT assay. Vascular endothelial growth factor was used to induce EA.hy926 cells, and the model of angiogenesis was replicated. Cell scratch assay and tube formation assay were performed to study the role and mechanism. (3) EA.hy926 cells were used for transcriptome sequencing to analyze the characteristic changes of cell differential genes and related functions after SAW-DCE intervention. RESULTS AND CONCLUSION: (1) SAW-ME and SAW-DCE downregulated the expression of vascular endothelial growth factor A in the rat knee cartilage and reduced the formation of “H” type vessels in osteoarthritis rats. SAW-ME could significantly decrease the level of vascular endothelial growth factor in serum of osteoarthritis rats (P < 0.05). SAW-DCE could also decrease the level of vascular endothelial growth factor in serum of osteoarthritis rats, but there was no significant change. (2) Both SAW-ME and SAW-DCE significantly inhibited vascular endothelial cell migration and tube formation, and downregulated the expression of Ang1 and Tie2 proteins. (3) Transcriptome sequencing analysis found that abnormal angiogenesis in osteoarthritis was related to the PI3K/AKT signaling pathway. (4) To conclude, SAW-ME and SAW-DCE can inhibit angiogenesis in the rat model of osteoarthritis, and the mechanism may be related to the Ang1/Tie2 and PI3K/AKT signaling pathways. [ABSTRACT FROM AUTHOR]

Objective: We investigated the mechanism whereby interleukin-6 (IL-6), an important inflammatory marker, influences trophoblast function during preeclampsia. Methods: Quantitative PCR and enzyme-linked immunosorbent assay were used to determine the IL-6 mRNA and protein levels, respectively. CCK8 and transwell assays were used to detect how IL-6 affects the proliferation and invasion abilities of HTR-8/SVneo cells respectively; the tube-forming assay was conducted to explore how IL-6 affects the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) after their co-culture with HTR-8/SVneo cells. Using tandem mass tag-based proteomics analysis, we screened for different proteins before and after IL-6 stimulation; Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to investigate the functions and signal pathways associated with these proteins. Results: The IL-6 levels were higher in the placenta of preeclampsia group than in the normal group. IL-6 suppressed the proliferation and invasion of HTR-8/SVneo cells, but promoted the angiogenesis of HUVECs. Seventy differentially expressed IL-6 downstream proteins were identified; these were enriched with various biological processes, molecular functions, cellular components, and biological pathways. Conclusions: IL-6 regulates trophoblast function by interacting with multiple proteins and pathways. Proteomics-based screening serves as a macroscopic approach to clarify the molecular mechanisms associated with preeclampsia. [ABSTRACT FROM AUTHOR]

Exosomes are a specialized vesicle secreted by cells that can transmit information molecules from the cells. Exosomes act as messengers in cell-to-cell signal transmission and play an important role in angiogenic coupling. Exosomes interact with cells through itself or self-contained various factors such as microRNA and signal transducer and activator of transcription, regulate the generation of blood vessels and bone regeneration, and then regulate the process of osteogenic coupling. Current research of exosomes is mostly from mesenchymal stem cells, tumor cells, macrophages, endothelial progenitor cells, etc. It has great potential in the treatment of vascular-related bone diseases. The recent domestic and foreign related literature on the role of exosomes in angiogenesis are widely reviewed and summarized in this note. We hope to provide reference for the subsequent studies on the coupling effect of exosomes and angiogenesis, and to provide ideas for finding new targets for the treatment of vascular-related bone diseases. [ABSTRACT FROM AUTHOR]

Studying tumor immune microenvironment (TIME) is pivotal to understand the mechanism and predict the outcome of cancer immunotherapy. Systems biology mathematical models can consider and control various factors of TIME and therefore explore the anti-tumor immune response meticulously. However, the role of tumor vasculature in the recruitment of T cells and the mechanism of T cell migration through TIME have not been studied comprehensively. In this work, we developed a hybrid discrete-continuum multi-scale model to study TIME. The mathematical model includes angiogenesis and T cell recruitment via tumor vasculature. Moreover, solid tumor growth, vascular growth and remodeling, interstitial fluid flow, hemodynamics, and blood rheology are all considered in the model. In addition, different aspects of T cells, including their migration, proliferation, subtype conversion, and interaction with tumor cells are thoroughly included. The model reproduces spatiotemporal distribution of tumor infiltrating T cells that mimics histopathological patterns. Furthermore, TIME model robustly recapitulates different phases of tumor immunoediting. We also examined a number of biomarkers to predict the outcome of immune checkpoint blockade (ICB) treatment. The results demonstrated that although tumor mutational burden (TMB) may predict non-responders to ICB, a combination of different biomarkers is essential to predict the majority of the responders. Based on our results, the ICB response rate varies significantly from 28 to 89% depending on the values of different parameters, even in the cases with high TMB. [ABSTRACT FROM AUTHOR]

The fibroblast growth factor-2 (FGF-2) is a critical protein for biological processes such as angiogenesis and tissue regeneration. Recently, hydrogels based on semi-synthetic sulfated polysaccharides have been developed for the controlled delivery of FGF-2. These affinity-based FGF-2 carriers utilizing hydrogels based on sulfated polysaccharides enable sustained delivery of FGF-2, yet choice of materials is limited. Here, we demonstrate a novel synthetic sulfated polysaccharide-based hydrogel based on bacterial polyglucuronic acid (PGU). We synthesized phenol-grafted sulfated PGU (PGUS-Ph), an enzymatically cross-linkable PGU derivative that exhibited an enhanced affinity for FGF-2. The aqueous solution of PGUS-Ph, when combined with FGF-2, could be injected into affected sites and form a hydrogel in a minimally invasive manner. The FGF-2 released from the PGUS-Ph hydrogel induced blood vessel formation, as proven by a chick embryo-based angiogenesis assay. Our results indicate that the PGUS-Ph has the potential as an enzymatically cross-linkable and minimally invasively injectable affinity-based FGF-2 delivery system. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a condition that includes symptoms, such as obesity, hyperglycemia, and hypertension, which elevate cardiovascular risk. An impaired angiogenic response of endothelial cells (ECs) in heart and peripheral organs has been proposed in MetS, but the mechanisms of this phenomenon have not been thoroughly explored. Results obtained from evaluating the whole myocardium are inconsistent, since different types of cells react differently to MetS environment and a variety of molecular pathways are involved in the angiogenic response. Therefore, the aim of this paper was to study one selected pathway—the VEGF/VEGFR pathway, which regulates the angiogenic response and microvascular permeability in ECs isolated from db/db mouse hearts. The expression of mRNAs for VEGF/VEGFR axis proteins was assessed with RT-PCR in ECs isolated from control and db/db mouse myocardium. The density of CD31-, VEGFR2-, and VE-cadherin-positive cells was examined with confocal microscopy, and the ultrastructure of ECs was analyzed with transmission electron microscopy. The aortic ring assay was used to assess the capacity of ECs to respond to angiogenic stimuli. Our results showed a decreased number of microvessels, diminished expression of VE-cadherin and VEGFR2 and widened gaps between the ECs of microcapillaries. The aortic ring assay showed a diminished number of sprouts in db/db mice. These results may indicate that ECs in MetS enhance the production of mRNA for VEGF/VRGFR axis proteins, yet sprout formation and vascular barrier maintenance are limited. These novel data may provide a foundation for further studies on ECs dysfunction in MetS. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is a subtype of stroke with the highest fatality and disability rate. Up to now, commonly used first-line therapies have limited value in improving prognosis. Angiogenesis is essential to neurological recovery after ICH. Recent studies have shown that microRNA-451(miR-451) plays an important role in angiogenesis by regulating the function of vascular endothelial cells. We found miR-451 was significantly decreased in the peripheral blood of ICH patients in the acute stage. Based on the clinical findings, we conducted this study to investigate the potential regulatory effect of miR-451 on angiogenesis after ICH. The expression of miR-451 in ICH mouse model and in a hemin toxicity model of human brain microvascular endothelial cells (hBMECs) was decreased the same as in ICH patients. MiR-451 negatively regulated the proliferation, migration, and tube formation of hBMECs in vitro. MiR-451 negatively regulated the microvessel density in the perihematoma tissue and affected neural functional recovery of ICH mouse model. Knockdown of miR-451 could recovered tight junction and protect the integrity of blood-brain barrier after ICH. Based on bioinformatic programs, macrophage migration inhibitory factor (MIF) was predicted to be the target gene and identified to be regulated by miR-451 inhibiting the protein translation. And p-AKT and p-ERK were verified to be downstream of MIF in angiogenesis. These results all suggest that miR-451 will be a potential target for regulating angiogenesis in ICH. [ABSTRACT FROM AUTHOR]

