Table 1.
A Glossary for BMDCs Implicated in Tumor Angiogenesis
| Definition (alphabetic order) | Description | References (selected) |
|---|---|---|
| CD11b+ Gr-1+ cells | CD11b and Gr-1 are cell surface markers broadly expressed by myeloid-lineage cells. The combination of such markers is commonly used to identify a myeloid cell population that expands in the bone marrow, blood, and spleen of tumor-bearing mice. The CD11b+Gr-1+ cells comprise both monocyte- and granulocyte-lineage cells and are also referred to as myeloid-derived suppressor cells (MDSCs). In tumors, CD11b+Gr-1+ cells are less abundant than classic macrophages (which are Gr-1−) and mostly comprise neutrophils and inflammatory monocytes. CD11b+Gr-1+ cells/MDSCs are thought to promote tumor progression mainly through immunosuppression; however, subsets of these cells—neutrophils in particular—may also promote angiogenesis via both VEGF-dependent and independent pathways. | 15,16,18,19 |
| Inflammatory monocytes | In the mouse, circulating monocytes can be separated into at least two main subsets: inflammatory (or classic) and resident monocytes. Inflammatory monocytes are considered the precursors of macrophages and dendritic cells recruited to inflamed tissues (including tumors); they express Ly6C and CCR2, the receptor for CCL2 (also known as monocyte chemoattractant protein-1, MCP-1). Once recruited to tumors, inflammatory monocytes are thought to differentiate into tumor-associated macrophages (TAMs). | 20,21,22 |
| Hemangiocytes | The term “hemangiocyte” was coined by Rafii and coworkers to designate a population of hematopoietic progenitors that express CD11b, VEGFR-1, CXCR4, Sca1, and Tie2. The relationship between these hemangiocytes and other hematopoietic progenitors or differentiated myeloid-lineage cells (such as monocytes, TEMs in particular) requires further investigation. VEGFR-1+ hemangiocytes and Tie2+ monocytes appear to be a major source of functional MMP9 in tumors. | 2 |
| M1 or classic macrophage activation | In response to microbial agents and Th1 cytokines such as interferon-γ, macrophages undergo an activation program referred to as “classic,” or “M1” activation. Classically activated macrophages are potent effector cells that can kill microorganisms and tumor cells and produce copious amounts of proinflammatory cytokines. In vitro–polarized M1 macrophages express high amounts of the antiangiogenic cytokines IL-12, CXCL9, and CXCL10. | 23,24 |
| M2 or alternative macrophage activation | Available information suggests that several tumor- and T cell–derived cytokines, such as IL-4, IL-13, IL-10, as well as glucocorticoid hormones and vitamin D3, can induce TAMs to undergo an “alternative” or “M2” activation program. M2-polarized macrophages produce a variety of growth factors that regulate tumor-cell proliferation and invasion, angiogenesis, and the deposition and dissolution of connective tissues. These include epidermal growth factor (EGF), members of the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) families, and transforming growth factor-β (TGF-β). It is generally believed that M2-polarized macrophages have a key role in promoting tumor growth and progression and subverting antitumor immunity. It is likely that fully polarized M1 and M2 macrophages are the extremes of a continuum of phenotypes variably expressed in different tumor microenvironments (see Figure 2). | 19,23,24 |
| MDSCs (myeloid-derived suppressor cells) | See CD11b+ Gr-1+ cells. | |
| Resident monocytes | Circulating resident monocytes are a monocyte subpopulation distinct from inflammatory monocytes. Resident monocytes, which are Ly6C− and CCR2−, patrol blood vessels and may differentiate into proangiogenic macrophages once extravasated at sites of tissue injury or ischemia. TEMs appear to be a subpopulation of resident monocytes; the role of resident monocytes in tumors is otherwise very poorly known. | 20,21,22 |
| TEMs (Tie2-expressing monocytes/macrophages) | TEMs express the angiopoietin receptor Tie2, a feature that distinguishes them from other monocytes/myeloid cells. TEMs circulate both in human and mouse peripheral blood and are recruited to sites of tissue remodeling, including tumors, where they appear to provide paracrine support to angiogenesis. | 5,25,26,27 |
| TAMs (tumor-associated macrophages) | TAMs are thought to derive from circulating inflammatory monocytes. F4/80+ TAMs make up a major proportion of the CD11b+ myeloid cells found in a variety of mouse tumor models. Defined factors present in the tumor microenvironment can induce TAMs to acquire distinct activation states (see M1 and M2 activation). In progressing tumors, TAMs are largely M2-polarized and produce a wide array of proangiogenic factors. | 3,28,29 |
| Vascular leukocytes | These cells represent a population of proangiogenic monocytes that coexpress myeloid (eg, CD11b) and EC markers (eg, VE-Cadherin and Tie2). Vascular leukocytes are particularly abundant in human ovarian cancers but are also detected in a number of murine tumors. Recently, vascular leukocytes have been shown to phenotypically overlap with TEMs. | 9,30,31 |