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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

ESR1 mediated circ{sub 0}004018 suppresses angiogenesis in hepatocellular carcinoma via recruiting FUS and stabilizing TIMP2 expression

Angiogenesis has been certified to account for tumor pathobiology. Circular RNAs (circRNAs) have been demonstrated to be involved in angiogenesis-related diseases, including hepatocellular carcinoma (HCC). Nevertheless, the regulatory roles of most circRNAs remain obscure. This study aims to uncover the function of hsa{sub c}irc{sub 0}004018 on angiogenesis in HCC. Firstly, quantitative real-time RT-PCR (RT-qPCR) analyzed that circ{sub 0}004018 was definitely down-regulated in HCC. Western blot analysis was conducted to detect the protein level of fused protein in sarcoma (FUS) and TIMP metallopeptidase inhibitor 2 (TIMP2). Functional assays were carried out to assess the impacts of circ{sub 0}004018 on HCC. From the experimental results, we found that overexpression of circ{sub 0}004018 significantly inhibited angiogenesis in HCC. The regulatory mechanism of circ{sub 0}004018 in HCC was determined by chromatin immunoprecipitation (ChIP), luciferase reporter assays and RNA immunoprecipitation (RIP) assay. Therefore, we proved that estrogen receptor 1 (ESR1) mediated circ{sub 0}004018 regulated TIMP2 by recruiting FUS. A series of rescue assays verified that circ{sub 0}004018 participated in angiogenesis in HCC via modulating TIMP2. In summary, this paper disclosed that ESR1 activated circ{sub 0}004018 inhibited angiogenesis in HCC via binding to FUS and stabilizing TIMP2 expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Formin‐like 2 promotes angiogenesis and metastasis of colorectal cancer by regulating the EGFL6 / CKAP4 / ERK axis

Abstract Increasing evidence indicates that angiogenesis plays a pivotal role in tumor progression. Formin‐like 2 (FMNL2) is well‐known for promoting metastasis; however, the molecular mechanisms by which FMNL2 promotes angiogenesis in colorectal cancer (CRC) remain unclear. Here, we found that FMNL2 promotes angiogenesis and metastasis of CRC in vitro and in vivo. The GDB/FH3 domain of FMNL2 directly interacts with epidermal growth factor‐like protein 6 (EGFL6). Formin‐like 2 promotes EGFL6 paracrine signaling by exosomes to regulate angiogenesis in CRC. Cytoskeleton associated protein 4 (CKAP4) is a downstream target of EGFL6 and is involved in CRC angiogenesis. Epidermal growth factor‐like protein 6 binds to the N‐terminus of CKAP4 to promote the migration of HUVECs by activating the ERK/MMP pathway. These findings suggest that FMNL2 promotes the migration of HUVECs and enhances angiogenesis and tumorigenesis in CRC by regulating the EGFL6/CKAP4/ERK axis. Therefore, the EGFL6/CKAP4/ERK axis could be a candidate therapeutic target for CRC treatment.

He, Guoyang↗
DOE OSTI2021

MiR-205–5p suppresses angiogenesis in gastric cancer by downregulating the expression of VEGFA and FGF1