Background: Around the world, non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths among all cancers. Despite advancements in new therapeutic approaches over the past few decades, the five-year survival rate still remains disappointing. The lack of effective anti-angiogenic and anti-migration drugs is the biggest obstacle to the treatment of metastatic lung cancer. Therefore, there is a need to develop new and effective therapeutic compounds targeting anti-angiogenic and anti-migration pathways for the treatment of lung cancer. Ornidazole is a nitroimidazole agent widely used in the treatment of parasitic infections such as trichomonas vaginalis, amebiasis and giardiasis. This study aimed to investigate the anti-proliferative, anti-angiogenic and anti-mitotic activities of the anti-parasitic drug Ornidazole in two human lung cancer cell lines (A549, H1299). Methods: We determined the effects of Ornidazole, on cell viability, apoptosis, migration, angiogenesis and metastatic ability against NSCLC in lung cancer cell lines. Its action on the mRNA and protein expression levels of VEGFA, VEGFR2, NRP1, Casp9, Casp3, Bax, Bcl-2, PIK3CA, AKT, MTOR, PTEN and FOX3A was assessed. Furthermore, in this study the effects on cell migration, cell viability and proliferation was evaluated through wound healing, MTT and Crystal violet assays. Results: This study demonstrated that Ornidazole effectively reduces cell viability and migration ability, inhibits angiogenesis and metastatic abilities in NSCLC cells. Conclusions: In conclusion, these results may shed light on the treatment of NSCLC, and we suggest the anti-parasitic drug Ornidazole as a new agent with potential anti-angiogenic and anti-mitotic activity by interfering with the molecular pathways that trigger tumor angiogenesis and migration. [ABSTRACT FROM AUTHOR]

Herein we described the biofabrication of samarium oxide nanoparticles (HT‐Sm2O3 NPs) by applying the aqueous fruit extract of Hyphaene thebaica was utilized as an eco‐friendly chelating agent. The prepared NPs were subjected to various physicochemical properties and potential in biomedical applications. X‐ray Diffraction (XRD) pattern revealed sharp peaks that corroborated with the Joint Committee on Powder Diffraction Standards (JCPDS) card no. 00–042‐1464. Crystallite size obtained from Debye–Scherrer approximation and Williamson–Hall (W–H) plot was 28.73 and 69.3 nm, respectively. Optical bandgap was calculated by employing Kubelka–Munk (K–M) function and was found to be ~4.58 eV. Raman shift was observed at 121, 351, 424—, and 561 cm−1. Photoluminescence (PL) spectra revealed two major peaks positioned at 360 and 540 nm. The high‐resolution transmission electron microscopy (HR‐TEM) analysis of HT‐Sm2O3 nanoparticles (NPs) showed that they predominantly have spherical to cuboidal shapes. Additionally, the selected area electron diffraction (SAED) pattern presented spotty rings, indicating a high level of crystallinity in these NPs. The potential nanomedicine applications were studied using diverse bioassays using different treatments. The antioxidant activity demonstrated 45.71% ± 1.13% inhibition at 1000 μg/mL. Brine shrimp lethality assay revealed the highest cytotoxicity of 46.67% ± 3.33% at 1000 μg/mL and LC50 value of 1081 μg/mL. HT‐Sm2O3 NPs exhibited inhibition of angiogenesis (20.41% ± 1.18%) at of 1000 μg/mL. MTT assay results indicated that HT‐Sm2O3 NPs exhibit inhibitory effects on cell lines. Specifically, these NPs showed an IC50 value of 104.6 μg/mL against 3T3 cells. Against MCF‐7 cells, the NPs demonstrated an IC50 value of 413.25 μg/mL. Additionally, in the inhibition of acetylcholinesterase (AChE), the newly synthesized NPs showed an IC50 value of 320 μg/mL. The antidiabetic assessment through α‐glucosidase and α‐amylase inhibition assays revealed, an IC50 value of 380 μg/mL for α‐glucosidase and 952 μg/mL for α‐amylase was calculated. Overall, our study suggested that the Sm2O3 NPs possess moderate anticancer, cholinesterase inhibition, and antidiabetic potential, however, needs further assessment. Research Highlights: In this work, nano‐samaria is synthesized using an eco‐friendly and green approach.The nanoparticles were characterized using techniques such as Raman, HR‐TEM, FTIR, DRS, XRD, and so on, and the applications were studied using multiple in vitro bioassays for Diabetes, Alzheimer, and Cancer.The nano‐samaria revealed good potential for potential biomedical applications. [ABSTRACT FROM AUTHOR]

Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti‐angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti‐angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4‐nitroquinoline 1‐oxide (4NQO)‐induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31‐immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of Hif1a and Vegfa along with hypoxic status and found that OED exhibited increased Vegfa expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti‐angiogenic therapy and found that anti‐VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO‐induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets. [ABSTRACT FROM AUTHOR]

