Zeltz Cédric, Pasko Elena, Cox Thomas R, Navab Roya, Tsao Ming-Sound
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
Cancers (Basel). 2019 May 22;11(5):705. doi: 10.3390/cancers11050705.
Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.
整合素α11是一种基质胶原受体，可促进非小细胞肺癌（NSCLC）的肿瘤生长和转移，并与肿瘤基质中胶原硬度的调节有关。我们之前报道过，作为一种基质交联酶的赖氨酰氧化酶样1（LOXL1）在整合素α11缺陷小鼠中表达下调。在本研究中，我们调查了LOXL1与整合素α11之间的关系，以及LOXL1在NSCLC致瘤性中的作用。我们的结果表明，在三个肺腺癌患者数据集中，LOXL1和整合素α11的表达相关，并且整合素α11确实调节基质细胞中LOXL1的表达。利用敲低或过表达LOXL1的癌症相关成纤维细胞（CAF），我们在体外以及NSCLC异种移植模型的体内证明了LOXL1在胶原基质重塑和胶原纤维排列中的作用。作为NSCLC肿瘤基质中胶原重组的结果，我们表明LOXL1支持肿瘤生长和进展。我们的研究结果表明，在整合素α11的调节下，基质LOXL1是NSCLC肿瘤发生的决定性因素，可能是该疾病中一个有趣的靶点。