Highlights: • MiR-205-5p was commonly downregulated in GC tissues from TCGA database and our hospital, and these events were associated with a worse TNM stagedistant metastasis and poor survival. • MiR-205-5p and CD31 expressions were negatively inter-related within GC tissues from TCGA database and our hospital. • GC cell lines expressed lower level of miR-205-5p significantly as compared with the normal gastric cell line. • MiR-205-5p upregulation significantly impaired proliferation and colony formation of GC cells and neovascularization induced by GC cells in vitro and in vivo. • The angiogenesis and ERK-signaling were depressed by VEGFA and FGF1 downregulation induced by miR-205-5p overexpression. The miR-205-5p inhibitor promoted malignant phenotypes by enhancing VEGFA and FGF1 expressions, as well as the activation of ERK-signaling. Anti-angiogenic therapy represents one of the most promising treatment modalities for human cancers. However, the response to antiangiogenic therapy in gastric cancer (GC) remains dismal. To help identify new strategies for antiangiogenic therapy in GC, we evaluated miR-205–5p expression in GC tissues from TCGA database and our hospital, and its functions in angiogenesis were explored in vitro and in vivo. We investigated miR-205–5p expression and microvessel densities (MVDs) in GC tissues and liver metastases from patients. The function and mechanisms of miR-205–5p were examined in human cell lines and in xenograft mouse models. Associations between miR-205–5p expression and clinical characteristics were analyzed using either Pearson's χ{sup 2} test or Fisher's exact test. Differences in overall survival (OS) distributions were evaluated using the log-rank test. Differences in measurement data were compared using Student's t-test and one-way ANOVA. We found that miR-205–5p expression was downregulated in GC tissues and was negatively correlated with CD31 expression in both TCGA and our clinical samples. GC cell lines expressed low levels of miR-205–5p, and miR-205–5p upregulation significantly impaired the proliferation and angiogenesis of GC cells. Moreover, vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1) expression and activation of extracellular-related kinase (ERK) signaling were suppressed by miR-205–5p. MiR-205–5p inhibition promoted malignant phenotypes by enhancing VEGFA and FGF1 expression, as well as the activation of ERK signaling. Angiogenesis and ERK signaling were decreased in response to VEGFA and FGF1 downregulation induced by miR-205–5p overexpression. The dual-luciferase reporter assay showed that VEGFA and FGF1 were direct targets of miR-205–5p. Xenograft mouse models revealed that miR-205–5p suppressed tumor growth by inhibiting neovascularization. Altogether, these results demonstrate that miR-205–5p suppresses angiogenesis in GC by attenuating the expression of VEGFA and FGF1, indicating that upregulation of miR-205–5p may represent as an antiangiogenic therapy for GC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

miR-126 regulates angiogenesis in myocardial ischemia by targeting HIF-1α

Promoting angiogenesis by targeting various angiogenic regulators has emerged as a new treatment strategy for myocardial ischemia (MI). MicroRNA-126 (miR-126) has been identified as the main regulator of compensatory angiogenesis; however, its role in MI is unclear. A rat MI model and an EA. hy926 endothelial cell hypoxia model were constructed and it was found that miR-126 was highly expressed in both models. The knockdown of HIF-1α expression in EA. hy926 cells in turn downregulated VEGF and CD34 expression and consequently inhibited angiogenesis. MiR-126 inhibitor inhibited EA. hy926 cell migration and tube formation as well as downregulated VEGF and CD34 expression, and these were reversed by transfection of miR-126 mimics. Rescue tests using miR-126 and HIF-1α demonstrated that miR-126-mediated regulation of angiogenesis was dependent on HIF-1α. In summary, miR-126 regulates the occurrence and progression of angiogenesis during MI via HIF-1α and may be a potential new therapeutic target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

HMGA2 contributes to vascular development and sprouting angiogenesis by promoting IGFBP2 production

Highlights: • Our findings demonstrates that HMGA2 promotes central arteries formation in zebrafish. • HMGA2 induces vascular development through modulation of IGFBP2 whatever in vivo or in vitro. • The mRNA expressions of HMGA2 and IGFBP2 increased significantly in peripheral blood of Hemangioma patients. • HMGA2-IGFBP2 are promising candidates towards therapeutical vascularization in vascular diseases like Hemangioma. Angiogenesis is the process by which new blood vessels form from preexisting vessels and regulates the processes of embryonic development, wound healing and tumorigenesis. HMGA2 is involved in the occurrence of several cancers, but its biological role and the exact downstream genes involved in vascular development and sprouting angiogenesis remain largely unknown. Here, we first found that HMGA2 knockdown in zebrafish embryos resulted in defects of central artery formation. RNA sequencing revealed that IGFBP2 was significantly downregulated by interference with HMGA2, and IGFBP2 overexpression reversed the inhibition of brain vascular development caused by HMGA2 deficiency. In vitro, we further found that HMGA2 knockdown blocked the migration, tube formation and branching of HUVECs. Similarly, IGFBP2 protein overexpression attenuated the impairments induced by HMGA2 deficiency. Moreover, the promotion of angiogenesis by HMGA2 overexpression was verified in a Matrigel plug assay. We next found that HMGA2 bound directly to a region in the IGFBP2 promoter and positively regulated IGFBP2 expression. Interestingly, the mRNA expression levels of HMGA2 and IGFBP2 were increased significantly in the peripheral blood of hemangioma patients, indicating that overexpression of HMGA2 and IGFBP2 results in vessel formation, consistent with the results of the in vivo and in vitro experiments. In summary, our findings demonstrate that HMGA2 promotes central artery formation by modulating angiogenesis via IGFBP2 induction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Sorafenib derivatives-functionalized gold nanoparticles confer protection against tumor angiogenesis and proliferation via suppression of EGFR and VEGFR-2