Liver cancer (LC) is a global health concern, marked by its high prevalence and mortality rates and known for its resistance to chemotherapy. The treatment of LC patients is facing great challenges. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a LC marker that has been discovered in recent years, and there are sporadic data suggesting that it has an impact on the level of chemoresistance, but the exact mechanism remains to be deciphered. Our investigation, grounded in bioinformatics strategies including the TCGA database, GEO database, K–M plot database, GSEA, Pearson correlation analysis, and detection of clinical samples, led to the identification of TPX2 and its upstream transcription factor E2F8 as differentially expressed elements in LC tissues. We also probed the role of the axis in glycolysis, angiogenesis, tumor progression, and chemoresistance in LC cells. This was achieved by a battery of molecular and cellular experiments, such as qRT-PCR, CCK-8, Transwell, flow cytometry, and angiogenesis assays. Both TPX2 and E2F8 were upregulated in LC tissues and cells with E2F8 being responsible for the upregulation of TPX2. Through bioinformatics analysis, we observed a significant enrichment of TPX2 in the glycolysis and angiogenesis pathways. Cell-based experiments corroborated these findings, demonstrating that TPX2 knockdown led to significant inhibition of glycolysis and angiogenesis, along with a suppression of the malignant progression of LC cells. This was mirrored by a reduction in the IC50 values for cisplatin and apatinib to 0.8257 µM and 10.79 µM, respectively. In contrast, E2F8 overexpression reversed these effects in LC cells, increasing the IC50 values to 3.375 and 16.06 µM, respectively. The E2F8-TPX2 axis promotes glycolysis and angiogenesis in LC cells, which in turn accelerates cancer progression and reduces chemosensitivity. [ABSTRACT FROM AUTHOR]

As the cornerstone of tissue engineering and regeneration medicine research, developing a cost‐effective and bionic extracellular matrix (ECM) that can precisely modulate cellular behavior and form functional tissue remains challenging. An artificial ECM combining polysaccharides and fibrillar proteins to mimic the structure and composition of natural ECM provides a promising solution for cardiac tissue regeneration. In this study, we developed a bionic hydrogel scaffold by combining a quaternized β‐chitin derivative (QC) and fibrin‐matrigel (FM) in different ratios to mimic a natural ECM. We evaluated the stiffness of those composite hydrogels with different mixing ratios and their effects on the growth of human umbilical vein endothelial cells (HUVECs). The optimal hydrogels, QCFM1 hydrogels were further applied to load HUVECs into nude mice for in vivo angiogenesis. Besides, we encapsulated human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) into QCFM hydrogels and employed 3D bioprinting to achieve batch fabrication of human‐engineered heart tissue (hEHT). Finally, the myocardial structure and electrophysiological function of hEHT were evaluated by immunofluorescence and optical mapping. Designed artificial ECM has a tunable modulus (220–1380 Pa), which determines the different cellular behavior of HUVECs when encapsulated in these. QCFM1 composite hydrogels with optimal stiffness (800 Pa) and porous architecture were finally identified, which could adapt for in vitro cell spreading and in vivo angiogenesis of HUVECs. Moreover, QCFM1 hydrogels were applied in 3D bioprinting successfully to achieve batch fabrication of both ring‐shaped and patch‐shaped hEHT. These QCFM1 hydrogels‐based hEHTs possess organized sarcomeres and advanced function characteristics comparable to reported hEHTs. The chitin‐derived hydrogels are first used for cardiac tissue engineering and achieve the batch fabrication of functionalized artificial myocardium. Specifically, these novel QCFM1 hydrogels provided a reliable and economical choice serving as ideal ECM for application in tissue engineering and regeneration medicine. [ABSTRACT FROM AUTHOR]

Injectable in situ‐forming scaffolds that induce both angiogenesis and osteogenesis have been proven to be promising for bone healing applications. Here, we report the synthesis of an injectable hydrogel containing cobalt‐doped bioactive glass (BG)‐loaded microspheres. Silk fibroin (SF)/gelatin microspheres containing BG particles were fabricated through microfluidics. The microspheres were mixed in an injectable alginate solution, which formed an in situ hydrogel by adding CaCl2. The hydrogel was evaluated for its physicochemical properties, in vitro interactions with osteoblast‐like and endothelial cells, and bone healing potential in a rat model of calvarial defect. The microspheres were well‐dispersed in the hydrogel and formed pores of >100 μm. The hydrogel displayed shear‐thinning behavior and modulated the cobalt release so that the optimal cobalt concentration for angiogenic stimulation, cell proliferation, and deposition of mineralized matrix was only achieved by the scaffold that contained BG doped with 5% wt/wt cobalt (A‐S‐G5Co). In the scaffold containing higher cobalt content, a reduced biomimetic mineralization on the surface was observed. The gene expression study indicated an upregulation of the osteogenic genes of COL1A1, ALPL, OCN, and RUNX2 and angiogenic genes of HIF1A and VEGF at different time points in the cells cultured with the A‐S‐G5Co. Finally, the in vivo study demonstrated that A‐S‐G5Co significantly promoted both angiogenesis and osteogenesis and improved bone healing after 12 weeks of follow‐up. These results show that incorporation of SF/gelatin microspheres containing cobalt‐doped BG in an injectable in situ‐forming scaffold can effectively enhance its bone healing potential through promotion of angiogenesis and osteogenesis. [ABSTRACT FROM AUTHOR]

Fat grafting is an emerging clinical technique to address soft tissue deficiencies. This study investigates whether the secretory function of beige adipose tissue(BeigeAT) grafts is involved in promoting soft tissue regeneration in fat grafting. In this study, mice were randomly divided into white adipose tissue (WAT) and BeigeAT groups. Each type of adipose tissue (0.3 mL) was transplanted into the respective groups, and samples were harvested at 2, 4, and 12 week. Subsequently, mice were further divided into three groups, BeigeAT group, BeigeAT with CXCL13 treatment group, and BeigeAT with TAK‐779 treatment group, to investigate the role of CXCL13 in BeigeAT transplants. Graft retention rate, vascularization, and fibrosis levels were compared among the groups. Compared to WAT transplants, BeigeAT transplants exhibited moderate inflammation, enhanced revascularization, reduced fibrosis, and increased infiltration of M2 macrophages and endothelial progenitor cells in the early stages following fat grafting. CXCL13 expression was significantly higher in BeigeAT transplants at 2, 4, and 12 week post‐grafting. Additionally, modulation of CXCL13 expression affected the infiltration of M2 macrophages and endothelial progenitor cells. However, BeigeAT transplants exhibited superior retention rates compared to BeigeAT CXCL13 groups and BeigeAT TAK‐779 groups after 12 weeks of fat grafting. BeigeAT transplants achieve improved retention rates through CXCL13‐induced infiltration of M2 macrophages and endothelial progenitor cells. [ABSTRACT FROM AUTHOR]

Delayed union or nonunion remains an extremely challenging predicament even after the application of currently available engineering scaffolds for the treatment of critical‐sized bone defects. The angiogenesis throughout the artificial bone repair scaffold to achieve “angiogenic‐osteogenic coupling” is regarded as an effective approach to solving this issue. The newly formed blood vessels can accelerate the supply of oxygen and nutrients, thereby triggering subsequent bone regeneration. Therefore, scaffolds featuring an angiogenic microenvironment that promotes cell adhesion and migration should be designed for superior bone repair. Herein, a magnesium ion‐doped hierarchical scaffold is fabricated using a polymer blend system of chitosan/polyethyleneimine with inherent micro‐phase separation and complexation. Due to the microscopic sea‐island structure and the stable doped magnesium ions, the cell adhesion behavior underwent a significant transformation. Meanwhile, the pathways related to cell adhesion, migration, and angiogenesis are activated, and the critical target thrombospondin 1 is upregulated. Consequently, the cell adhesion capacity is augmented, 6 times the cell migration rate is attained, and the angiogenesis of human umbilical vein endothelial cells is significantly expedited. Eventually, rapid bone ingrowth and satisfactory bone defect repair are approximated in vivo, making the composite scaffold a promising clinical candidate for bone engineering. [ABSTRACT FROM AUTHOR]

