Neuropilin-1 Identifies a Subset of Bone Marrow Gr1− Monocytes That Can Induce Tumor Vessel Normalization and Inhibit Tumor Growth
Copyright policy )Neuropilin-1 Identifies a Subset of Bone Marrow Gr1− Monocytes That Can Induce Tumor Vessel Normalization and Inhibit Tumor Growth
AbstractImproving tumor perfusion, thus tempering tumor-associated hypoxia, is known to impair cancer progression. Previous work from our laboratory has shown that VEGF-A165 and semaphorin 3A (Sema3A) promote vessel maturation through the recruitment of a population of circulating monocytes expressing the neuropilin-1 (Nrp1) receptor (Nrp1-expressing monocytes; NEM). Here, we define the characteristics of bone marrow NEMs and assess whether these cells might represent an exploitable tool to induce tumor vessel maturation. Gene expression signature and surface marker analysis have indicated that NEMs represent a specific subset of CD11b+ Nrp1+ Gr1− resident monocytes, distinctively recruited by Sema3A. NEMs were found to produce several factors involved in vessel maturation, including PDGFb, TGF-β, thrombospondin-1, and CXCL10; consistently, they were chemoattractive for vascular smooth muscle cells in vitro. When directly injected into growing tumors, NEMs, isolated either from the bone marrow or from Sema3A-expressing muscles, exerted antitumor activity despite having no direct effects on the proliferation of tumor cells. NEM inoculation specifically promoted mural cell coverage of tumor vessels and decreased vascular leakiness. Tumors treated with NEMs were smaller, better perfused and less hypoxic, and had a reduced level of activation of HIF-1α. We conclude that NEMs represent a novel, unique population of myeloid cells that, once inoculated into a tumor, induce tumor vessel normalization and inhibit tumor growth. Cancer Res; 72(24); 6371–81. ©2012 AACR.
- University of Turin Italy
- University of Trieste Italy
- King's College London United Kingdom
- International Centre for Genetic Engineering and Biotechnology Italy
- Kings College London, University of London United Kingdom
Angiogenesis Inhibitors; genetics/metabolism/physiology, Animals, Bone Marrow Cells; metabolism/physiology, Bone Marrow Transplantation, Cell Line; Tumor, Cell Proliferation, Humans, Mice, Mice; Inbred BALB C, Mice; Inbred C57BL, Monocytes; metabolism/physiology, Neoplasms; blood supply/pathology/therapy, Neuropilin-1; genetics/metabolism/physiology, Receptors; Cell Surface; genetics/metabolism/physiology, Tumor Markers; Biological; genetics/metabolism/physiology, hologic; prevention /&/ control/therapy, Inbred BALB C, Mice, 610, Angiogenesis Inhibitors, Bone Marrow Cells, Receptors, Cell Surface, blood supply/pathology/therapy, Neuropilin-1, Monocytes, Mice, Cell Line, Tumor, Neoplasms, genetics/metabolism/physiology, hologic, Biomarkers, Tumor, Animals, Humans, prevention /&/ control/therapy, Bone Marrow Transplantation, Cell Proliferation, Mice, Inbred BALB C, genetics/metabolism/physiology, Tumor Marker, Neovascularization, Pathologic, metabolism/physiology, Neoplasm, tumor vessel normalization; Semaphorin 3A; bone marrow-derived cells, Biological, genetics/metabolism/physiology, Receptor, Neuropilin-1, Mice, Inbred C57BL, genetics/metabolism/physiology, Animals, Bone Marrow Cell, metabolism/physiology, Bone Marrow Transplantation, Cell Line, Cell Surface, Tumor, Cell Proliferation, Humans, Mice, Mice, Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Bone Marrow Cells; Bone Marrow Transplantation; Cell Line, Tumor; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; Neoplasms; Neovascularization, Pathologic; Neuropilin-1; Receptors, Cell Surface; Cell Proliferation, Angiogenesis Inhibitor, Inbred C57BL, Monocyte
Angiogenesis Inhibitors; genetics/metabolism/physiology, Animals, Bone Marrow Cells; metabolism/physiology, Bone Marrow Transplantation, Cell Line; Tumor, Cell Proliferation, Humans, Mice, Mice; Inbred BALB C, Mice; Inbred C57BL, Monocytes; metabolism/physiology, Neoplasms; blood supply/pathology/therapy, Neuropilin-1; genetics/metabolism/physiology, Receptors; Cell Surface; genetics/metabolism/physiology, Tumor Markers; Biological; genetics/metabolism/physiology, hologic; prevention /&/ control/therapy, Inbred BALB C, Mice, 610, Angiogenesis Inhibitors, Bone Marrow Cells, Receptors, Cell Surface, blood supply/pathology/therapy, Neuropilin-1, Monocytes, Mice, Cell Line, Tumor, Neoplasms, genetics/metabolism/physiology, hologic, Biomarkers, Tumor, Animals, Humans, prevention /&/ control/therapy, Bone Marrow Transplantation, Cell Proliferation, Mice, Inbred BALB C, genetics/metabolism/physiology, Tumor Marker, Neovascularization, Pathologic, metabolism/physiology, Neoplasm, tumor vessel normalization; Semaphorin 3A; bone marrow-derived cells, Biological, genetics/metabolism/physiology, Receptor, Neuropilin-1, Mice, Inbred C57BL, genetics/metabolism/physiology, Animals, Bone Marrow Cell, metabolism/physiology, Bone Marrow Transplantation, Cell Line, Cell Surface, Tumor, Cell Proliferation, Humans, Mice, Mice, Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Bone Marrow Cells; Bone Marrow Transplantation; Cell Line, Tumor; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; Neoplasms; Neovascularization, Pathologic; Neuropilin-1; Receptors, Cell Surface; Cell Proliferation, Angiogenesis Inhibitor, Inbred C57BL, Monocyte
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