Deficiency of bone marrow beta3-integrin enhances non-functional neovascularization.
beta3-Integrin is a cell surface adhesion and signalling molecule important in the regulation of tumour angiogenesis. Mice with a global deficiency in beta3-integrin show increased pathological angiogenesis, most likely due to increased vascular endothelial growth factor receptor 2 expression on beta3-null endothelial cells. Here we transplanted beta3-null bone marrow (BM) into wild-type (WT) mice to dissect the role of BM beta3-integrin deficiency in pathological angiogenesis. Mice transplanted with beta3-null bone marrow show significantly enhanced angiogenesis in subcutaneous B16F0 melanoma and Lewis lung carcinoma (LLC) cell models and in B16F0 melanoma lung metastasis when compared with tumours grown in mice transplanted with WT bone marrow. The effect of bone marrow beta3-integrin deficiency was also assessed in the RIPTAg mouse model of pancreatic tumour growth. Again, angiogenesis in mice lacking BM beta3-integrin was enhanced. However, tumour weight between the groups was not significantly altered, suggesting that the enhanced blood vessel density in the mice transplanted with beta3-null bone marrow was not functional. Indeed, we demonstrate that in mice transplanted with beta3-null bone marrow a significant proportion of tumour blood vessels are non-functional when compared with tumour blood vessels in WT-transplanted controls. Furthermore, beta3-null-transplanted mice showed an increased angiogenic response to VEGF in vivo when compared with WT-transplanted animals. BM beta3-integrin deficiency affects the mobilization of progenitor cells to the peripheral circulation. We show that VEGF-induced mobilization of endothelial progenitor cells is enhanced in mice transplanted with beta3-null bone marrow when compared with WT-transplanted controls, suggesting a possible mechanism underlying the increased blood vessel density seen in beta3-null-transplanted mice. In conclusion, although BM beta3-integrin is not required for pathological angiogenesis, our studies demonstrate a role for BM beta3-integrin in VEGF-induced mobilization of bone marrow-derived cells to the peripheral circulation and for the functionality of those vessels in which BM-derived cells become incorporated.
Watson
Alan R
AR
Histopathology Unit, Cancer Research UK London Research Institute, UK.
Pitchford
Simon C
SC
Reynolds
Louise E
LE
Direkze
Natalie
N
Brittan
Mairi
M
Alison
Malcolm R
MR
Rankin
Sara
S
Wright
Nicholas A
NA
Hodivala-Dilke
Kairbaan M
KM
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology; D039661:Integrin beta3 / Q000502:physiology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000556:secondary; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply; D013234:Stem Cells / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000633:toxicity
D039661:Integrin beta3; D042461:Vascular Endothelial Growth Factor A