Sorafenib is a multi-kinase inhibitor that has been highlighted as a tumor suppressor due to its anti-proliferative and anti-angiogenic properties, whereas the clinical application of Sorafenib is restricted by the side effects it may cause. The past decade has witnessed the development of a series of sorafenib derivatives to improve the clinical performance of sorafenib. Gold nanoparticles (AuNPs) have been widely utilized in drug delivery systems due to their unique properties, including biocompatible nature, simple preparation, and easy surface modification. Herein, this study is aimed to investigate the anti-tumor effects of new sorafenib derivatives-capped gold nanoparticles (AuNPs-New Sor) in tumor formation and metastasis as well as the underlying mechanisms. Initially, new sorafenib derivatives were constructed and combined with AuNPs to form AuNPs-New Sor, and the properties of synthesized AuNPs-New Sor were identified in a mouse model of tumorigenesis. The effect of AuNPs-New Sor on tumor vascular normalization was investigated by assessing vascular permeability and perfusion rate. Next, we evaluated the effect of AuNPs-New Sor on migration and viability of tumor cells and human umbilical vein endothelial cells (HUVECs) as well as on HUVEC angiogenesis in vitro. A melanoma mouse model was further established for in vivo substantiation of the anti-tumor effect of AuNPs-New Sor. According to the results, AuNPs could deliver new sorafenib derivatives into tumor tissues and downregulate the expression of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), thereby suppressing tumor migration, EMT, and angiogenesis in vitro. In addition, AuNPs-New Sor displayed competitive anti-tumor activities in vivo. Taken together, AuNPs-New Sor may attenuate tumor development and angiogenesis through downregulation of EGFR and VEGFR-2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Nutraceuticals and their role in tumor angiogenesis

Angiogenesis plays a pivotal role in cancer initiation, maintenance, and progression. Diet may inhibit, retard or reverse these processes affecting angiogenesis (angioprevention). Nutraceuticals, such as omega-3 fatty acids, amino acids, proteins, vitamins, minerals, fibers, and phenolic compounds, improve health benefits as they are a source of bioactive compounds that, among other effects, can regulate angiogenesis. The literature concerning the pro-angiogenic and/or anti-angiogenic nutraceuticals and the possible activated pathways in cancer and other non-neoplastic diseases by in vivo and in vitro experiments are reviewed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Lymphocytic microparticles suppress retinal angiogenesis via targeting Müller cells in the ischemic retinopathy mouse model

Highlights: F0B7 • LMPs possess strong angiogenesis-inhibiting properties. F0B7 • LMPs suppress Müller cell-derived angiogenic/chemoattractant factors. F0B7 • LMPs attenuate pathological retinal NV and the infiltration of macrophages in vivo. F0B7 • LMPs downregulate ERK1/2 and HIF-1α both in vitro and in vivo. Retinopathy of prematurity (ROP) is the primary cause of visual impairment and vision loss in premature infants, which results from the formation of aberrant retinal neovascularization (NV). An emerging body of evidence has shown that Müller cells are the predominant source of vascular endothelial growth factor (VEGF), which also serves as a chemoattractant for monocyte/macrophage lineage. The recruitment of macrophages is increased during retinal NV, and they exert a pro-angiogenic role in ROP. We have shown that lymphocytic microparticles (microvesicles; LMPs) derived from apoptotic human T lymphocytes possess strong angiogenesis-inhibiting properties. Here, we investigated the effect of LMPs on the chemotactic capacity of Müller cells in vitro using rat Müller cell rMC-1 and mouse macrophage RAW 264.7. In addition, the impact of LMPs was determined in vivo using a mouse model of oxygen-induced ischemic retinopathy (OIR). The results revealed that LMPs were internalized by rMC-1 and reduced their cell proliferation dose-dependently without inducing cell apoptosis. LMPs inhibited the chemotactic capacity of rMC-1 on RAW 264.7 via reducing the expression of VEGF. Moreover, LMPs attenuated pathological retinal NV and the infiltration of macrophages in vivo. LMPs downregulated ERK1/2 and HIF-1α both in vitro and in vivo. These findings expand our understanding of the effects of LMPs, providing evidence of LMPs as a promising therapeutic approach for the treatment of retinal NV diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Simultaneously characterization of tumoral angiogenesis and vasculogenesis in stem cell-derived teratomas

