PMID- 11085545
OWN - NLM
STAT- MEDLINE
DCOM- 20001130
LR  - 20061115
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 60
IP  - 21
DP  - 2000 Nov 1
TI  - Unfractionated and low molecular weight heparin affect fibrin structure and 
      angiogenesis in vitro.
PG  - 6196-200
AB  - Cancer patients treated for venous thromboembolism with low molecular weight 
      heparin (LMWH) have a better survival rate than patients treated with 
      unfractionated heparin (UFH). Because fibrin-associated angiogenesis is an 
      important determinant in the progression and metastasis of many solid tumors, the 
      effects of heparins on in vitro angiogenesis were investigated. Both UFH and LMWH 
      inhibited bFGF-induced proliferation of human microvascular endothelial cells 
      (hMVECs) to the same the extent (36-60%). VEGF165-induced proliferation was 
      inhibited to a to a lesser extent (19-33%). Turbidity measurements and electron 
      microscopy showed that the presence of LMWH during polymerization of the fibrin 
      matrix led to a more transparent rigid network with thin fibrin bundles, whereas 
      the presence of UFH resulted in a more opaque more porous network with thick 
      fibrin fibers. We used a human in vitro angiogenesis model, which consisted of 
      hMVECs seeded on top of a fibrin matrix, and stimulated the cells with basic 
      fibroblast growth factor plus tumor necrosis factor a to induce capillary-like 
      tubular structures. The formation of capillary-like tubular structures was 
      retarded with matrices polymerized in the presence of LMWH (46% inhibition 
      compared with a control matrix for both 1.5 and 10 units/ml LMWH), whereas 
      matrices polymerized in the presence of UFH facilitated tubular structure 
      formation (72 and 36% stimulation compared with a control matrix for 1.5 and 10 
      units/ml UFH, respectively). Similar results were obtained for cells stimulated 
      with vascular endothelial growth factor plus tumor necrosis factor alpha. These 
      data demonstrate the inhibitory effect of heparins on proliferation of hMVECs and 
      provide a novel mechanism by which LMWH may affect tumor progression, namely 
      reduced ingrowth of microvascular structures in a fibrinous stroma matrix by 
      rendering it less permissive for invasion.
FAU - Collen, A
AU  - Collen A
AD  - Gaubius Laboratory TNO-PG, Leiden, The Netherlands.
FAU - Smorenburg, S M
AU  - Smorenburg SM
FAU - Peters, E
AU  - Peters E
FAU - Lupu, F
AU  - Lupu F
FAU - Koolwijk, P
AU  - Koolwijk P
FAU - Van Noorden, C
AU  - Van Noorden C
FAU - van Hinsbergh, V W
AU  - van Hinsbergh VW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 9001-31-4 (Fibrin)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Cell Division/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Endothelium, Vascular/cytology/drug effects/growth & development
MH  - Fibrin/*metabolism
MH  - Fibrinolytic Agents/*pharmacology
MH  - Heparin/*pharmacology
MH  - Heparin, Low-Molecular-Weight/*pharmacology
MH  - Humans
MH  - Neovascularization, Physiologic/*drug effects
EDAT- 2000/11/21 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/11/21 11:00
PHST- 2000/11/21 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/11/21 11:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2000 Nov 1;60(21):6196-200.