Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages
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Serpin E2 promotes breast cancer.pdf
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11.09 MB
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Author(s)
Smirnova, Tatiana
Bonapace, Laura
MacDonald, Gwen
Kondo, Shunya
Wyckoff, Jeffrey
Ebersbach, Hilmar
Fayard, Bérengère
Doelemeyer, Arno
Coissieux, Marie-May
Heideman, Marinus R.
Date Issued
November 2016
Journal
Oncotarget
Publisher
Impact Journals/National Center for Biotechnology Information (U.S.)
Citation
Smirnova, Tatiana et al. “Serpin E2 Promotes Breast Cancer Metastasis by Remodeling the Tumor Matrix and Polarizing Tumor Associated Macrophages.” Oncotarget (2015): n. pag.
Version
Final published version
Abstract
The extracellular serine protease inhibitor serpinE2 is overexpressed in breast cancer and has been shown to foster metastatic spread. Here, we investigated the hypothesis that serpinE2 creates tumor-promoting conditions in the tumor microenvironment (TME) by affecting extracellular matrix remodeling. Using two different breast cancer models, we show that blocking serpinE2, either by knock-down (KD) in tumor cells or in response to a serpinE2 binding antibody, decreases metastatic dissemination from primary tumors to the lungs. We demonstrate that in response to serpinE2 KD or antibody treatment there are dramatic changes in the TME. Multiphoton intravital imaging revealed deposition of a dense extracellular collagen I matrix encapsulating serpinE2 KD or antibody-treated tumors. This is accompanied by a reduction in the population of tumor-promoting macrophages, as well as a decrease in chemokine ligand 2, which is known to affect macrophage abundance and polarization. In addition, TIMP-1 secretion is increased, which may directly inhibit matrix metalloproteases critical for collagen degradation in the tumor. In summary, our findings suggest that serpinE2 is required in the extracellular milieu of tumors where it acts in multiple ways to regulate tumor matrix deposition, thereby controlling tumor cell dissemination.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 3.0 Unported license
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DOI of Published Version
https://doi.org/10.18632/oncotarget.12927
