Tumor Vessel Normalization: A Window to Enhancing Cancer Immunotherapy

Hostile microenvironment produced by abnormal blood vessels, which is characterized by hypoxia, low pH value and increasing interstitial fluid pressure, would facilitate tumor progression, metastasis, immunosuppression and anticancer treatments resistance. These abnormalities are the result of the imbalance of pro-angiogenic and anti-angiogenic factors (such as VEGF and angiopoietin 2, ANG2). Prudent use of anti-angiogenesis drugs would normalize these aberrant tumor vessels, resulting in a transient window of vessel normalization. In addition, use of cancer immunotherapy including immune checkpoint blockers when vessel normalization is achieved brings better outcomes. In this review, we sum up the advances in the field of understanding and application of the concept of tumor vessels normalization window to treat cancer. Moreover, we also outline some challenges and opportunities ahead to optimize the combination of anti-angiogenic agents and immunotherapy, leading to improve patients’ outcomes.

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Tumor vasculature remolding by thalidomide increases delivery and efficacy of cisplatin

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1366-x ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 6

Author(s):

Yanwei Shen ◽

Shuting Li ◽

Xin Wang ◽

Mengying Wang ◽

Qi Tian ◽

...

Keyword(s):

Tumor Growth ◽

Solid Tumors ◽

Tumor Model ◽

Tumor Vasculature ◽

Angiogenic Factors ◽

Tumor Vessel ◽

Tumor Vessels ◽

Vessel Normalization ◽

Vascular Physiology ◽

And Function

Abstract Background A promising strategy to overcome the chemoresistance is the tumor blood vessel normalization, which restores the physiological perfusion and oxygenation of tumor vasculature. Thalidomide (Thal) has been shown to increase the anti-tumor effect of chemotherapy agents in solid tumors. However, it is not yet known whether the synergistic effect of Thal combined with other cytotoxic drugs is attributable to tumor vascular normalization. Methods We used two homograft mice models (4 T1 breast tumor model and CT26 colorectal tumor model) to investigate the effect of Thal on tumor growth, microvessel density, vascular physiology, vascular maturity and function, drug delivery and chemosensitivity. Immunofluorescence, immunohistochemistry and scanning electron microscopy were performed to determine the vessel changes. Protein array assay, qPCR and western blotting were used to detect the molecular mechanism by which Thal regulates tumor vascular. Results Here we report that Thal potently suppressed tumor growth, angiogenesis, hypoxia, and vascular permeability in animal models. Thal also induced a regular monolayer of endothelial cells in tumor vessels, inhibiting vascular instability, and normalized tumor vessels by increasing vascular maturity, pericyte coverage and endothelial junctions. The tumor vessel stabilization effect of Thal resulted in a decrease in tumor vessel tortuosity and leakage, and increased vessel thickness and tumor perfusion. Eventually, the delivery of cisplatin was highly enhanced through the normalized tumor vasculature, thus resulting in profound anti-tumor and anti-metastatic effects. Mechanistically, the effects of Thal on tumor vessels were caused in part by its capability to correct the imbalance between pro-angiogenic factors and anti-angiogenic factors. Conclusions Our findings provide direct evidence that Thal remodels the abnormal tumor vessel system into a normalized vasculature. Our results may lay solid foundation for the development of Thal as a novel candidate agent to maximize the therapeutic efficacy of chemotherapeutic drugs for solid tumors.

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The Anti-Angiogenic Agent Lenvatinib Induces Tumor Vessel Normalization and Enhances Radiosensitivity in Hepatocellular Tumors

10.21203/rs.3.rs-194550/v1 ◽

2021 ◽

Author(s):

Norikazu Une ◽

Mayumi Takano-Kasuya ◽

Narufumi Kitamura ◽

Mineto Ohta ◽

Tomoya Inose ◽

...

Keyword(s):

Combination Therapy ◽

Kinase Inhibitors ◽

Tumor Hypoxia ◽

Fluid Pressure ◽

Immunohistochemical Analysis ◽

Structure And Function ◽

Tumor Vessel ◽

Vascular Normalization ◽

Tumor Vessels ◽

And Function

Abstract The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.

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Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF

Cancer Immunology Research ◽

10.1158/2326-6066.cir-18-0865 ◽

2019 ◽

Vol 7 (12) ◽

pp. 1910-1927 ◽

Cited By ~ 12

Author(s):

Mariangela Di Tacchio ◽

Jadranka Macas ◽

Jakob Weissenberger ◽

Kathleen Sommer ◽

Oliver Bähr ◽

...

