Thomas R. Cox, Jan 2013
LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis
My recent research article on LOX-mediated collagen crosslinking and its role in fibrosis-enhanced metastasis has just been published in the journal Cancer Research.
Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer.
Cox TR, Bird D, Baker AM, Barker HE, Ho MW-Y, Lang G, Erler JT. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis.
Cancer Research 73; 1721. (2013) | doi: 10.1158/0008-5472.CAN-12-2233
This study was supported by funding from Cancer Research UK (C107/A10433), the Institute of Cancer Research (ICR), Biotech Research & Innovation Centre (BRIC) at the University of Copenhagen (UCPH), Hoffmann La Roche and a Hallas Møller Stipend from the Novo Nordisk Foundation.