Background: Telocytes, recently recognized as interstitial cells with a diverse range of potential functions, have attracted considerable attention for their involvement in tumorigenesis. Nevertheless, owing to certain challenges in the isolation and cultivation of telocytes, the research on telocytes has advanced rather slowly. Therefore, it is imperative to study the role and mechanisms of telocytes in tumors. Methods: We improved the separation method and successfully isolated telocytes by exploiting the combination of cell adhesion and magnetic bead sorting. Telocytes conditioned medium was collected to culture tumor cells and explore the role and mechanisms of telocytes in tumors. Results: MTT and colony formation assays demonstrated that telocytes promoted tumor cell proliferation. Wound healing experiments and transwell assays indicated that telocytes enhanced tumor cell migration. Real-time reverse transcriptase PCR analysis showed that the expression of E-cadherin was decreased, and that of Vimentin was notably increased. ELISA results revealed that telocytes secreted high levels of vascular endothelial growth factor (VEGF). And the promoting effects were alleviated by the VEGF inhibitor bevacizumab. Conclusion: Our findings revealed that telocytes promoted tumor cell proliferation, migration, and angiogenesis through VEGF. Notably, these effects were inhibited by the addition of bevacizumab. In conclusion, our findings illuminated the role of telocytes in promoting tumor progression, and confirmed their crucial regulatory role in the growth of tumor cells. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is known for its poor prognosis and resistance to conventional therapies, largely due to the presence of cancer stem cells (CSCs) and aggressive angiogenesis. Effectively targeting these CSCs and associated angiogenic pathways is crucial for effective treatment. This study leverages single-cell multi-omics to explore a novel therapeutic approach involving Chimeric Antigen Receptor (CAR) macrophages engineered to target the c-Met protein on pancreatic CSCs. Methods: We employed single-cell RNA sequencing to analyze pancreatic cancer tissue, identifying c-Met as a key marker of CSCs. CAR macrophages were engineered using a lentiviral system to express a c-Met-specific receptor. The phagocytic efficiency of these CAR macrophages against pancreatic CSCs was assessed in vitro, along with their ability to inhibit angiogenesis. The in vivo efficacy of CAR macrophages was evaluated in a mouse model of pancreatic cancer. Results: CAR macrophages demonstrated high specificity for c-Met + CSCs, significantly enhancing phagocytosis and reducing the secretion of angiogenic factors such as VEGFA, FGF2, and ANGPT. In vivo, these macrophages significantly suppressed tumor growth and angiogenesis, prolonging survival in pancreatic cancer-bearing mice. Conclusion: CAR macrophages targeting c-Met represent a promising therapeutic strategy for pancreatic cancer, offering targeted elimination of CSCs and disruption of tumor angiogenesis. This study highlights the potential of single-cell multi-omics in guiding the development of precision immunotherapies. [ABSTRACT FROM AUTHOR]

Background: Curcumin is an age old traditional medicine. Although curcumin has several advantages, its water solubility and bioavailability limit its use as a natural therapeutic agent. Polymeric nano curcumin could be an excellent option to overcome these challenges to augment its therapeutic efficacy. This work aimed to synthesize curcumin-loaded PLGA nanoparticles and assess their angiogenic and antioxidant potential in the zebrafish model. Results: The double emulsion solvent evaporation process was employed to make curcumin-loaded PLGA nanoparticles. Curcumin showed ~ 28.23 (± 2.49) encapsulation efficacy with an average diameter of PLGA nanoparticles 168.5 (± 2.5) nm and curcumin nanoparticles about 281.6 (± 17.2) nm, respectively. The curcumin nanoparticles showed no developmental toxicity to the zebrafish embryos while reduced toxicity compared to the native curcumin. Further, the curcumin nanoparticles reduced the generation of reactive oxygen species and improved angiogenesis in the model system. All these results confirmed that the nanoparticle has had higher bio-efficacy than that of native curcumin. Conclusion: This study shows that PLGA curcumin nanoparticles hold an excellent therapeutic promise for wound healing, tissue regeneration and other biomedical applications where angiogenesis and ROS play critical role. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion Introduce a new intrapapillary capillary loop (IPCL) classification using narrow‐band imaging (NBI) to diagnose early malignant transformation in oral potentially malignant disorders (OPMDs).In the exploratory phase, NBI images from 241 patients with OPMDs and oral squamous cell carcinoma (OSCC) were assessed for three basic IPCL features—dilation, unevenness, and tortuosity—to identify patterns associated with OPMDs malignant transformation. Chi‐square analysis and logistic regression differentiated these patterns between low‐risk (no/mild dysplasia) and high‐risk (moderate/severe dysplasia, invasive carcinoma) lesions, establishing a new classification system. In the validation phase, the system was applied to 90 patients with histopathological results confirming diagnostic accuracy.Four distinct IPCL types were identified: normal, dilated, irregular, and chaotic, with increasing odds ratios for high‐risk lesions. The ROC curve had an AUC of 0.913, with irregular and chaotic types providing the best diagnostic performance, achieving sensitivities and specificities of 84.2% and 88.4%, respectively. In the validation phase, the new classification achieved an overall diagnostic accuracy of 84.4% and substantial inter‐observer consistency (κ = 0.694).The new IPCL classification effectively identifies high‐risk oral lesions, enhancing the diagnostic utility of NBI for early detection of OPMDs malignant transformations. [ABSTRACT FROM AUTHOR]

Angiogenesis, which involves many essential processes, such as human reproduction, organ development, and wound healing, is regulated by multiple signaling pathways. QKCMP is a polypeptide with similar effects to vascular endothelial growth factor (VEGF), which promotes angiogenesis. In this study, zebrafish were treated with different concentrations of QKCMP, and it was found that QKCMP significantly promoted the growth of blood vessels. Human umbilical vein endothelial cells (HUVECs) was then treated with different concentrations of QKCMP, which proved that QKCMP could promote cell proliferation and inhibit cell apoptosis, and thus obtain a complete gene expression matrix. Genes and biological functions or pathways significantly associated with QKCMP were obtained using differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and enrichment analyses. Among them, genes significantly related to QKCMP are enriched in biological processes (BP) such as vascular formation and development, as well as the main signaling pathway: PI3K/AKT signaling pathway. The proproliferative and antiapoptotic effects of QKCMP on the HUVECs and the induction of cell cycle were then verified using cell counting kit 8 (CCK-8) and flow cytometry. Finally, it was confirmed that QKCMP promotes angiogenesis and rapid endothelialization by stimulating the PI3K-AKT and Hippo signaling pathways using quantitative real-time PCR (qRT-PCR) and western blot (WB). [ABSTRACT FROM AUTHOR]