Keyword(s):

Tumor Vessel ◽

Vessel Normalization ◽

Angiopoietin 2

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Control of interstitial fluid pressure: Role of [beta ]-integrins

Seminars in Nephrology ◽

10.1053/snep.2001.21646 ◽

2001 ◽

Vol 21 (3) ◽

pp. 222-230 ◽

Cited By ~ 42

Author(s):

Rolf K. Reed ◽

Ansgar Berg ◽

Eli-Anne B. Gjerde ◽

Kristofer Rubin

Keyword(s):

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure

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Sialic acid-modified mesoporous polydopamine induces tumor vessel normalization to enhance photodynamic therapy by inhibiting VE-cadherin internalization

Chemical Engineering Journal ◽

10.1016/j.cej.2021.128743 ◽

2021 ◽

Vol 414 ◽

pp. 128743

Author(s):

Xiao-Ling Xu ◽

Mei-Xuan Chen ◽

Xue-Fang Lou ◽

Yu-Yin Du ◽

Gao-Feng Shu ◽

...

Keyword(s):

Photodynamic Therapy ◽

Sialic Acid ◽

Tumor Vessel ◽

Vessel Normalization

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Dynamics of Interstitial Fluid Pressure in Extracellular Matrix Hydrogels in Microfluidic Devices

Journal of Biomechanical Engineering ◽

10.1115/1.4031020 ◽

2015 ◽

Vol 137 (9) ◽

Cited By ~ 5

Author(s):

Joe Tien ◽

Le Li ◽

Ozgur Ozsun ◽

Kamil L. Ekinci

Keyword(s):

Extracellular Matrix ◽

Pressure Distribution ◽

Interstitial Fluid ◽

Scaling Laws ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

External Loading ◽

Interstitial Pressure ◽

Time Resolved ◽

Long Time

In order to understand how interstitial fluid pressure and flow affect cell behavior, many studies use microfluidic approaches to apply externally controlled pressures to the boundary of a cell-containing gel. It is generally assumed that the resulting interstitial pressure distribution quickly reaches a steady-state, but this assumption has not been rigorously tested. Here, we demonstrate experimentally and computationally that the interstitial fluid pressure within an extracellular matrix gel in a microfluidic device can, in some cases, react with a long time delay to external loading. Remarkably, the source of this delay is the slight (∼100 nm in the cases examined here) distension of the walls of the device under pressure. Finite-element models show that the dynamics of interstitial pressure can be described as an instantaneous jump, followed by axial and transverse diffusion, until the steady pressure distribution is reached. The dynamics follow scaling laws that enable estimation of a gel's poroelastic constants from time-resolved measurements of interstitial fluid pressure.

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Functional Nanoparticles for Tumor Penetration of Therapeutics

Pharmaceutics ◽

10.3390/pharmaceutics10040193 ◽

2018 ◽

Vol 10 (4) ◽

pp. 193 ◽

Cited By ~ 24

Author(s):

Yu-Lin Su ◽

Shang-Hsiu Hu

Keyword(s):

Therapeutic Efficacy ◽

Tumor Heterogeneity ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Drug Particle ◽

Tumor Penetration ◽

Functional Nanoparticles ◽

Particle Penetration ◽

Enhanced Permeability And Retention ◽

Theranostic Nanoparticles

Theranostic nanoparticles recently received great interest for uniting unique functions to amplify therapeutic efficacy and reduce side effects. Despite the enhanced permeability and retention (EPR) effect, which amplifies the accumulation of nanoparticles at the site of a tumor, tumor heterogeneity caused by the dense extracellular matrix of growing cancer cells and the interstitial fluid pressure from abnormal angiogenesis in the tumor inhibit drug/particle penetration, leading to inhomogeneous and limited treatments. Therefore, nanoparticles for penetrated delivery should be designed with different strategies to enhance efficacy. Many strategies were developed to overcome the obstacles in cancer therapy, and they can be divided into three main parts: size changeability, ligand functionalization, and modulation of the tumor microenvironment. This review summarizes the results of ameliorated tumor penetration approaches and amplified therapeutic efficacy in nanomedicines. As the references reveal, further study needs to be conducted with comprehensive strategies with broad applicability and potential translational development.

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