HPCs AND THEIR PROGENY
The role of hematopoietic cells in tumor angiogenesis has recently received great attention. HPC from the bone marrow emigrate to the blood and tissues and differentiate to form cells of the innate and adaptive immune system. Tumor-infiltrating leukocytes can either protect against or promote tumor formation. The simplest example of the former is loss of immune surveillance and spontaneous tumor formation in some strains of immunodeficient mice. On the other hand, CD4+ T lymphocytes may promote tumor cell invasion and metastasis by altering the function of tumor-associated macrophages (TAMs). Myeloid lineage cells, including monocytes/macrophages, neutrophils, dendritic cells, eosinophils, and mast cells feature prominently in the stroma of most solid tumors. Although direct stimulation of malignant cells by these hematopoietic cells is possible, the tumor-promoting abilities of the recruited myelomonocytic pool is largely related to their secretion of a variety of proangiogenic factors and ability to orchestrate the formation of new blood vessels.

One of the first clues that HPC might be required for angiogenesis came from studies in the developing embryo. For example, acute myeloid leukemia 1 (AML1) deficient embryos, which lack definitive hematopoiesis, showed impaired angiogenesis in the head and pericardium that was rescued by addition of HPC-expressing angiopoietin 1 (ANG-1). Thus, even physiological angiogenesis is dependent on crosstalk between the remodeling endothelium and recruited HPC. Moreover, we showed that engineered blood vessels in the adult mouse are also dependent on hematopoietic cell recruitment, as selective elimination of GR-1+-circulating myeloid cells impaired blood vessel development and anastomosis with host vasculature. Pathological angiogenesis (e.g., solid tumors) is also characterized by recruitment of an array of myelomonocytic cells with overlapping phenotypes and functions. For example, a novel population of proangiogenic TEK tyrosine kinase with Ig and EGF homology domains-2 (TIE-2) expressing monocytes was recently identified in tumors. Selective elimination of TIE-2 monocytes impairs tumor growth and angiogenesis. On the other hand, similar to MPC, TIE-2 monocytes (and other HPC) may be used as vectors for drug delivery due to their tumor-homing properties.

The catalytic function of hematopoietic cells during tumor progression may be related to their expression of proangiogenic and tissue-remodeling factors including MMPs and VEGF. Furthermore, tumor-derived factors may activate or change the phenotype of the recruited pool of hematopoietic cells. A good example is the M2 skewing of TAMs as tumors become more vascular and invasive. Macrophages invade most solid tumors in great numbers and elicit inflammatory responses that are generally protumorigenic and proangiogenic. The numbers of TAMs in Hodgkin's lymphoma is associated with a poor patient prognosis although the factor(s) mediating their tropism to the tumor site were not identified. A hypoxia inducible factor alpha (HIF-1α)/chemokine ligand 12 (CXCL-12) axis was shown to mobilize proangiogenic MMP9-expressing monocytic cells from bone marrow, which controls a postulated angiogenic switch in tumors. These marrow-derived monocytic cells are important mediators of resistance to anti-VEGF therapies and angiogenesis rebound following radiotherapy. Thus, depletion of specific populations of HPC and their progeny can have a favorable antitumor response, perhaps by indirectly controlling the rate of angiogenesis.

In addition to their paracrine functions, myeloid-lineage cells may act as vascular bridges by guiding and connecting nascent blood vessels. Proangiogenic TIE-2+ macrophages, for example, were recently shown to guide tip-cell fusion, a critical step during blood vessel anastomosis. The ability of myeloid-lineage cells to directly form blood vessels is also possible. Transdifferentiation of CD45+ myeloid cells to form endothelial-like cells was described by Bailey. Yang et al. found that Gr-1+/CD11b+ cells acquired properties of endothelial cells in tumors, expressed VE-cadherin and lined blood vessels. Similarly, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)+ macrophages were shown to differentiate to form lymphatic endothelium, a feature probably related to their inherent plasticity. Taken together, myeloid-lineage cells, through diverse mechanisms, may facilitate angiogenesis and enable tumor progression. It will be important to further clarify the factors mediating trafficking and differentiation of myeloid cells at the tumor site. The use of humanized mice engrafted with tumor cells could be an important tool for dissecting the function of HPC and their progeny in the laboratory.

Sources: Juan M. Melero-Martin, Andrew C. Dudley