Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin.
BACKGROUND
Clinical studies suggest a survival advantage in cancer patients receiving low molecular weight heparin (LMWH). A suggested mechanism for this beneficial effect may reside in the antiangiogenic activity of heparins.


OBJECTIVE
In this study we investigated whether two different LMWHs, i.e. enoxaparin and dalteparin, and unfractionated heparin (UFH), affect the angiogenic potential of human microvascular endothelial cells (HMEC-1) promoted by tumor cells.


METHODS
HMEC-1 cells were incubated with tumor cell conditioned media (TCM) derived from human breast cancer and leukemic cells (i.e. MCF-7, MDA.MB.231, and NB4 cell lines) or recombinant cytokines (i.e. VEGF, FGF-2, TNF-alpha) +/-heparins. Capillary-like tube formation in Matrigel and cell proliferation were evaluated.


RESULTS
All three TCM induced a significant (p<0.05) increase in total length of tubes formed by HMEC-1 in Matrigel. These increases were significantly counteracted (62 to 100% mean inhibition) by enoxaparin and dalteparin, but were significantly less affected by UFH. Similarly, the tube formation induced by standard VEGF, FGF-2, or TNF-alpha was 100% inhibited by enoxaparin, and 70-90% by dalteparin, whereas minor or no inhibition was observed with UFH. VEGF was the most active cytokine in TCM of both breast cancer and leukemic cells. EC proliferation was significantly increased by standard angiogenic factors, and slightly affected by breast cancer TCM (p=ns). The addition of heparins significantly counteracted the proliferative stimuli.


CONCLUSIONS
These results support a major role for LMWH compared to UFH in inhibiting the proangiogenic effect exerted by tumor cells or purified angiogenic factors on microvascular endothelium.
Marchetti
Marina
M
Department of Hematology, Ospedali Riuniti di Bergamo, Largo Barozzi, 1-24128 Bergamo, Italy.
Vignoli
Alfonso
A
Russo
Laura
L
Balducci
Donatella
D
Pagnoncelli
Marcella
M
Barbui
Tiziano
T
Falanga
Anna
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006493:Heparin / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D020533:Angiogenesis Inhibitors; D006495:Heparin, Low-Molecular-Weight; D042461:Vascular Endothelial Growth Factor A; D006493:Heparin