PMID- 23160925
OWN - NLM
STAT- MEDLINE
DCOM- 20130527
LR  - 20220310
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 137
IP  - 1
DP  - 2013 Jan
TI  - Heparins modulate the IFN-gamma-induced production of chemokines in human breast 
      cancer cells.
PG  - 109-18
LID - 10.1007/s10549-012-2334-8 [doi]
AB  - Heparins seem to improve survival in patients with advanced malignancies 
      independently of their anticoagulatory function. As the treatment options in 
      advanced and metastatic breast cancer are still very limited, heparins might be 
      an interesting addition to the existing systemic therapies. The interferon 
      (IFN)-gamma-inducible chemokines CXCL9 and CXCL10 play an essential role in the 
      regulation of the immune milieu in malignant tumours, thereby being interesting 
      targets for an immunological intervention. We therefore wanted to test whether 
      heparins have an impact on the chemokines CXCL9 and CXCL10 as well as the IFN-gamma 
      signalling in human breast cancer cells in vitro. The well-established cell lines 
      BT-474, MCF-7, SK-BR-3 and MDA-MB-231 were incubated with IFN-gamma, unfractionated 
      heparin (UFH), different low molecular weight heparins (LMWHs) and the 
      heparin-related polyanions danaparoid and dextran sulphate. The production of 
      CXCL9 and CXCL10 was measured by ELISA and real-time RT-PCR, the phosphorylation 
      of signal transducer and activator of transcription (STAT) 1 was detected by an 
      in-cell western assay and the amount of cellular bound IFN-gamma was analysed by a 
      high sensitivity ELISA. We observed that IFN-gamma induced CXCL9 and CXCL10 
      production in MCF-7, SK-BR-3 and MDA-MB-231 cells but not in BT-474. UFH dose 
      dependently inhibited the effect of IFN-gamma on the secretion and expression of 
      CXCL9 and CXCL10. LMWHs and heparin-related compounds differentially modulated 
      IFN-gamma-effects-the results depended on their molecular size and charge, but were 
      independent of their anticoagulatory properties. As a reason for these heparin 
      effects, we could show that the IFN-gamma-induced phosphorylation of STAT1 was 
      modulated by heparins, caused by an interaction with the cellular binding of 
      IFN-gamma. In conclusion, these results support the significance of the 
      immunomodulatory properties of heparins independently of their classical 
      anticoagulatory function. Heparin-derived sulphated polysaccharides with distinct 
      molecular properties might thus be interesting candidates for new therapeutic 
      strategies in breast cancer.
FAU - Fluhr, Herbert
AU  - Fluhr H
AD  - Department of Obstetrics and Gynecology, University of Greifswald, 
      Sauerbruchstr., 17475 Greifswald, Germany. herbert.fluhr@uni-greifswald.de
FAU - Seitz, Tina
AU  - Seitz T
FAU - Zygmunt, Marek
AU  - Zygmunt M
LA  - eng
PT  - Journal Article
DEP - 20121118
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CXCL10 protein, human)
RN  - 0 (CXCL9 protein, human)
RN  - 0 (Chemokine CXCL10)
RN  - 0 (Chemokine CXCL9)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Chemokine CXCL10/genetics/*metabolism
MH  - Chemokine CXCL9/genetics/*metabolism
MH  - Female
MH  - Gene Expression/drug effects
MH  - Gene Expression Regulation, Neoplastic
MH  - Heparin/*pharmacology
MH  - Humans
MH  - Interferon-gamma/antagonists & inhibitors/*physiology
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Processing, Post-Translational/drug effects
MH  - STAT1 Transcription Factor/metabolism
MH  - Transcriptional Activation/*drug effects
EDAT- 2012/11/20 06:00
MHDA- 2013/05/29 06:00
CRDT- 2012/11/20 06:00
PHST- 2012/07/03 00:00 [received]
PHST- 2012/11/01 00:00 [accepted]
PHST- 2012/11/20 06:00 [entrez]
PHST- 2012/11/20 06:00 [pubmed]
PHST- 2013/05/29 06:00 [medline]
AID - 10.1007/s10549-012-2334-8 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2013 Jan;137(1):109-18. doi: 10.1007/s10549-012-2334-8. 
      Epub 2012 Nov 18.