Tumor vasculature remolding by thalidomide increases delivery and efficacy of cisplatin

Yanwei Shen,Peijun Liu,Mengying Wang,Biyuan Wang,Xin Wang,Shuting Li,Jichang Wang,Jin Yang,Qi Tian,Jiao Yang

doi:10.1186/s13046-019-1366-x

Abstract

BackgroundA 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.MethodsWe 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.ResultsHere 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.ConclusionsOur 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.

Highlights

A promising strategy to overcome the chemoresistance is the tumor blood vessel normalization, which restores the physiological perfusion and oxygenation of tumor vasculature
The dysfunctionality of tumor vasculature has profound consequences for the tumor microenvironment (TME) and convert the tumor into a hostile hypoxic and acidic milieu surrounded by high interstitial fluid pressure (IFP), which acts as a pathologic barrier to drug delivery into tumors [15, 16]
Cell lines and reagents Murine breast cancer 4 T1 and colorectal cancer CT26 cell lines were originally obtained from American Type Culture Collection (ATCC, Manassas, VA, USA), and human umbilical vein endothelial cells (HUVECs) were obtained from Merck Millipore (Temecula, CA, USA). 4 T1 and CT26 cell cultures were maintained using RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (P/S)

Summary

Introduction

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 It is not yet known whether the synergistic effect of Thal combined with other cytotoxic drugs is attributable to tumor vascular normalization. Tumor vessels exhibit altered behaviors and are functionally distinct from the normal vasculature During tumor progression, it has been described an alteration of the balance of pro-angiogenic and anti-angiogenic signaling and a relentless production of angiogenic stimulators in the tumor context. It has been described an alteration of the balance of pro-angiogenic and anti-angiogenic signaling and a relentless production of angiogenic stimulators in the tumor context This unbalance induces the formation of immature, malformed, disorganized and tortuous tumor vessels, lacking tight association between pericytes and endothelial cells layer and unable to efficiently deliver oxygen [13, 14]. The dysfunctionality of tumor vasculature has profound consequences for the tumor microenvironment (TME) and convert the tumor into a hostile hypoxic and acidic milieu surrounded by high interstitial fluid pressure (IFP), which acts as a pathologic barrier to drug delivery into tumors [15, 16]

Methods

Results

Discussion

Conclusion