Highlights: • CAM supports the growth and differentiation of embryonic stem cells into teratomas. • In teratomas, parenchymal Embryonic stem cell-derived endothelial cells form chimeric vessels with stromal endothelial cells. • CAM allows the simultaneously characterization of vasculogenesis and angiogenesis processes. Tumor neovascularization may occur via both angiogenic and vasculogenic events. In order to investigate the vessel formation during tumor growth, we developed a novel experimental model that takes into account the differentiative and tumorigenic properties of Embryonic Stem cells (ESCs). Leukemia Inhibitory Factor-deprived murine ESCs were grafted on the top of the chick embryo chorionallantoic membrane (CAM) in ovo. Cell grafts progressively grew, forming a vascularized mass within 10 days. At this stage, the grafts are formed by cells with differentiative features representative of all three germ layers, thus originating teratomas, a germinal cell tumor. In addition, ESC supports neovascular events by recruiting host capillaries from surrounding tissue that infiltrates the tumor mass. Moreover, immunofluorescence studies demonstrate that perfused active blood vessels within the tumor are of both avian and murine origin because of the simultaneous occurrence of angiogenic and vasculogenic events. In conclusion, the chick embryo ESC/CAM-derived teratoma model may represent a useful approach to investigate both vasculogenic and angiogenic events during tumor growth and for the study of natural and synthetic modulators of the two processes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Development of a recombinant anti-VEGFR2-EPCAM bispecific antibody to improve antiangiogenic efficiency

Highlights: • Targeted therapy can be a useful therapeutic method along with traditional methods for breast cancer treatment. • Decreasing Akt/Nf-Kβ signaling pathway is crucial target in order to decreasing angiogenesis in TNBC. • The recombinant antibody can have inhibitory effects on production IL6,8, MMP2, and MMP9. Tumor progression and metastasis, especially in invasive cancers (such as triple-negative breast cancer [TNBC]), depend on angiogenesis, in which vascular epithelial growth factor (VEGF)/vascular epithelial growth factor receptor [1] has a decisive role, followed by the metastatic spread of cancer cells. Although some studies have shown that anti-VEGFR2/VEGF monoclonal antibodies demonstrated favorable results in the clinic, this approach is not efficient, and further investigations are needed to improve the quality of cancer treatment. Besides, the increased expression of epithelial cell adhesion molecule (EpCAM) in various cancers, for instance, invasive breast cancer, contributes to angiogenesis, facilitating the migration of tumor cells to other parts of the body. Thus, the main goal of our study was to target either VEGFR2 or EpCAM as pivotal players in the progression of angiogenesis in breast cancer. Regarding cancer therapy, the production of bispecific antibodies is easier and more cost-effective compared to monoclonal antibodies, targeting more than one antigen or receptor; for this reason, we produced a recombinant antibody to target cells expressing EpCAM and VEGFR2 via a bispecific antibody to decrease the proliferation and metastasis of tumor cells. Following the cloning and expression of our desired anti-VEGFR2/EPCAM sequence in E. coli, the accuracy of the expression was confirmed by Western blot analysis, and its binding activities to VEGFR2 and EPCAM on MDA-MB-231 and MCF-7 cell lines were respectively indicated by flow cytometry. Then, its anti-proliferative potential was indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis assay to evaluate inhibitory effects of the antibody on tumor cells. Subsequently, the data indicated that migration, invasion, and angiogenesis were inhibited in breast cancer cell lines via the bispecific antibody. Furthermore, cytokine analysis indicated that the bispecific antibody could moderate interleukin 8 (IL-8) and IL-6 as key mediators in angiogenesis progression in breast cancer. Thus, our bispecific antibody could be considered as a promising candidate tool to decrease angiogenesis in TNBC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Involvement of multiple scavenger receptors in advanced glycation end product-induced vessel tube formation in endothelial cells

