Stromal Lysyl Oxidase-Like 1 Increases Extracellular Matrix Stiffness and Enhances Collagen Fibre Alignment in Non-Small Cell Lung Cancer

Cancer associated fibroblasts (CAFs) represent a large portion of non-small cell lung cancer (NSCLC) stroma where they mediate extracellular matrix (ECM) remodelling and its interactions with neoplastic cells. A recognized NSCLC CAF marker, fibrillar collagen-binding receptor integrin alpha11 (alpha11), known to promote lung tumour growth and metastasis, was highly correlated with stromal lysyl oxidase-like 1 (LOXL1) in two NSCLC patient cohorts. Both genes were up-regulated in tumour stroma compared to normal lung tissue and were associated with desmoplasia status in patient tumour samples. Over-expression of alpha11 resulted in up-regulation of LOXL1 in three in vitro models. When cultured within three-dimensional collagen matrices, cells with over-expressed alpha11 caused linearization, alignment and contraction of collagen fibres. In the absence of alpha11 expression, over-expression of LOXL1 rescued this phenotype. LOXL1 expression was directly proportional to tissue stiffness; degree of gel contraction; and collagen fibre linearization in in vitro and xenograft tumour models.