Infected fracture healing is a complicated process that includes intricate interactions at the cellular and molecular levels. In addition to angiogenesis and osteogenesis, the significance of neurogenesis in fracture healing has also been recognized in recent years. Here, a nanocomposite hydrogel containing pH‐responsive zinc‐gallium‐humic acids (HAs) nanoparticles is developed. Through the timed release of Zn2+, Ga3+, and HAs, the hydrogel exhibits potent antibacterial effects and promotes angiogenesis, osteogenesis, and neurogenesis. The enhanced neurogenesis further promotes angiogenesis and osteogenesis, forming a mutually supportive angiogenesis–osteogenesis–neurogenesis cycle at the fracture site. The hydrogel achieves rapid infected fracture healing and improves tissue regeneration in mice. This study proposes a comprehensive treatment approach that combines antibacterial effects with the regulation of tissue regeneration to improve infected fracture healing. [ABSTRACT FROM AUTHOR]

Background: This phase II randomized controlled trial tested whether the intracarotid arterial administration (ICAA) of autologous CD34 + cells to patients within 14 ± 7 days after acute ischemic stroke (IS) could be safe and further improve short- and long-term outcomes. Methods: Between January 2018 and March 2022, 28 consecutive patients were equally randomly allocated to the cell-treated group (CD34 + cells/3.0 × 107/patient) or the control group (receiving optimal medical therapy). CD34 + cells were transfused into the ipsilateral brain infarct zone of cell-treated patients via the ICAA in the catheterization room. Results: The results demonstrated 100% safety and success rates for the procedure, and no long-term tumorigenesis was observed in cell-treated patients. In cell-treated patients, the angiogenesis capacity of circulating endothelial progenitor cells (EPCs)/Matrigel was significantly greater after treatment than before treatment with granulocyte colony-stimulating factor (all p < 0.001). Blood samples from the right internal jugular vein of the cell-treated patients presented significantly greater levels of the stromal cell-derived factor 1α/EPC at 5, 10 and 30 min compared with 0 min (all p < 0.005). The National Institute of Health Stroke Scale scores were similar upon presentation, but a greater response was observed by Days 30 and 90 in the cell-treated group than in the control group. Tc-99 m brain perfusion was significantly greater at 180 days in the cell-treated group than in the control group (p = 0.046). The combined long-term end points (defined as death/recurrent stroke/or severe disability) were notably lower in the control group compared with the cell-treated group (14.3% vs. 50.0%, p = 0.103). Conclusion: Intracarotid transfusion of autologous CD34 + cells is safe and might improve long-term outcomes in patients with acute IS. Trial registration ISRCTN, ISRCTN15677760. Registered 23 April 2018- Retrospectively registered, https://doi.org/10.1186/ISRCTN15677760 [ABSTRACT FROM AUTHOR]

Background: Deep partial-thickness burns have a significant impact on both the physical and mental health of patients. Our previous study demonstrated human Umbilical Cord Mesenchymal stem cells (hUCMSCs) could enhance the healing of severe burns in small animal burn models, such as rats. Furthermore, our team has developed a deep partial-thickness burn model in Bama miniature pigs, which can be utilized for assessing drug efficacy in preclinical trials for wound healing. Therefore, this study further determine the optimal dosage of hUCMSCs in future clinical practice by comparing the efficacy of low-to-high doses of hUCMSCs on deep partial-thickness burn wounds in Bama miniature pigs. Materials and methods: The male Bama miniature pigs (N = 8, weight: 23–28 kg and length: 71–75 cm) were used to establish deep partial-thickness burn models, which used a continuous pressure of 1 kg and contact times of 35 s by the invented electronic burn instrument at 100℃ to prepare 10 round burn wounds with diameter of 5 cm according to our previous report. And then, 0 × 10^7, 1 × 10^7, 2 × 10^7, 5 × 10^7 and 1 × 10^8 doses of hUCMSCs were respectively injected into burn wounds of their corresponding groups. After treatment for 7, 14 and 21 days, the burned wound tissues were obtained for histological evaluation, including HE staining for histopathological changes, immunohistochemistry for neutrophil (MPO+) infiltration and microvessel (CD31+) quantity, as well as Masson staining for collagen deposition. The levels of inflammatory factors TNF-α, IL-1β, IL-10 and angiogenesis factors angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), as well as collagen type-I/type-III of the wound tissues were quantified by ELISA. Results: All of doses hUCMSCs can significantly increase wound healing rate and shorten healing time of the deep partial-thickness burn pigs in a dose-dependent manner. Furthermore, all of doses hUCMSCs can significantly promote epithelialization and decreased inflammatory reaction of wound, including infiltration of inflammatory cells and levels inflammatory factors. Meanwhile, the amounts of microvessel were increased in all of doses hUCMSCs group than those in the burn group. Furthermore, the collagen structure was disordered and partially necrotized, and ratios of collagen type-I and type-III were significantly decreased in burn group (4:1 in normal skin tissue), and those of all hUCMSCs groups were significantly improved in a dose-dependent manner. In a word, 1 × 10^8 dose of hUCMSCs could regenerate the deep partial-thickness burn wounds most efficaciously compared to other dosages groups and the burn group. Conclusion: This regenerative cell therapy study using hUCMSCs demonstrates the best efficacy toward a high dose, that is dose of 1 × 10^8 of hUCMSCs was used as a reference therapeutic dose for treating 20 cm2 deep partial-thickness burns wound in future clinical practice. [ABSTRACT FROM AUTHOR]

Background: Abnormal pulmonary vascular development poses significant clinical challenges for infants with bronchopulmonary dysplasia (BPD). Although numerous factors have been suggested to control the development of pulmonary blood vessels, the mechanisms underlying the role of long noncoding RNAs (lncRNAs) in this process remain unclear. Methods: A lncRNA array was used to measure the differential expression of lncRNAs in premature infants with and without BPD. The expression of lncRNA-VSIG2-1:1 in patients with BPD and hyperoxia-induced human pulmonary microvascular endothelial cells (HPMECs) was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Fluorescence in situ hybridization (FISH) assay was performed to detect the subcellular localization of lncRNA-VSIG2-1:1. Pulmonary microvascular endothelial cells were stably transfected with adenoviral vectors to silence or overexpress lncRNA-VSIG2-1:1. The effects of lncRNA-VSIG2-1:1 on the proliferation, migration, and tube formation abilities of HPMECs subjected to hyperoxia were examined by performing Cell Counting Kit‐8 (CCK-8), cell migration, and tubule formation assays. RNA sequencing (RNA-seq) was performed to determine the correlation between lncRNA-VSIG2-1:1 and phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT). The protein levels of vascular endothelial growth factor (VEGF), p-PI3K, PI3K, p-AKT, and AKT were determined using western blotting. Results: The expression of lncRNA-VSIG2-1:1 was upregulated in patients with BPD and hyperoxia-treated HPMECs. Inhibiting lncRNA-VSIG2-1:1 expression promoted the proliferation, migration, and tube-formation abilities of HPMECs, while significantly increasing VEGF, p-PI3K, and p-AKT levels. Conclusion: Our findings reveal that the suppression of lncRNA-VSIG2-1:1 expression stimulates angiogenesis in vitro by inducing the initiation of the VEGF/PI3K/AKT signaling pathway. This observation may aid the development of novel therapeutic targets for treating BPD. [ABSTRACT FROM AUTHOR]

