Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors

Abstract

It is now established that bone marrow-derived myeloid cells regulate tumor angiogenesis. This was originally inferred from studies of human tumor biopsies in which a positive correlation was seen between the number of tumor-infiltrating myeloid cells, such as macrophages and neutrophils, and tumor microvessel density. However, unequivocal evidence was only provided once mouse models were used to examine the effects on tumor angiogenesis by genetically or pharmacologically targeting myeloid cells. Since then, identifying the exact myeloid cell types involved in this process has proved challenging because of myeloid cell heterogeneity and the expression of overlapping phenotypic markers in tumors. As a result, investigators often simply refer to them now as "bone marrow-derived myeloid cells." Here we review the findings of various attempts to phenotype the myeloid cells involved and discuss the therapeutic implications of correctly identifying-and thus being able to target-this proangiogenic force in tumors.

Figure 1

Various myeloid-lineage cell types implicated to date in the regulation of tumor angiogenesis. Markers expressed (or not expressed) by each of the distinct cell types are indicated. Note that several markers are coexpressed by different myeloid cell types, raising the question of whether some of these represent distinct cell types, rather then overlapping cell subsets or differentiation states of a same cell type.

Figure 2

A schematic illustrating the possible relationships among monocyte/macrophage subpopulations found in tumors. Tumor-infiltrating macrophages are known to derive from circulating CCR2+ inflammatory monocytes; however, it remains to be investigated whether inflammatory monocytes give raise to each of the distinct macrophage subpopulations found in tumors. The contribution of CCR2–resident monocytes to tumor macrophages is currently unknown. Dashed arrows indicate putative developmental relationships.