Highlights: • Multiple scavenger receptors contribute to AGE-induced angiogenesis. • RAGE contributes to AGE-induced angiogenesis by upregulation of scavenger receptors. • AGE activates mTOR signaling. Toxic advanced glycation end products (toxic AGEs) derived from glycolaldehyde (AGE3) have been implicated in the development of diabetic vascular complications such as retinopathy characterised by excessive angiogenesis. Different receptor types, such as receptor for AGEs (RAGE), Toll like receptor-4 and scavenger receptors, are expressed in endothelial cells and contribute to AGE-elicited alteration of cell function. In the present study, we examined the involvement of AGE-related receptors on AGE-induced angiogenesis in endothelial cells. The effects of pharmacological inhibitors or receptor neutralizing antibodies on AGE3-induced tube formation were investigated using the in vitro Matrigel tube formation assay in b.End5 cells (mouse endothelial cells). AGE3-induced signalling pathways and receptor expression changes were analysed by Western blot analysis and flow cytometry, respectively. Both FPS-ZM1, a RAGE inhibitor, and fucoidan, a ligand for scavenger receptors, suppressed AGE3-induced tube formation. Cocktails of neutralizing antibodies against the scavenger receptors CD36, CD163 and LOX-1 prevented AGE3-induced tube formation. AGE3 activated mTOR signalling, resulting in facilitation of tube formation. Activation of the AGE-RAGE pathway also led to the upregulation of scavenger receptors. Taken together, our findings suggest that the scavenger receptors CD36, CD163 and LOX-1 in conjunction with the RAGE receptor work together to mediate toxic AGE-induced facilitation of angiogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Modeling and simulation of vascular tumors embedded in evolving capillary networks

Here in this work, we present a coupled 3D–1D model of solid tumor growth within a dynamically changing vascular network to facilitate realistic simulations of angiogenesis. Additionally, the model includes erosion of the extracellular matrix, interstitial flow, and coupled flow in blood vessels and tissue. We employ continuum mixture theory with stochastic Cahn–Hilliard type phase-field models of tumor growth. The interstitial flow is governed by a mesoscale version of Darcy’s law. The flow in the blood vessels is controlled by Poiseuille flow, and Starling’s law is applied to model the mass transfer in and out of blood vessels. The evolution of the network of blood vessels is orchestrated by the concentration of the tumor angiogenesis factors (TAFs); blood vessels grow towards the increasing TAFs concentrations. This process is not deterministic, allowing random growth of blood vessels and, therefore, due to the coupling of nutrients in tissue and vessels, makes the growth of tumors stochastic. We demonstrate the performance of the model by applying it to a variety of scenarios. Numerical experiments illustrate the flexibility of the model and its ability to generate satellite tumors. Simulations of the effects of angiogenesis on tumor growth are presented as well as sample-independent features of cancer.

3D–1D coupled blood flow models↗
DOE OSTI2021

Metformin attenuates expression of angiogenic and inflammatory genes in human endometriotic stromal cells

Highlights: • Metformin reduced cell migration, and proliferation of endometriotic stromal cells. • Metformin attenuated the expression of angiogenic and inflammatory genes in human endometriotic stromal cells. • Metformin could be used as an effective adjuvant in endometriosis treatment. Endometriosis is a benign gynecological disease that is manifested by the presence and growth of endometrial cells and glands outside the uterine. Active angiogenesis, migration, and invasion of endometrial tissue outside the uterine are critical for the development of endometriosis and lead to the survival and growth of endometriotic lesions. Metformin, as an anti-diabetic agent, represents anti-angiogenic property. Here, we performed a study using human normal endometrial stromal cells (N-ESCs) from healthy endometrial tissue and human eutopic endometrial stromal cells (EU-ESCs) and ectopic endometrial stromal cells (ECT-ESCs) from endometriosis patients. ESCs were cultured and treated with different concentrations of Metformin (0–20 mmol/l) for 72 h to evaluate Metformin effect on cell viability, proliferation, migration was measured by methyl thiazolyl tetrazolium (MTT) assay and scratch test respectively as well as expression of angiogenesis and migration markers. The Metformin reduced cell migration, and proliferation of endometriotic stromal cells in a time and concentration dependently manner. Furthermore, Metformin attenuated the expression of angiogenic and inflammatory genes in human endometriotic stromal cells. The direct anti-proliferative effect on ECT-ESCs combined with the effects of Metformin on inflammatory and angiogenesis-related genes expression supports its therapeutic potential for endometriosis. Metformin could be used as an effective adjuvant in endometriosis treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