Cold temperatures have been shown to slow skin wound healing. However, the specific mechanisms underlying cold-induced impairment of wound healing remain unclear. Here, we demonstrate that small extracellular vesicles derived from cold-exposed mouse plasma (CT-sEVs) decelerate re-epithelialization, increase scar width, and weaken angiogenesis. CT-sEVs are enriched with miRNAs involved in the regulation of wound healing-related biological processes. Functional assays revealed that miR-423-3p, enriched in CT-sEVs, acts as a critical mediator in cold-induced impairment of angiogenic responses and poor wound healing by inhibiting phosphatase and poly(A) binding protein cytoplasmic 1 (PABPC1). These findings indicate that cold delays wound healing via miR-423-3p in plasma-derived sEVs through the inhibition of the ERK or AKT phosphorylation pathways. Our results enhance understanding of the molecular mechanisms by which cold exposure delays soft tissue wound healing. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), a globally prevalent form of cancer, is featured by aggressive growth and early metastasis. Elucidating the underlying mechanism and identifying the effective therapy are critical for advanced HCC patients. In the study, we detect that KRT80 was upregulated in HCC samples. HCC patients with higher KRT80 are associated with worse overall survival after surgery. Gain‐of and loss‐of function studies show that KRT80 enhanced HCC cells proliferation, migration, invasion, and angiogenesis, whereas its silencing abolishes the effects in vivo and in vitro. Mechanistic investigation shows that KRT80 may function as an independent prognostic risk factor and act as an oncogene by influencing EMT and modulating the PI3K/AKT signaling pathway. Together, these findings suggest that KRT80 may be a potential oncogene and a good indicator in predicting prognosis. Targeting KRT80 can offer new insights into the prevention and treatment of HCC. [ABSTRACT FROM AUTHOR]

Background: Extracellular vesicles (EVs) are a group of nanoscale cell-derived membranous structures secreted by all cell types, containing molecular cargoes involved in intercellular communication. EVs can be used to mimic "nature's delivery system" to transport nucleic acids, peptides, lipids, and metabolites to target recipient cells. EVs offer a range of advantages over traditional synthetic carriers, thus paving the way for innovative drug delivery approaches that can be used in different diseases, including cancer. Here, by using breast cancer (BC) cells treated with the multi-kinase inhibitor sorafenib, we generated EVs enriched in specific non-coding RNAs (miR-23b-3p, miR-126-3p, and the long ncRNA GAS5) and investigated their potential impact on the aggressive properties of the BC in vitro and in vivo using zebrafish. Methods: EVs were collected from 4 different BC cell lines (HCC1937, MDA-MB-231, MCF-7, and MDA-MB-453) and characterized by western blotting, transmission electron microscopy and nanoparticle tracking analysis. Levels of encapsulated miR-23b-3p, miR-126-3p, and GAS5 were quantified by ddPCR. The role of the EVs as carriers of ncRNAs in vivo was established by injecting MDA-MB-231 and MDA-MB-453 cells into zebrafish embryos followed by EV-based treatment of the xenografts with EVs rich in miR-23b-3p, miR-126-3p and GAS5. Results: ddPCR analysis revealed elevated levels of miR-23b-3p, miR-126-3p, and GAS5, encapsulated in the EVs released by the aforementioned cell lines, following sorafenib treatment. The use of EVs as carriers of these specific ncRNAs in the treatment of BC cells resulted in a significant increase in the expression levels of the three ncRNAs along with the inhibition of cellular proliferation in vitro. In vivo experiments demonstrated a remarkable reduction of xenograft tumor area, suppression of angiogenesis, and decreased number of micrometastasis in the tails after administration of EVs enriched with these ncRNAs. Conclusions: Our study demonstrated that sorafenib-induced EVs, enriched with specific tumor-suppressor ncRNAs, can effectively inhibit the aggressive BC characteristics in vitro and in vivo. Our findings indicate an alternative way to enrich EVs with specific tumor-suppressor ncRNAs by treating the cells with an anticancer drug and support the development of new potential experimental molecular approaches to target the aggressive properties of cancer cells. [ABSTRACT FROM AUTHOR]

Tilapia is a kind of fish with a huge amount of aquaculture, and a lot of byproducts are wasted in processing. Of these, fish skin is the most valued due to its high content of gelatin, which has good characteristics such as low hypoallergenic, biocompatibility, and permeability. In this study, a novel pentapeptide (Leu‐Ser‐Gly‐Tyr‐Gly, LYG) was isolated from gelatin gastrointestinal digests of tilapia skin and verified the anti‐inflammatory and antiangiogenic activity of LYG, which can inhibit scar formation. In addition, the active sites were analyzed using molecular docking. The key active amino acids Leu and Tyr of LYG were able to form hydrogen bonds and good hydrophobic structures with transforming growth factor β1 (TGF‐β1). Hyperplastic scar (HS) is a common fibrous proliferative disorder of the skin, and fibrosis is the process of scar formation. It is well known that the inhibition of collagen and angiogenesis is an effective way to combat HS. The results of this study show that LYG inhibited collagen synthesis and inflammatory stress in mouse fibroblasts (L929), suppressed the angiogenic signaling pathway in vascular endothelial cells (HUVECs), and reduced scar formation after wound healing in mice. This study provides new ideas for improving the diversified use of tilapia resources. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate the expression levels of vascular endothelial growth factor (VEGF), Peroxiredoxin 1 (PRX1), glucose transporter 1 (GLUT1) and type I collagen (COL1) and the rate of tooth movement comparing 3 accelerated tooth movement (ATM) methods: Corticopuncture (CP), photobiomodulation (PBM) and the combined technique (CP + PBM) on days 1, 3, 7 and 14. Methods: Orthodontic tooth movement was induced in 24 male Wistar rats. CP procedure included three perforations: two in the palate and one mesial to the molars. GaAlAs diode laser irradiation was performed on days 0, 2, 4 and 6, totaling 4 irradiations. 14 days (810 nm, 100 mW, 15 s). Gingival tissue was collected from the cervical area of both first molars and qPCR was performed to isolate and quantify mRNA levels. Results: All ATM groups showed increased tooth displacement compared to control after 14 days (20% for PBM; 40% for CP and 60% for CP + PBM). PBM showed higher VEGF expression on days 1,3 and 7 followed by CP and CP + PBM. PRX1 levels increased on days 1 and 3 in PBM and CP + PBM. GLUT1 increased on day 3 in all groups. No difference was found on levels of VEGF, PRX1 and GLUT1 among the groups on day 14, except for COL1 which increased significantly in PBM group. Conclusion: All ATM methods showed higher expression of all of VEGF, PRX1, GLUT1, COL1 than control group. PBM and CP + PBM groups had more expression related to angiogenesis, glucose uptake, oxidative stress and collagen synthesis. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a leading cause of heart failure, disability and mortality worldwide. In this study, the effects of intramyocardial injection of human platelet lysate (HPL), bone marrow mesenchymal stem cells pretreated with HPL (PMSCs), and PMSC lysate (lys), alone and in combination were investigated on MI-induced by LAD ligation in male Wistar rats. The experiment was carried out on sham, vehicle (Veh), HPL, PMSCs, PMSC lysate (PMSC lys), HPL + PMSCs, and HPL + PMSC lys groups. SBP, DBP, and ± dp/dt max were monitored by the PowerLab physiograph. The MSC characteristics and CD31, NKX2.5, and cardiac troponin I (cTnI) contents were determined by flow cytometry, immunohistochemistry, and immunofluorescence, respectively. SBP, DBP, and ± dp/dt max that decreased in the MI group were recovered by HPL, PMSC, PMSC lys, HPL + PMSC, and HPL + PMSC lys treatments. CD31 density was higher in all treated groups compared to the Veh group. CD31 density in the HPL + PMSCs and HPL + PMSC lys groups was higher than in the PMSCs group. The number of Dil+/NKX2.5 + and Dil+/cTnI + cells was higher in the HPL + PMSCs group compared to the PMSCs group. The HPL and PMSCs mitigates heart injuries and cardiac dysfunction after MI. HPL provides an appropriate environment for cardiomyocyte differentiation from PMSCs. [ABSTRACT FROM AUTHOR]

