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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)774-784
Number of pages11
JournalCell Reports
Volume19
Issue number4
DOIs
StatePublished - 25 Apr 2017
Externally publishedYes

Funding

FundersFunder number
Academy of Finland Center of Excellence251314
S. Juselius Foundation
Seventh Framework Programme260633
European Research Council
Jane ja Aatos Erkon Säätiö
Associazione Italiana per la Ricerca sul Cancro

    Keywords

    • breast cancer
    • host response
    • hypoxia
    • lysyl oxidase
    • metastasis
    • pre-metastatic niche
    • surgery

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