VEGF and the Tumor Microenvironment

Stroma and tumor-associated endothelium nourish and support the growing cell mass of solid tumors.242 Similarly the stroma of hematopoietic organs support processes of normal and malignant hematopoiesis, that is, "liquid" tumors or leukemias and MM. For example, Friend Murine leukemia virus (F-MuLV)-infected splenocytes secrete elevated levels of IL-6, VEGF, MCP-5, sTNFR1, IL-12p70, TNF-a, and IL-2 compared with normal splenocytes, thereby sustaining proliferation of primary erythroleukemic cells in vitro. Importantly, in vivo administration of a neutralizing VEGF antibody extends survival times of erythroleu-kemic mice in comparison to controls.243 Moreover, CLL, marginal zone NHL, hairy cell leukemia, and chronic myelogenous leukemia (CML) are associated with splenomegaly, suggesting that growth response elements are contributed by the spleen.244-246 Conversely, the BM microenvironment is a heterogeneous population of cells including HSCs; endothelial cells; stromal cells including fibroblasts, macrophages, T lymphocytes; as well as cells involved in bone homeostasis such as chondroclasts, osteoclasts, and osteoblasts (Figure 4.2). Differentiation, maintenance, and expansion of MM cells within the BM microenvironment is a highly coordinated process involving: (1) multiple growth factors, cytokines, and chemokines secreted by tumor cells (autocrine loop), stromal cells (paracrine loop), as well as nonhema-topoietic organs (e.g., kidney and liver); as well as (2) direct MM cell-stromal cell contact (juxtacrine loop).

The function of VEGF and its receptors is one component of regulatory processes contributing to pathogenesis of MM in particular, and hematologic malignancies in general. In MM, VEGF is present in the patient BM microenvironment and associated with neovascularization at sites of MM cell infiltration.247 The secreted isoforms VEGF121, VEGF145, and VEGF165, as well as ECM- and surface-bound VEGF18g and VEGF206, are produced by MM cell lines, as well as by patient MM and PCL cells.33 Importantly, the ECM serves as a reservoir of ECM-bound VEGF isoforms. In addition to their effects on basement membrane and the ECM, uPA, plasmin, heparin, heparan sulfate, and heparinases release this ECM-sequestered VEGF, thereby further regulating the bioavailability of VEGF.22'24

In hematologic malignancies including leukemia and MM, there is a "public" (or external) autocrine loop: for example, VEGF secreted by tumor cells activates receptors on tumor cells, as well as other cells. "Private" (or internal) autocrine loops, where the factor activates autonomous cell growth via an intracellular receptor without secretion,248 have been described in AML cells and in murine experimental models. In contrast to the "public" autocrine loop, cell proliferation mediated by a "private" VEGF autocrine loop is not cell density dependent, and neutralizing antibodies do not prevent continued cell growth or differentiation.248-254 Importantly, this independence of factor secretion contrasts the regulatory role of VEGF during hematopoiesis versus angiogenesis. The role of "private" autocrine loops in MM pathogenesis, specifically in the development of the tumor cell clone as well as in tumor cell proliferation under nutrient-deprived conditions, remains to be determined. Autocrine VEGF and a4^1-integrin are involved in chemokine-dependent motility of patient CLL, but not normal, B cells on and through endothelium.255

In MM, IL-6 secreted by BMSCs enhances the production and secretion of VEGF by MM cells, thereby augmenting MM cell growth and survival36,256,257; conversely, binding of MM cells to BMSCs enhances IL-6, IGF-1, as well as VEGF secretion in BMSCs.256 258 259 Specifically, IGF-1 induces HIF-1a, which triggers VEGF expression260; consequently, inhibition of IGFR-1 activity markedly decreases VEGF secretion in MM/BMSC cocul-tures.258 Other mechanisms regulating VEGF expression in MM cells include c-maf and CD40: (1) c-maf-driven expression of integrin-^7 enhances adhesion to BM stroma and thereby increases VEGF production261 and (2) CD40 activation induces p53-dependent VEGF secretion.262

What is the functional role of VEGF in MM pathogenesis? In addition to stimulating angiogenesis, our studies show that VEGF directly stimulates MM cell migration on fibro-nectin, proliferation, and survival via autocrine and paracrine loops. Importantly, the range of VEGF target cells within the BM compartment of MM may be even broader since VEGF: (1) dramatically affects the differentiation of multiple hematopoietic lineages in vivo; (2) increases the production of B cells and generation of myeloid cells177,263; (3) regulates HSC survival by an internal autocrine loop mechanism121; (4) increases both osteoclastic bone-resorbing activity178 and osteoclast chemotaxis180; and (5) inhibits maturation of dendritic cells.177 For example, we have shown that addition of anti-VEGF antibodies to MM patients' BM sera abrogates its inhibitory effect on dendritic cell maturation.264 Therefore besides angiogenesis, dysregulation of VEGF plays an important role in MM pathogenesis and clinical manifestations, including lytic lesions of the bone and immune deficiency. Inhibition of VEGF in MM may therefore target not only endothelial cells and MM cells, but also a broad array of cells contributing to MM pathogenesis.

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