CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma.

Chia-Chia Chao,Po-Chun Chen,Tsung-Ming Chang,Chiang-Wen Lee,Ju-Fang Liu

doi:10.3390/cancers12020459

Abstract

Osteosarcoma, the most common of all bone malignancies, has a high likelihood of lung metastasis. Up until now, the molecular mechanisms involved in osteosarcomas with lung metastases are not clearly understood. Recent observations have shown that the chemokine CXCL1 and its receptor CXCR2 assist with the homing of neutrophils into the tumor microenvironment. Here, we show that the CXCL1/CXCR2 paracrine axis is crucial for lung metastasis in osteosarcoma. In an in vivo lung metastasis model of osteosarcoma, lung blood vessels expressed CXCL1 and osteosarcoma cells expressed the CXCR2 receptor. CXCR2 expression was higher in osteosarcoma cell lines than in normal osteoblast cells. Immunohistochemistry staining of clinical osteosarcoma specimens revealed positive correlations between CXCR2 expression and pathology stage and also vascular cell adhesion molecule 1 (VCAM-1) expression. High levels of CXCL1 secreted by human pulmonary artery endothelial cells (HPAECs) promoted osteosarcoma cell mobility, which was mediated by the upregulation of VCAM-1 expression. When HPAECs-conditioned media was incubated in osteosarcoma cells, we observed that the CXCR2 receptor and FAK/PI3K/Akt/NF-κB signaling cascade were required for VCAM-1 expression. Our findings illustrate a molecular mechanism of lung metastasis in osteosarcoma and indicate that CXCL1/CXCR2 is worth targeting in treatment schemas.

Highlights

Of all bone malignancy diagnoses in children and young adults, osteosarcoma is the most common and frequently presents with metastasis at diagnosis, which contributes to mortality [1].Cancers 2020, 12, 459; doi:10.3390/cancers12020459 www.mdpi.com/journal/cancersApproximately one-third of patients presenting with localized disease will relapse, as will about three-quarters of patients with metastases at diagnosis
To clarify the mechanism involved in osteosarcoma lung metastasis, we created a metastatic lung cancer model using intravenous injections of MG63 cells
As the CXCL1/CXCR2 axis is required for lung metastasis in breast cancer [19], we analyzed levels of CXCL1/CXCR2 expression in lung specimens

Summary

Introduction

One-third of patients presenting with localized disease will relapse, as will about three-quarters of patients with metastases at diagnosis. As many as 90% of these relapses are due to lung metastases [2]. Organs involved in metastasis secrete attractant molecules that guide cancer cells to specific sites [3]. It is known that chemokines, low molecular chemotactic cytokines that mediate connection between different cell types, help to regulate leukocyte homing besides promoting cancer growth [4]. Chemokines play important roles in various biological functions including cell migration, angiogenesis, and hematopoietic cell homing [5]. They play crucial roles in the progression and metastasis of different cancers. The CXCL12/CXCR4 axis is implicated in the homing of cancer cells to metastatic sites [6,7]

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