Bone marrow-derived cells contribute to tumor angiogenesis. Here, we demonstrate that monocytes expressing the Tie2 receptor (Tie2-expressing monocytes [TEMs]) (1) are a distinct hematopoietic lineage of proangiogenic cells, (2) are selectively recruited to spontaneous and orthotopic tumors, (3) promote angiogenesis in a paracrine manner, and (4) account for most of the proangiogenic activity of myeloid cells in tumors. Remarkably, TEM knockout completely prevented human glioma neovascularization in the mouse brain and induced substantial tumor regression. Besides TEMs and endothelial cells (ECs), Tie2 expression distinguished a rare population of tumor stroma-derived mesenchymal progenitors representing a primary source of tumor pericytes. Therefore, Tie2 expression characterizes three distinct cell types required for tumor neovascularization: ECs, proangiogenic cells of hematopoietic origin, and pericyte precursors of mesenchymal origin.

Angiogenic tumor vessels are promising targets for the activity and the selective delivery of cancer therapeutics. The bone marrow contributes different cell types to the tumor stroma, including hematopoietic cells and, as recently suggested, vascular endothelial cells (ECs). Thus, transplantation of genetically modified bone marrow progenitors may represent a vehicle for the transport of gene therapy to tumors. We transduced bone marrow progenitors with lentiviral vectors expressing genes from transcription-regulatory elements of Tie2/Tek gene. When tumors were grown in the transplanted mice, the new vector marked a distinct hematopoietic population that 'homed' to the tumor and closely interacted with vascular ECs at the tumor periphery. These Tie2-expressing mononuclear (TEM) cells had a distinguishable phenotype and were present selectively at angiogenic sites. Unexpectedly, we did not find bone marrow-derived ECs in tumor vessels when we transplanted bone marrow progenitors constitutively expressing a marker gene from the Tie2 or ubiquitously active promoters. By delivering a 'suicide' gene, we selectively eliminated the TEM cells and achieved substantial inhibition of angiogenesis and slower tumor growth without systemic toxicity. Thus, TEM cells may account for the proangiogenic activity of bone marrow-derived cells in tumors, may represent a new target for drug development and may provide the means for selective gene delivery and targeted inhibition of tumor angiogenesis.

Tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs), have been implicated in tumor progression. We recently described a lineage of mouse monocytes characterized by expression of the Tie2 angiopoietin receptor and required for the vascularization and growth of several tumor models. Here, we report that TIE2 expression in human blood identifies a subset of monocytes distinct from classical inflammatory monocytes and comprised within the less abundant "resident" population. These TIE2-expressing monocytes (TEMs) accounted for 2% to 7% of blood mononuclear cells in healthy donors and were distinct from rare circulating endothelial cells and progenitors. In human cancer patients, TEMs were observed in the blood and, intriguingly, within the tumors, where they represented the main monocyte population distinct from TAMs. Conversely, TEMs were hardly detected in nonneoplastic tissues. In vitro, TEMs migrated toward angiopoietin-2, a TIE2 ligand released by activated endothelial cells and angiogenic vessels, suggesting a homing mechanism for TEMs to tumors. IntroductionHematopoietic cells of diverse lineages contribute to tumor progression. [1][2][3][4][5][6][7] Among these cells, tumor-associated macrophages (TAMs) play important roles in tumorigenesis. 3,[8][9][10] TAMs derive from circulating monocytes, which differentiate into macrophages upon homing to tumors. In tumors, TAMs play dichotomous functions. Although TAMs may exert direct antitumor activities, 11,12 increasing data indicate that they are skewed by the tumor microenvironment to a protumoral phenotype. 8,13 Indeed, TAMs can blunt antitumor immunity and stimulate angiogenesis, cell migration, invasion, and metastasis. 3,9 Whereas the divergent TAM functions (ie, antitumoral and protumoral activities) are thought to be contextually modulated by the tumor microenvironment, 8 emerging data suggest that distinct subsets of circulating monocytes exist that are committed to specific functions, including tissue remodeling and proangiogenic activity. [14][15][16] In this regard, we recently identified in mouse tumor models a subset of tumor-infiltrating monocytes characterized by the expression of the angiopoietin receptor Tie2/Tek, 15,17 a molecule previously known to be restricted to endothelial and hematopoietic stem cells. 18,19 In mice, Tie2-expressing monocytes (TEMs) home to tumors, where they are required for angiogenesis. Indeed, selective elimination of TEMs by a suicide gene strategy prevented angiogenesis and induced tumor regression. 15,17 In these tumor models, angiogenesis was inhibited despite the fact that TAM recruitment to tumors was not impaired, indicating that a specific subset of myeloid-lineage cells was primarily responsible for promoting angiogenesis. This concept has received support from other studies that reported proangiogenic activity of selected myeloid cell subsets in mouse tumors, including VEGFR-1 ϩ CD11b ϩ myeloid cells, Gr-1 ϩ CD11b ϩ myeloid suppressor cells, and CD11c ϩ MHC-II ϩ dendritic cell prec...