Blocking Surgically Induced Lysyl Oxidase Activity Reduces the Risk of Lung Metastases

Publication date: 25 April 2017
Source:Cell Reports, Volume 19, Issue 4
Author(s): Chen Rachman-Tzemah, Shelly Zaffryar-Eilot, Moran Grossman, Dario Ribero, Michael Timaner, Joni M. Mäki, Johanna Myllyharju, Francesco Bertolini, Dov Hershkovitz, Irit Sagi, Peleg Hasson, Yuval Shaked
Surgery remains the most successful curative treatment for cancer. However, some patients with early-stage disease who undergo surgery eventually succumb to distant metastasis. Here, we show that in response to surgery, the lungs become more vulnerable to metastasis due to extracellular matrix remodeling. Mice that undergo surgery or that are preconditioned with plasma from donor mice that underwent surgery succumb to lung metastases earlier than controls. Increased lysyl oxidase (LOX) activity and expression, fibrillary collagen crosslinking, and focal adhesion signaling contribute to this effect, with the hypoxic surgical site serving as the source of LOX. Furthermore, the lungs of recipient mice injected with plasma from post-surgical colorectal cancer patients are more prone to metastatic seeding than mice injected with baseline plasma. Downregulation of LOX activity or levels reduces lung metastasis after surgery and increases survival, highlighting the potential of LOX inhibition in reducing the risk of metastasis following surgery.

Graphical abstract

Teaser

Rachman-Tzemah et al. find that surgery promotes extracellular matrix (ECM) remodeling in the lungs due to increased lysyl oxidase activity. In turn, ECM remodeling contributes to tumor cell seeding and enhances metastasis. This study highlights effects that can occur in response to surgery and a potential impact on metastasis.


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