Molecular Regulation in Mesenchymal Stromal and Hematopoietic Cells during Tumor Neovascularization

An important functional component in tumor neovascularization is carried out by stromal and hematopoietic cells. These cells migrate and populate the tumor tissue where they can promote angiogenesis by multiple pathways. One mechanism by which fibroblasts and many hematopoietic cells control new vessel formation is expression of a multitude of proangiogenic factors (VEGF, MMPs, IL-8, Ang-2, among others). Another mechanism is direct incorporation in the vessel wall as part of the endothelial lining [46-48] or perivascular layer [14,22,24].

Fibroblasts may influence carcinogenesis directly. Normal fibroblasts can prevent [91,92] the progression of transformed epithelial cells in a TGF-^-dependent manner [93]. In contradistinction, tumor-activated fibroblasts can enhance malignant epithelial transformation [94,95]. Fibroblasts in tumors express VEGF [13], SDF-1 [95,96], and constitute promising cellular targets for cancer therapy. Some of the same molecular players that control endothelial and mural cell in tumors also affect the fibroblast and hematopoietic cell function. Fibroblasts express PDGFR-a and migrate to tumors in response to factors such as PDGF-A or PDGF-C [97]. TGF-p has been shown to control differentiation of these cells into myofibroblasts in tumors, which results in an increased production of MMPs.

Growth factors produced by the tumors act as potent chemoattractants for hematopoietic cells: VEGF, SDF-1, Ang-1, PlGF, and BDNF [66,98]. The recruitment of hematopoietic BMDCs and the infiltration of these cells into diseased tissue are often massive in scale, particularly in tumors. The predominant populations are myeloid cells (macrophages, neutro-phils, etc.), and they also produce chemokines, angiogenic growth factors, and MMPs, thus promoting tumor angiogenesis and progression [10,11]. However, T and B cells may also play important roles at certain stages of carcinogenesis [99,100]. But if the presence of these cells is indicative of a response of the immune system directed against the cancer cells or of a nonspecific inflammatory response that favors tumor growth remains to be determined. Alternatively, if the immune cell infiltrate in tumors is the result of the exponential expansion of precursors (i.e., stem or progenitor cells), the function of BMDCs in the tumor might be significantly different. Increasing evidence suggests that the contribution of hematopoietic stem cells and myeloid progenitor cells is, in fact, critical for new vessel formation in tumors [22]. However, the mechanism of action and the degree of plasticity of these cells are not sufficiently understood. Once they have homed to the tumor, multipotent BMDCs have the potential to modulate neovascularization and to become part of all three nonmalignant tumor compartments: hematopoietic, endothelial, and mesenchymal. Moreover, a recent study showed that gastric cancer induced by Helicobacter pylori originated from BMDCs [101]. Both the relative contribution of different BMDCs to solid tumors' stroma and the timing of their incorporation remain unclear [82].

The difficulty of assessing the relative contribution of each lineage of BMDCs to tumor neovascularization has led to debate and hampered the identification of new clinical targets, inhibiting clinical translation of the progress made in preclinical models. Nevertheless, these data suggested that a generic approach of inhibiting chronic inflammation might prevent carcinogenesis. This approach is supported by epidemiological data that have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce their risk of developing colorectal cancer [102]. In addition, two promising therapeutic approaches have been tested in preclinical or clinical models that targeted hematopoietic cell contribution to angiogenesis in tumors. One was targeting these cells using cytokines that also participate in angiogenesis (by inhibition of VEGF, SDF-1, TGF-p, IL-8, COX-2, and so on, or alternatively, promotion of IL-12, IFN-a, or IFN-y). Another strategy was targeting molecules produced by hematopoietic cells in tumors, such as urokinase plasminogen activator receptor (uPAR [103]), MMP-9 [35,104], cathepsins [105] among others.

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