Anti-metastatic effect of methylprednisolone targeting vascular endothelial cells under surgical stress

Yukinori Kurokawa,Tsuyoshi Takahashi,Makoto Yamasaki,Hidetoshi Eguchi,Takuro Saito,Noboru Kobayashi,Kotaro Yamashita,Kiyokazu Nakajima,Koji Tanaka,Tomoki Makino,Takaomi Hagi,Yuichiro Doki

doi:10.1038/s41598-021-85241-2

Yukinori Kurokawa, Tsuyoshi Takahashi + Show 10 more

Open Access

https://doi.org/10.1038/s41598-021-85241-2

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Journal: Scientific Reports	Publication Date: Mar 18, 2021
Citations: 5	License type: open-access

Affiliation: Osaka University

Abstract

Perioperative systemic inflammation induced by surgical stress elevates the risk of hematogenous cancer metastasis. This study investigated the anti-metastatic effects and mechanisms of methylprednisolone (MP) administration for surgical stress. We examined the effects of MP on the expression of adhesion molecules in human vascular endothelial cells and in a murine hepatic metastasis model under lipopolysaccharide (LPS) administration, which mimics systemic inflammation induced by surgical stress. Serum E-selectin level was measured in blood samples obtained from 32 gastric cancer patients who were randomly assigned to treat preoperatively with or without MP. The expression of E-selectin in LPS-induced vascular endothelial cells was suppressed by MP. An adhesion assay showed the number of LPS-induced adherent tumour cells was significantly lower following MP. In the in vivo study, LPS significantly elevated the number of hepatic metastases, but pretreatment with MP before LPS significantly inhibited this elevation. The LPS-induced expression of E-selectin in the vascular endothelium of the portal vein was suppressed by MP. In human clinical samples, serum E-selectin level was significantly decreased by preoperative MP. Suppression of surgically induced systemic inflammation by MP administration might prevent hematogenous cancer metastases by suppressing the induction of E-selectin expression in the vascular endothelium.

Highlights

Perioperative systemic inflammation induced by surgical stress elevates the risk of hematogenous cancer metastasis
We investigated the effects of LPS and MP on the expression of major adhesion molecules in human umbilical vein endothelial cells (HUVEC) and human hepatic sinusoidal endothelial cells (HHSEC)
MP administration strongly suppressed the expression of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) induced by LPS in the analysis of western blotting in HHSEC (Fig. 1d,e)

Summary

Introduction

Perioperative systemic inflammation induced by surgical stress elevates the risk of hematogenous cancer metastasis. We examined the effects of MP on the expression of adhesion molecules in human vascular endothelial cells and in a murine hepatic metastasis model under lipopolysaccharide (LPS) administration, which mimics systemic inflammation induced by surgical stress. The expression of E-selectin induced by inflammatory stimuli facilitates the adhesion of circulating tumour cells, which increases hematogenous metastasis[11,12] Despite these findings, only one study has focused on these adhesion molecules as a therapeutic target for tumour metastasis by suppressing inflammation induced by surgical stress[13]. We previously reported that tumour growth promoted by administration of lipopolysaccharide (LPS), which causes systemic inflammation mimicking that induced by surgical stress, could be inhibited by pretreatment with methylprednisolone (MP), and safety of these drugs when administered to mice[14].

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