Photobiomodulation (PBM) therapy is a continuously growing approach to stimulating healing and reducing inflammation and pain. However, its effects in the fields of regenerative medicine and tissue engineering are still under investigation. Studying PBM effects on the regenerative capacity of zebrafish can allow the application of novel clinical approaches where the impact of PBM will be cross‐linked with the stem‐cell therapeutic approaches. This study was done to establish an in‐vivo experimental setup for studying the effects of laser and ultraviolet therapy on zebrafish caudal‐fin regeneration and vascularization. Thirty zebrafish were randomly and equally allocated into three groups. The caudal‐fins of all zebrafish were amputated under anaesthesia. In the first control group, the caudal‐fin was only monitored until fully regenerated. In the second group, the amputated‐fin was irradiated with ultraviolet. Finally, in the third group, the amputated‐fin was irradiated with laser. Caudal‐fin regeneration and vascularization were assessed at days 0, 3, 6, 9, 12, and 15 in all fish. In terms of regeneration, the results indicated that it is possible to discriminate the regenerative effect of laser with the experimental setup as laser therapy showed a statistically significant difference when compared to control‐group. It was also found that regenerative stimulation of the group that received ultraviolet therapy showed significant difference when compared to the control group. In terms of vascularization, there was a statistically significant difference in all groups of the study, which may suggest that laser as well as ultraviolet have limited effects in terms of improving vascularization. This study presented a novel, simple and inexpensive method for the assessment of PBM effects on zebrafish. Laser and ultraviolet therapy appeared to act as regenerative stimulators for caudal‐fin regeneration of zebrafish. However, laser therapy results were, to some extent, better than ultraviolet therapy. This novel in‐vivo design of the experiment led to more rapid and reproducible results than in‐vitro experiments. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, increasing studies have shown that low-intensity pulsed ultrasound can promote the healing of acute tendon injuries, but the specific mechanism is still unclear. OBJECTIVE: To observe the effect of low-intensity pulsed ultrasound on early angiogenesis after acute tendon injury, and to detect the regulatory relationship of low-intensity pulsed ultrasound with vascular endothelial growth factor-related signaling pathways, so as to reveal its potential mechanism of action. METHODS: Animal models of acute Achilles tendon injury were established using local injection of type I collagenase for 3 days in SPF male Sprague-Dawley rats aged 8-12 weeks, and were then randomly divided into ultrasound group and control group. In the ultrasound group, low-intensity pulsed ultrasound was treated daily with a small ultrasonic probe with an effective radiation area of 1 cm2 perpendicular to the Achilles tendon. No intervention was performed in the control group. Ultrasound imaging examination was performed 2 weeks later to observe the early healing of the tendon. Hematoxylin-eosin staining and CD31 immunohistochemical staining were performed to observe the changes in the number of blood vessels in the tissues after 1 and 2 weeks of treatment. The expression of vascular endothelial growth factor-related signaling pathway molecules in Achilles tendon tissues was detected by western blot or qRT-PCR. RESULTS AND CONCLUSION: Compared with the control group, the Achilles tendon in the ultrasound group was more continuous, the echo intensity was lower and more uniform, and the tendon thickness was significantly reduced (P < 0.05). Hematoxylin-eosin staining and CD31 immunohistochemical staining results showed that after 2 weeks of treatment, the number of new vessels in the ultrasound group was significantly increased compared with the control group (P < 0.05). Western blot and qRT-PCR results showed that after 2 weeks of continuous ultrasound intervention, the protein or mRNA expressions of vascular endothelial growth factor, Yes-associated protein, angiopoietin-2 and cysteine-rich angiogenic inducer 61 in the Achilles tendon of the ultrasound group were significantly higher than those of the control group (P < 0.05). These finding indicate that low-intensity pulsed ultrasound significantly increases the number of blood vessels in the early stage of acute tendon injury and accelerate tendon healing by up-regulating vascular endothelial growth factor expression. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the role of angiogenesis, the process through which new blood vessels form, in tumor progression and clinical outcomes in canine osteosarcoma. We analyzed the relationship between microvessel density within tumors and the expression of factors associated with low oxygen levels (hypoxia) in 28 samples of appendicular canine osteosarcoma. The results revealed that specimens with a higher microvessel count were associated with a higher histological grade. Additionally, increased levels of vascular endothelial growth factor (VEGF) expression, a key regulator of blood vessel growth, were correlated with shorter disease-free interval. This suggests that VEGF may serve as a valuable marker for predicting disease progression in dogs bearing osteosarcoma. In addition, while the expression of another hypoxia-related protein, HIF-1α, showed a trend towards poorer patient survival, this was not statistically significant. These findings underscore the potential of targeting angiogenesis as part of a comprehensive treatment strategy for dogs with osteosarcoma. However, further research is necessary to gain a better understanding of the complex relationship between hypoxia, blood vessel growth, and tumor behavior, and to develop more effective therapies aimed at improving survival rates in affected dogs. Canine osteosarcoma (OSA) is an aggressive and highly malignant tumor of bone with a poor prognosis and it mirrors the disease in humans. Angiogenesis, the formation of new blood vessels, is driven by hypoxia-induced factors such as HIF-1α and VEGF, both of which play a crucial role in tumor growth and metastasis. However, the role of angiogenesis in OSA remains a topic of ongoing debate. This study aimed to investigate the relationship between angiogenesis, measured by intratumoral microvessel density (MVD), hypoxic markers, and clinical outcomes in 28 dogs diagnosed with appendicular OSA. Clinicopathological data such as age, breed distribution, tumor localization, histopathological subtypes, and metastatic behavior were consistent with reported epidemiologic characteristics of canine OSA, though no significant correlation was found among these variables. The results indicated a significant association between higher MVD and high-grade OSA (p = 0.029), suggesting that increased tumor vascularization is linked to more aggressive tumor behavior. Additionally, elevated VEGF expression was strongly correlated with disease-free interval DFI), with a p-value of 0.045. Although HIF-1α positivity showed a trend towards poorer survival, the results did not reach statistical significance (p = 0.07). These findings highlight the potential role of VEGF as a valuable prognostic marker in canine OSA, which could have potentially important implications for therapeutic targeting and clinical management of the disease. This study advances the understanding of angiogenesis in canine OSA, while emphasizing the need for continued research into the complex mechanisms regulating the interplay between hypoxia, angiogenesis and tumor progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal cancer type. Despite recent progress in our understanding of DLBCL biology, the translation of this knowledge into clinical initiatives has lagged, and the first-line treatment for this tumor type, the immunochemotherapy R-CHOP, has been the same for more than two decades. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as a critical modulator of B-cell receptor (BCR) signals and PI3K activity in DLBCL. Pre-clinically and clinically, we confirmed that PDE4 inhibition suppressed PI3K activity, and downstream to it, angiogenesis in the lymphoma microenvironment. Here, we report on a phase 1 clinical trial that combines the PDE4 inhibitor roflumilast with R-CHOP in treatment-naïve DLBCL patients. We show that this combination is safe, active, and inhibits PI3K activity and VEGF-A levels. Further, we preliminarily identified the genetic subtypes of DLBCL that may be especially vulnerable to this new drug combination. Background: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. The standard-of-care immunochemotherapy, R-CHOP, cures only about 60% of DLBCL patients. Improving this cure rate will likely require the effective translation of basic biology knowledge into clinical activities. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as an important modulator of lymphomagenic processes. We also showed that the FDA-approved PDE4 inhibitor roflumilast can suppress B-cell receptor (BCR) signals, phosphoinositide 3-kinase (PI3K) activity and angiogenesis. These data suggested that combining roflumilast with R-CHOP may be beneficial in DLBCL. Methods: We conducted a single-center, single-arm, open-label, phase 1 study of roflumilast in combination with the standard of care, R-CHOP (Ro+R-CHOP), in pathologically proven, treatment-naïve, high-risk DLBCL patients. Results: Ro+R-CHOP was safe, and at a median follow-up time of 44 months, 70% of patients were alive and disease free (median OS not reached, PFS 44% (95% CI, 21–92). In this pilot series, we found that the addition of roflumilast suppressed PI3K activity in peripheral blood mononuclear cells, and VEGF-A secretion in the urine. We also encountered preliminary evidence to suggest that the Ro+R-CHOP combination may be particularly beneficial to patients diagnosed with high-risk genetic subtypes of DLBCL, namely MCD and A53. Conclusions: These initial findings suggest that roflumilast may be an alternative agent able to inhibit BCR/PI3K activity and angiogenesis in DLBCL, and that the testing of Ro+R-CHOP in a larger series of genetically characterized tumors is warranted. This study was registered at ClinicalTrials.gov, number NCT03458546. [ABSTRACT FROM AUTHOR]

