Tumor vasculature remolding by thalidomide increases delivery and efficacy of cisplatin

Journal of Experimental & Clinical Cancer Research - Tập 38 Số 1 - 2019
Yanwei Shen1, Shuting Li1, Xin Wang1, Mengying Wang2, Qiang Tian1, Yang Jiao1, Jichang Wang3, Biyuan Wang1, Peijun Liu4
1Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
2Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University Health Science Center, Xi’an, China
3Department of Vascular Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
4Key Laboratory for Tumor Precision Medicine of Shaanxi Province First Affiliated Hospital of Xi'an Jiaotong University Xi'an China

Tóm tắt

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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Journal of Experimental & Clinical Cancer Research

Tập 38 Số 1

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