Tumour blood vessel normalisation by prolyl hydroxylase inhibitor repaired sensitivity to chemotherapy in a tumour mouse model

Satoshi Koyama,Masaki Imanishi,Shuhei Tomita,Shinji Matsunaga,Hiroya Kitano,Hiromi Takeuchi,Yoichi Maekawa

doi:10.1038/srep45621

Satoshi Koyama, Masaki Imanishi + Show 5 more

Open Access

https://doi.org/10.1038/srep45621

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Abstract

Blood vessels are important tissue structures that deliver oxygen and nutrition. In tumour tissue, abnormal blood vessels, which are hyperpermeable and immature, are often formed; these tissues also have irregular vascularisation and intravasation. This situation leads to hypoperfusion in tumour tissue along with low oxygen and nutrition depletion; this is also called the tumour microenvironment and is characterised by hypoxia, depleted nutrition, low pH and high interstitial pressure. This environment induces resistance to anticancer drugs, which causes an increase in anticancer drug doses, leading to increased side effects. We hypothesised that normalised tumour blood vessels would improve tumour tissue perfusion, resupply nutrition and re-oxygenate the tumour tissue. Chemotherapy would then be more effective and cause a decrease in anticancer drug doses. Here we report a neovascularisation-inducing drug that improved tumour vascular abnormalities, such as low blood flow, blood leakage and abnormal vessel structure. These results could lead to not only an increased chemo-sensitivity and tissue-drug distribution but also an up-regulated efficiency for cancer chemotherapy. This suggests that tumour blood vessel normalisation therapy accompanied by angiogenesis may be a novel strategy for cancer therapy.

Highlights

Blood vessels are important tissue structures that deliver oxygen and nutrition
We examined the functional features associated with the tumour microenvironment, such as tissue perfusion, vessel permeability and hypoxia, and the features resulting in chemotherapy efficiency
We focused on the tumour blood vessels, the endothelial cells (ECs), which were stained for CD31

Summary

Introduction

Blood vessels are important tissue structures that deliver oxygen and nutrition. In tumour tissue, abnormal blood vessels, which are hyperpermeable and immature, are often formed; these tissues have irregular vascularisation and intravasation. We report a neovascularisationinducing drug that improved tumour vascular abnormalities, such as low blood flow, blood leakage and abnormal vessel structure These results could lead to an increased chemo-sensitivity and tissue-drug distribution and an up-regulated efficiency for cancer chemotherapy. Due to a lack of tight junctions and pericytes, tumour tissue has low blood flow, poor perfusion and high blood leakage[6] These features lead to challenging environment with hypoxia, acidosis, starvation and increased interstitial pressure; this is called the tumour microenvironment[7]. We hypothesised that stimulating the HIF signalling pathway following PHD inhibition may induce angiogenesis and vasculogenesis in tumour tissue and improve tissue blood flow, perfusion and the tumour microenvironment These phenomena may enhance anticancer drug and radiation sensitivity in tumours and prove beneficial in cancer therapy. We show that transient PHD inhibition led to the normalisation of tumour blood vessels, which could enhance anticancer drug sensitisation in a tumour mouse model

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