Bioengineered livers are currently an acceptable alternative to orthotopic liver transplants to overcome the scarcity of donors. However, the challenge of using a bioengineered liver is the lack of an intact endothelial layer in the vascular network leading to thrombosis. Heparin-modified surfaces have been demonstrated to decrease thrombogenicity in earlier research. However, in our study, we aimed to apply heparin immobilization to enhance the hemocompatibility, endothelial cell (EC) adhesion, and angiogenesis of rat decellularized liver scaffolds (DLS). Heparin was immobilized on the DLS by the end-point attachment technique. The scaffold's hemocompatibility was assessed using ex vivo blood perfusion and platelet adhesion studies. The heparinized scaffold (HEP-DLS) showed a significantly reduced thrombogenicity and platelet aggregation. HEP-DLS was recellularized with EA.hy926 cells via the portal vein and maintained in the bioreactor for 7 days, showing increased EC adhesion and coverage within the blood vessels. The Resazurin reduction assay confirmed the presence of actively proliferating cells in the HEP-DLS. The scaffolds were implanted subcutaneously into the dorsum of mice for 21 days to evaluate cell migration and angiogenesis. The results showed significant increases in the number of blood vessels in the HEP-DLS group. Our results demonstrated that heparin immobilization reduces thrombosis, promotes re-endothelialization, and enhances angiogenesis in DLS. The research provides insight into the potential use of heparin in the formation of a functioning vasculature. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma cell malignancy that resides within the bone marrow microenvironment, relying heavily on interactions with its cellular components. Among these, endothelial cells (ECs) play a pivotal role in MM progression and the development of therapeutic resistance. In this study, we analyzed publicly available single-cell RNA sequencing data to identify unique pathway activations distinguishing ECs from MM patients and healthy donors. We developed a novel protocol to isolate and culture endothelial progenitor cells (EPCs) and ECs directly from MM patient bone marrow, demonstrating their ability to promote myeloma cell proliferation. Validation studies confirmed that these MM-derived ECs exhibit angiogenic potential as well as the expression of characteristic endothelial lineage markers. These findings underscore the critical role of bone marrow ECs in the MM tumor microenvironment and highlight potential new therapeutic targets to disrupt MM progression. [ABSTRACT FROM AUTHOR]

Lymphoma growth, progression, and dissemination require tumor cell interaction with supporting vessels and are facilitated through tumor-promoted angiogenesis, lymphangiogenesis, and/or lymphoma vessel co-option. Vessel co-option has been shown to be responsible for tumor initiation, metastasis, and resistance to anti-angiogenic treatment but is largely uncharacterized in the setting of lymphoma. We developed an in vitro model to study lymphoma–vessel interactions and found that mantle cell lymphoma (MCL) cells co-cultured on Matrigel with human umbilical vein (HUVEC) or human lymphatic (HLEC) endothelial cells migrate to and anneal with newly formed capillary-like (CLS) or lymphatic-like (LLS) structures, consistent with lymphoma–vessel co-option. To inhibit this interaction, we constructed an antibody fusion protein, αCD20-EndoP125A, linking mutant anti-angiogenic endostatin (EndoP125A) to an αCD20-IgG1-targeting antibody. αCD20-EndoP125A inhibited both CLS and LLS formation, as well as MCL migration and vessel co-option. Lymphoma vessel co-option requires cell migration, which is regulated by chemokine–chemokine receptor interactions. CXCL12 and its receptor, CXCR4, are highly expressed by both endothelial cells forming CLS and by MCL cells during vessel co-option. αCD20-EndoP125A suppressed expression of both CXCL12 and CXCR4, which were required to facilitate CLS assembly and vessel co-option. We also tested αCD20-EndoP125A effects in vivo using an aggressive murine B cell lymphoma model, 38c13-hCD20, which demonstrated rapid growth and dissemination to tumor-draining lymph nodes (TDLNs) and the spleen, lung, and brain. The pattern of lymphoma distribution and growth within the lung was consistent with vessel co-option. As predicted by our in vitro model, αCD20-EndoP125A treatment inhibited primary tumor growth, angiogenesis, and lymphangiogenesis, and markedly reduced the number of circulating tumor cells and lymphoma dissemination to TDLNs and the lungs, spleen, and brain. αCD20-EndoP125A inhibited lymphoma vessel co-option within the lung. Marked inhibition of MCL primary tumor growth and dissemination were also seen using an MCL xenograft model. The ability of αCD20-EndoP125A to inhibit angiogenesis, lymphangiogenesis, and lymphoma vessel co-option provides a novel therapeutic approach for inhibition of lymphoma progression and dissemination. [ABSTRACT FROM AUTHOR]