Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK

Abstract

The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic activity is required for LOX-mediated effects on proliferation and invasion in both in vitro and in vivo models of CRC. Furthermore, we use rheology to measure the relative stiffness of modified collagen matrices and subcutaneous tumors, and show that LOX-induced collagen cross-linking results in stiffening of the matrix both in vitro and in vivo. We observe a strong association between matrix stiffness and activation of the FAK (focal adhesion kinase)/SRC-signaling pathway, with a stiffer environment resulting in increased FAK/SRC phosphorylation and a more proliferative and invasive phenotype. We are the first to show a direct relationship between LOX enzymatic activity and tissue stiffness, and to demonstrate a role for stiffness in driving CRC progression. Our findings provide significant evidence to suggest that therapeutic inhibition of LOX activity may provide a novel effective treatment option for patients with metastatic CRC.

Expression and Significance of Hypoxia Inducible Factor-1α and Lysyl Oxidase in Non-small Cell Lung Cancer

“…In breast cancer, in addition to local effects on invasion, secreted LOX is critical for the formation of the premetastatic niche by accumulating at the distant sites, cross-linking collagen Ⅳ in the basement membrane and promoting the recruitment of bone marrow derived cells that stimulate angiogenesis (Wong et al, 2011;Wong et al, 2012). LOX also facilitates colorectal cancer cell migration and adhesion through the hydrogen peroxide regulation of FAK and SRC signal pathways (Baker et al, 2013). Similar to other solid tumors, knockdown of LOX with small interference RNA in hypoxic NSCLC cells induced the decrease of Snail and phosphorylated SRC expression, impairing the invasiveness and metastasis ability (Wei et al, 2012).…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…Both non-malignant and malignant epithelial cells respond to the biomechanics of their surrounding matrix [35], through multiple mechanisms [6,33,35,102]. Lysyl oxidases, by crosslinking collagens increase tumor stiffness [103], and predict prognosis [86].…”

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“…Increasing evidence indicates that the tumour suppressor activity of LOX lies in the cleaved LOX-PP (18-kDa) which can re-enter the nucleus following extracellular cleavage from the mature enzyme and repress oncogenes such as bcl-2 [4,[16][17][18]. On the contrary, the secreted LOX mature enzyme is typically reported to increase ECM stiffness, activate oncogenic signalling pathways and play a tumour promoting role [19,20].…”