PMID- 27793045
OWN - NLM
STAT- MEDLINE
DCOM- 20180221
LR  - 20181113
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 50
DP  - 2016 Dec 13
TI  - Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and 
      polarizing tumor associated macrophages.
PG  - 82289-82304
LID - 10.18632/oncotarget.12927 [doi]
AB  - 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.
FAU - Smirnova, Tatiana
AU  - Smirnova T
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Bonapace, Laura
AU  - Bonapace L
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - MacDonald, Gwen
AU  - MacDonald G
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Kondo, Shunya
AU  - Kondo S
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Wyckoff, Jeffrey
AU  - Wyckoff J
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
AD  - Koch Institute for Integrated Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, MA, USA.
FAU - Ebersbach, Hilmar
AU  - Ebersbach H
AD  - Novartis Institute for Biomedical Research, Basel, Switzerland.
FAU - Fayard, Berengere
AU  - Fayard B
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Doelemeyer, Arno
AU  - Doelemeyer A
AD  - Novartis Institute for Biomedical Research, Basel, Switzerland.
FAU - Coissieux, Marie-May
AU  - Coissieux MM
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Heideman, Marinus R
AU  - Heideman MR
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Bentires-Alj, Mohamed
AU  - Bentires-Alj M
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
FAU - Hynes, Nancy E
AU  - Hynes NE
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
AD  - University of Basel, Basel, Switzerland.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Collagen Type I)
RN  - 0 (SERPINE2 protein, human)
RN  - 0 (Serpin E2)
RN  - 0 (Serpine2 protein, mouse)
RN  - 0 (TIMP1 protein, human)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Breast Neoplasms/drug therapy/genetics/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - *Cell Movement/drug effects
MH  - Chemokine CCL2/metabolism
MH  - Collagen Type I/metabolism
MH  - Extracellular Matrix/*metabolism/pathology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/genetics/*metabolism/prevention & control/secondary
MH  - Macrophages/drug effects/*metabolism/pathology
MH  - Mice, Inbred BALB C
MH  - Mice, SCID
MH  - Neoplasm Invasiveness
MH  - Phenotype
MH  - RNA Interference
MH  - Serpin E2/antagonists & inhibitors/genetics/*metabolism
MH  - Signal Transduction
MH  - Tissue Inhibitor of Metalloproteinase-1/metabolism
MH  - Transfection
MH  - Tumor Microenvironment
MH  - Xenograft Model Antitumor Assays
PMC - PMC5347692
OTO - NOTNLM
OT  - breast cancer
OT  - collagen I
OT  - metastasis
OT  - serine protease inhibitors
OT  - tumor associated macrophages
COIS- CONFLICT OF INTEREST The authors disclose no potential conflicts of interest.
EDAT- 2016/10/30 06:00
MHDA- 2018/02/22 06:00
PMCR- 2016/12/13
CRDT- 2016/10/30 06:00
PHST- 2016/06/16 00:00 [received]
PHST- 2016/10/19 00:00 [accepted]
PHST- 2016/10/30 06:00 [pubmed]
PHST- 2018/02/22 06:00 [medline]
PHST- 2016/10/30 06:00 [entrez]
PHST- 2016/12/13 00:00 [pmc-release]
AID - 12927 [pii]
AID - 10.18632/oncotarget.12927 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Dec 13;7(50):82289-82304. doi: 10.18632/oncotarget.12927.