RESUMEN
The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.
Asunto(s)
Movimiento Celular , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/fisiopatología , Neoplasias/metabolismo , Neoplasias/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Adhesión Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular , Medios de Cultivo Condicionados/farmacología , Fibronectinas/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Diferenciación/metabolismo , Integrina alfa4beta1/metabolismo , Metaloproteinasa 9 de la Matriz , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Transgénicos , Especificidad de Órganos , Especificidad por Sustrato , Regulación hacia Arriba , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Neoangiogenesis involves both bone marrow-derived myelomonocytic and endothelial progenitor cells as well as endothelial cells coopted from surrounding vessels. Cytokines induce these cells to proliferate, migrate, and exit the cell cycle to establish the vasculature; however, which cell cycle regulators play a role in these processes is largely unknown. Here, we report that mice lacking the cell cycle inhibitors p130 and p27 show defects in tumor neoangiogenesis, both in xenografts and spontaneously arising tumors. This defect is associated with impaired mobilization of endothelial and myelomonocytic angiogenic progenitors from the bone marrow. This article documents the role of these molecules in angiogenesis and further suggests that cell expansion and mobilization from the bone marrow of angiogenic precursors are separable events.