Matrix metalloproteinase 12 promotes tumor propagation in the lung

Ezra Ella, Yaniv Harel, Michal Abraham, Hanna Wald, Ofra Benny, Adi Karsch-Bluman, Dive Vincent, Devel Laurent, Gail Amir, Uzi Izhar, Oz M. Shapira, David Yoon, Hyun Sung Lee, David J. Sugarbaker, Bryan Burt, Amnon Peled, Ori Wald*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Objective: Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. Methods: We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non–small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. Results: Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. Conclusions: We suggest that tumor cell–derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.

Original languageAmerican English
Pages (from-to)2164-2175.e1
JournalJournal of Thoracic and Cardiovascular Surgery
Volume155
Issue number5
DOIs
StatePublished - May 2018

Bibliographical note

Publisher Copyright:
© 2018 The American Association for Thoracic Surgery

Keywords

  • lung
  • non–small cell lung cancer
  • orthotopic animal model
  • tumor microenvironment

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