Human breast tumors override the antiangiogenic effect of stromal thrombospondin-1 in vivo.
The antiangiogenic extracellular matrix protein thrombospondin-1 (TSP-1) inhibits tumor growth and metastasis in animals. However, the clinical relevance of such findings are equivocal as increased stromal TSP-1 expression has been associated with either good or poor prognosis. In an effort to obtain a more integrated understanding of the role of TSP-1 in breast cancer, we first used a breast tumorigenesis model in which tumor-associated stromal fibroblasts were engineered to produce high levels of TSP-1. We demonstrate here that stromal TSP-1 delayed human MDA-MB-231/B02 breast tumor growth. However, this delay in MDA-MB-231/B02 tumor growth upon exposure to TSP-1 was associated with an increased vascular endothelial growth factor (VEGF) expression in tumor cells themselves, leading to a tumor growth rate comparable to that of tumors whose fibroblasts did not overproduce TSP-1. Clinical evidence also suggested that primary breast carcinomas have adapted to escape the effects of stromal TSP-1. TSP-1 was found to be expressed in the stroma of human breast carcinomas where, although its level correlated with decreased vascularization, it was unexpectedly associated with a reduction of relapse-free survival. In metastatic axillary lymph nodes, tumor cells expressed high levels of VEGF and TSP-1 expression were no longer associated with a decreased vascularization. Overall, these results suggest that a resistance may develop early in human breast cancers as a result of high in situ exposure to stromal TSP-1, leading to disease progression.
Fontana
Aurélie
A
INSERM Research Unit 664, Laënnec School of Medicine, Lyon, France.
Filleur
Stéphanie
S
Guglielmi
Julien
J
Frappart
Lucien
L
Bruno-Bossio
Gabriella
G
Boissier
Sandrine
S
Cabon
Florence
F
Clézardin
Philippe
P
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019700:Thrombospondin 1 / Q000032:analysis / Q000502:physiology*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A