Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy.

ABSTRACT: The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

SUBMITTER: Sun Y

PROVIDER: S-EPMC8749958 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

JP1 normalizes tumor vasculature to suppress metastasis and facilitate drug delivery by inhibiting IL-8.

Project description:Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In this study, we report that the antitumor peptide JP1 regulated mitochondrial metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improved the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibited the secretion of IL-8 by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature resulted in mature and regular blood vessels, which made the tumor microenvironment form a benign feedback loop consisting of vascular normalization, sufficient perfusion, and an oxygen-rich microenvironment, prevented tumor cells from entering the vasculature, and inhibited metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel maintained a certain vascular density in the tumor and promoted tumor vascular normalization, increasing the delivery of oxygen and drugs and enhancing the antitumor effect. Collectively, our work highlights the antitumor peptide JP1 as an inhibitor of metastasis initiation and its mechanism of action.

| S-EPMC10371244 | biostudies-literature

Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis.

Project description:Integrin alphanubeta3 is found on a subset of tumor blood vessels where it is associated with angiogenesis and malignant tumor growth. We designed an alphanubeta3-targeted nanoparticle (NP) encapsulating the cytotoxic drug doxorubicin (Dox) for targeted drug delivery to the alphanubeta3-expressing tumor vasculature. We observed real-time targeting of this NP to tumor vessels and noted selective apoptosis in regions of the alphanubeta3-expressing tumor vasculature. In clinically relevant pancreatic and renal cell orthotopic models of spontaneous metastasis, targeted delivery of Dox produced an antimetastatic effect. In fact, alphanubeta3-mediated delivery of this drug to the tumor vasculature resulted in a 15-fold increase in antimetastatic activity without producing drug-associated weight loss as observed with systemic administration of the free drug. These findings reveal that NP-based delivery of cytotoxic drugs to the alphanubeta3-positive tumor vasculature represents an approach for treating metastatic disease.

| S-EPMC2453735 | biostudies-literature

Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide.

Project description:Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs.

| S-EPMC3241764 | biostudies-literature

Nanotopography-based lymphatic delivery for improved anti-tumor responses to checkpoint blockade immunotherapy.

Project description:Rationale: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a co-inhibitory checkpoint receptor that is expressed by naïve T-cells in lymph nodes (LNs) to inhibit activation against "self" antigens (Ags). In cancer, anti-CTLA-4 blocks inhibitory action, enabling robust activation of T-cells against tumor Ags presented in tumor draining LNs (TDLNs). However, anti-CTLA-4 is administered intravenously with limited exposure within TDLNs and immune related adverse events (irAEs) are associated with over-stimulation of the immune system. Methods: Herein, we first deliver anti-CTLA-4 in an orthotopic mammary carcinoma murine model using a nanotopographical microneedle-array device to compare its anti-tumor response to that from systemic administration. Additionally, to demonstrate the feasibility of lymphatic delivery in humans using the device, we use near-infrared fluorescence imaging to image delivery of ICG to LNs. Results: Our data show that lymphatic infusion results in more effective tumor growth inhibition, arrest of metastases, increased tumor infiltrating lymphocytes and complete responses when compared to conventional systemic administration. In clinical studies, we demonstrate for the first time that nanotopographic infusion can deliver ICG through the lymphatics directly to the axilla and inguinal LNs of healthy human volunteers. Conclusion: Taken together, these results suggest that regional delivery using a nanotopography-based microneedle array could revolutionize checkpoint blockade immunotherapy by reducing systemic drug exposure and maximizing drug delivery to TDLNs where tumor Ags present. Future work is needed to determine whether lymphatic delivery of anti-CTLA-4 can alleviate irAEs that occur with systemic dosing.

| S-EPMC6857054 | biostudies-literature

Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.

Project description:Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.

| S-EPMC4948740 | biostudies-literature

Hollow mesoporous silica nanoparticles for tumor vasculature targeting and PET image-guided drug delivery.

Project description:Development of multifunctional and well-dispersed hollow mesoporous silica nanoparticles (HMSNs) for tumor vasculature targeted drug delivery and PET imaging.Amine functionalized HMSNs (150-250 nm) were conjugated with a macrocyclic chelator, (S)-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA), PEGylated and loaded with antiangiogenesis drug, Sunitinib. Cyclo(Arg-Gly-Asp-D-Tyr-Lys) (cRGDyK) peptide was attached to the nanoconjugate and radiolabeled with (64)Cu for PET imaging.(64)Cu-NOTA-HMSN-PEG-cRGDyK exhibited integrin-specific uptake both in vitro and in vivo. PET results indicated approximately 8% ID/g uptake of targeted nanoconjugates in U87MG tumors, which correlated well with ex vivo and histological analyses. Enhanced tumor-targeted delivery of sunitinib was also observed.We successfully developed tumor vasculature targeted HMSNs for PET imaging and image-guided drug delivery.

| S-EPMC4430331 | biostudies-other

Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery.

Project description:Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can "normalize" their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.

| S-EPMC4330784 | biostudies-literature

Drug-loaded microbubble delivery system to enhance PD-L1 blockade immunotherapy with remodeling immune microenvironment.

Project description:BackgroundAlthough programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy.MethodsDocetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models.ResultsThe dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases.ConclusionPD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.

| S-EPMC9909878 | biostudies-literature

Modified C-type natriuretic peptide normalizes tumor vasculature and improves solid tumor therapies

Project description:Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic problems and generation of immunosuppressive TME undermine the efficacy of cancer treatment. These problems can be partially alleviated by angiogenesis inhibitors. Here we propose an alternative agonist-based normalization approach utilizing a derivative of the C-type natriuretic peptide (dCNP). This well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and reinvigorated the anti-tumor immune responses. Treatment with dCNP decelerated growth of primary tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio- or immune-therapeutic regimens increased their efficacy against solid tumors. These results demonstrate the proof of principle for using activators of normalized angiogenesis to improve therapies against solid tumors and characterize dCNP as the first in class amongst such agents.

2023-10-16 | GSE243040 | GEO

Gold Nanoparticle-Mediated Targeted Delivery of Recombinant Human Endostatin Normalizes Tumour Vasculature and Improves Cancer Therapy.

Project description:Tumour vasculature is generally disordered because of the production of excessive angiogenic factors by tumour cells, which results in tumour progression and reduces the effectiveness of radiotherapy or chemotherapy. Transient anti-angiogenic therapies that regulate tumour vascular morphology and function and improve the efficiency of antitumour therapy are under investigation. Recombinant human endostatin (Endostar/rhES) is a vascular angiogenesis-disrupting agent that has been used to treat non-small cell lung cancer (NSCLC) in the clinical setting. In this study, we used gold nanoparticles (AuNPs) as a drug-delivery system (DDS) for targeted tumour delivery of rhES for short therapy, which resulted in transient tumour vascular normalization, reduced permeability and hypoxia, strengthened blood vessel integrity, and increased blood-flow perfusion. Moreover, combination therapy with 5-FU over this timeframe was substantially more effective than 5-FU monotherapy. In conclusion, our research demonstrates the potential use of AuNPs as a drug-delivery platform for transporting rhES into a tumour to induce transient tumour vascular normalization and enhance the antitumour efficacy of cytotoxic drugs.

| S-EPMC4965746 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data