Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages
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 remodelin...
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| Vydané v: | Oncotarget Ročník 7; číslo 50; s. 82289 |
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| Hlavní autori: | , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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13.12.2016
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | MacDonald, Gwen Wyckoff, Jeffrey Heideman, Marinus R Bentires-Alj, Mohamed Kondo, Shunya Doelemeyer, Arno Fayard, Bérengère Bonapace, Laura Hynes, Nancy E Ebersbach, Hilmar Coissieux, Marie-May Smirnova, Tatiana |
| Author_xml | – sequence: 1 givenname: Tatiana surname: Smirnova fullname: Smirnova, Tatiana organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 2 givenname: Laura surname: Bonapace fullname: Bonapace, Laura organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 3 givenname: Gwen surname: MacDonald fullname: MacDonald, Gwen organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 4 givenname: Shunya surname: Kondo fullname: Kondo, Shunya organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 5 givenname: Jeffrey surname: Wyckoff fullname: Wyckoff, Jeffrey organization: Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA – sequence: 6 givenname: Hilmar surname: Ebersbach fullname: Ebersbach, Hilmar organization: Novartis Institute for Biomedical Research, Basel, Switzerland – sequence: 7 givenname: Bérengère surname: Fayard fullname: Fayard, Bérengère organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 8 givenname: Arno surname: Doelemeyer fullname: Doelemeyer, Arno organization: Novartis Institute for Biomedical Research, Basel, Switzerland – sequence: 9 givenname: Marie-May surname: Coissieux fullname: Coissieux, Marie-May organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 10 givenname: Marinus R surname: Heideman fullname: Heideman, Marinus R organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 11 givenname: Mohamed surname: Bentires-Alj fullname: Bentires-Alj, Mohamed organization: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland – sequence: 12 givenname: Nancy E surname: Hynes fullname: Hynes, Nancy E organization: University of Basel, Basel, Switzerland |
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| SubjectTerms | Animals Antineoplastic Agents - pharmacology Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Line, Tumor Cell Movement - drug effects Chemokine CCL2 - metabolism Collagen Type I - metabolism Extracellular Matrix - metabolism Extracellular Matrix - pathology Extracellular Signal-Regulated MAP Kinases - metabolism Female Humans Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - prevention & control Lung Neoplasms - secondary Macrophages - drug effects Macrophages - metabolism Macrophages - pathology Mice, Inbred BALB C Mice, SCID Neoplasm Invasiveness Phenotype RNA Interference Serpin E2 - antagonists & inhibitors Serpin E2 - genetics Serpin E2 - metabolism Signal Transduction Tissue Inhibitor of Metalloproteinase-1 - metabolism Transfection Tumor Microenvironment Xenograft Model Antitumor Assays |
| Title | Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages |
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