An elastin-like polymer targeting vascular endothelial growth factor receptor-1 reduces survival in serum-starved endothelial cells

Peptides often exhibit biological activity that depends on the context in which they are displayed and delivered. Understanding and controlling these contextual effects on peptide function is critical for designing targeted and responsive peptide-based biomaterials and therapeutics. Genetically engineered protein polymers such as elastin-like polypeptides (ELPs) can incorporate bioactive peptide motifs and are attractive candidates for biomaterials used in tissue engineering and targeted drug delivery. They also present an opportunity for investigating and modulating cell signaling pathways by presenting a peptide ligand in various defined chemical and physical environments. Vascular endothelial growth factor receptor-1 (VEGFR1) signaling plays important and complex roles in cell survival and angiogenesis, but polymeric materials that interact with this signaling axis are scarce. In this study, a novel genetically engineered elastin-like polymer that targets VEGFR1 is characterized. This polymer, termed R1B-ELP, binds to human endothelial cells in a manner dependent on its VEGFR1-targeting motif and, based on cell proliferation and cytotoxicity assays, demonstrates activity consistent with disrupting pro-survival signaling necessary for endothelial cell function under conditions of environmental stress. Notably, these findings indicate that ELP fusion alters the functional behavior of the targeting peptide. Modulators of VEGFR1 signaling have potential applications in basic studies of angiogenesis as well as in therapeutic applications targeting vascular or inflammatory diseases.

36 MATERIALS SCIENCE↗
DOE OSTI2021

CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid 30 cancers, most of them become resistant to this therapy and develop into progressive disease. 31 Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described herein, we found that cancer-derived small extracellular vesicles (EVs) package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. Notably, small EV-VEGF (eVEGF) is not recognized by bevacizumab and can be transferred to endothelial cells and trigger intracrine signaling and promote angiogenesis. Also, serum eVEGF was present at higher levels in ovarian cancer mouse models with adaptive resistance to bevacizumab than in models sensitive to it. Ovarian cancer cell-derived eVEGF increased tumor growth despite treatment with bevacizumab. Notably, the eVEGF level was elevated in patient serum after bevacizumab-containing therapy. Proteomic data of small EVs from mouse models suggested that several novel biomarkers are promising for drug response prediction. Collectively, these data demonstrated a new mechanism whereby eVEGF evades recognition by therapeutic antibodies and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and new therapeutic strategies for ovarian cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Novel CHI3L1 ‐Associated Angiogenic Phenotypes Define Glioma Microenvironments: Insights From Multi‐Omics Integration

ABSTRACT The CHI3L1 signaling pathway significantly influences glioma angiogenesis, but its role in the tumor microenvironment (TME) remains elusive. We propose a novelCHI3L1‐associated vascular phenotype classification for glioma through integrative analyses of multiple datasets with bulk and single‐cell transcriptome, genomics, digital pathology, and clinical data. We investigated the biological characteristics, genomic alterations, therapeutic vulnerabilities, and immune profiles within these phenotypes through a comprehensive multi‐omics approach. We constructed the vascular‐related risk (VR) score based onCHI3L1‐associated vascular signatures (CAVS) identified by machine learning algorithms. Utilizing unsupervised consensus clustering, gliomas were stratified into three distinct vascular phenotypes: Cluster A, marked by high vascularization and stromal activation with a relatively low levels of tumor‐infiltrating lymphocytes (TILs); Cluster B, characterized by moderate vascularization and stromal activity, coupled with a high density of TILs; and Cluster C, defined by low vascularization and sparse immune cell infiltration. We observed that the CAVS effectively indicated glioma‐associated angiogenesis and immune suppression by single‐cell RNA‐seq analysis. Moreover, the high‐VR‐score group exhibited enhanced angiogenic activity, reduced immune response, resistance to immunotherapy, and poorer clinical outcomes. The VR score independently predicted glioma prognosis and, combined with a nomogram, provided a robust clinical decision‐making tool. Potential drug prediction based on transcription factors for high‐risk patients was also performed. Our study reveals thatCHI3L1‐associated vascular phenotypes shape distinct immune landscapes in gliomas, offering insights for optimizing therapeutic strategies to improve patient outcomes.

Oncology↗