LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity
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
St Vincent’s Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(5), 705; https://doi.org/10.3390/cancers11050705
Received: 15 April 2019 / Revised: 13 May 2019 / Accepted: 17 May 2019 / Published: 22 May 2019
(This article belongs to the Special Issue The Role of Integrins in Cancer)
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.