Thomas R. Cox, May 2012
Our recent paper titled “Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK” has just been published in Oncogene.
In this paper we show that the activity of the cancer secreted enzyme Lysyl Oxidase (LOX) is critically important in mediating the growth and metastasis of colorectal cancers. By manipulating the expression and activity of LOX we show that primary tumour growth is dependent on the enzymatic activity. The result of this enzymatic activity is an increase in the stiffness of tumours which leads to enhanced phosphorylation of Focal Adhesion Kinase (FAK) and Src Kinase. We show that the downstream effects of LOX activity on tumour cell invasion and metastasis can thus be blocked by treatment with FAK and Src inhibitors indicating that CRC patients with high LOX expressing tumours may benefit from treatment with these inhibitors.
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.
Baker AM, Lang G, Bird D, Cox TR*, Erler JT*. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK.
Oncogene 4;32(14):1863-8 (2013) |doi:10.1038/onc.2012.202
*Senior authors contributed equally
This study was supported by the Medical Research Council (G0800102), the Institute of Cancer Research (ICR), Cancer Research UK (C107/A10433) and the Biotech Research & Innovation Centre (BRIC) at the University of Copenhagen (UCPH).