Tumoral and choroidal vascularization: differential cellular mechanisms involving plasminogen activator inhibitor type I.
An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1(-/-) mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1(-/-) BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis.
Jost
Maud
M
Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie, CHU (B23), Sart Tilman; B-4000 Liège, Belgium.
Maillard
Catherine
C
Lecomte
Julie
J
Lambert
Vincent
V
Tjwa
Marc
M
Blaise
Pierre
P
Alvarez Gonzalez
Maria-Luz
ML
Bajou
Khalid
K
Blacher
Silvia
S
Motte
Patrick
P
Humblet
Chantal
C
Defresne
Marie Paule
MP
Thiry
Marc
M
Frankenne
Francis
F
Gothot
André
A
Carmeliet
Peter
P
Rakic
Jean-Marie
JM
Foidart
Jean-Michel
JM
Noël
Agnès
A
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002277:Carcinoma / Q000098:blood supply*; D020256:Choroidal Neovascularization / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000473:pathology / Q000637:transplantation; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000098:blood supply*
D017395:Plasminogen Activator Inhibitor 1
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