The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism

Sifan Wu,Xiaoxia Xing,Yaohui Wang,Xi Zhang,Miao Li,Mimi Wang,Zhiming Wang,Jie Chen,Dongmei Gao,Yan Zhao,Rongxin Chen,Zhenggang Ren,Kezhi Zhang,Jiefeng Cui

doi:10.1016/j.ejca.2021.01.011

Abstract

ObjectiveThe mechanisms underlying the contribution of primary tumour to pre-metastatic niche formation remains largely unknown in hepatocellular carcinoma (HCC). We previously reported that the released LOXL2 from HCC cells under higher stiffness stimulation facilitated the formation of lung pre-metastatic niche. Here, we further clarified the pathological role of LOXL2 in promoting lung pre-metastatic niche formation and lung metastasis occurrence in HCC and its relevant molecular mechanism. MethodsUsing two different animal models and an in vitro system of mechanically tuneable gel mirroring lung tissue stiffness, we explored the underlying mechanism of LOXL2 in pre-metastatic niche formation. ResultsWe applied tail vein injection of CM-LV-LOXL2-OEsimulating tumour-released soluble factors to induce lung pre-metastatic niche formation and found that the injected LOXL2 remarkably enhanced CD11b+/CD45+ bone marrow-derived cells (BMDCs) recruitment and fibronectin expression in lung. Subsequently, LOXL2-overexpressed xenograft HCC models validated that tumour-secreted LOXL2 significantly promoted the occurrence of pulmonary metastasis. In vitro, LOXL2 and LOXL2-caused matrix stiffening not only obviously upregulated the expressions of MMP9 and fibronectin in lung fibroblasts, but also evidently increased the number of adherent HCC cells and the expression of chemokine CXCL12. The activation of PI3K-AKT pathway mediated LOXL2-upregulated fibronectin. HCC patients in High-LOXL2 group had higher ratio of tumour recurrence than HCC patients in Low-LOXL2 group, supporting a significance of LOXL2 in HCC progression and unfavourable outcome. ConclusionPrimary tumour-released LOXL2 promotes lung pre-metastatic niche formation and lung metastasis occurrence. LOXL2-caused matrix stiffening synergistically regulates lung pre-metastatic niche formation. Targeting LOXL2-induced lung pre-metastatic niche may be a novel intervention approach against HCC metastasis.

Highlights

The mechanisms underlying the contribution of primary tumor to pre-metastatic niche formation remains largely unknown in Hepatocellular carcinoma (HCC)
Primary tumor-released Lysyl oxidase like 2 (LOXL2) contributes to the formation of lung pre-metastatic niche and the occurrence of lung metastasis
We reported that the released LOXL2 from HCC cells under higher stiffness stimulation educated lung fibroblast and recruited Bone marrow derived cells (BMDCs) to promote lung pre-metastatic niche formation in vitro [28]

Summary

Introduction

We previously reported that the released Lysyl oxidase like 2 (LOXL2) from HCC cells under higher stiffness stimulation facilitated the formation of lung premetastatic niche. Primary tumor-released soluble factors or exosomes enter the blood stream and reach distant target organ to induce a permissive environment before the arrival of metastatic tumor cells, termed the pre-metastatic niche. Our previous research demonstrated that the secreted Lysyl oxidase like 2 (LOXL2) from HCC cells under higher stiffness stimulation educated lung fibroblast and recruited BMDCs to induce lung pre-metastatic niche formation in vitro [28]. We further clarified the pathological roles of LOXL2 in premetastatic niche formation in two animal models and HCC tissues, simultaneously applied an in vitro system of mechanically tunable gel simulating lung tissue stiffness to investigate its underlying mechanism

Methods

Results

Discussion

Conclusion