Cancer and Tumor Angiogenesis

VEGF receptors obviously play a critical role in cancer because of their active regulation of angiogenesis and vascular permeability (see above reviews). There is also some evidence that they may have a more direct role in some cancers by regulating the proliferation or survival of the tumor cells. For example, VEGFr1/Flt1 has been reported to have the potential to transform cells when appropriately activated (Maru et al., 1998). In endothelial cells over-expressing VEGFr1/Flt1, PlGF binding has been shown to stimulate cell proliferation (Landgren et al., 1998). The specific ligands for VEGFr1/Flt1 (PlGF and VEGFB/VRF) also induce the secretion of urokinase plasminogen activator (uPA) from endothelial cells (Landgren, 1998; Olofsson et al., 1998). Activation of the uPA is considered to be important for the invasive growth and metastasis of tumor cells (Conese and Blasi, 1995; Schmitt et al., 1995). Thus, these observations suggest that aberrant expression and/or activation of VEGF receptors could contribute to neoplasia of cell types other than endothelial cells. At present, there is some evidence for a direct effect of VEGF on tumor cells derived from leukemias and Kaposi's sarcoma.

Leukemia

VEGFr2/Fli2/Flk1/KDR was reported to be expressed in hematopoietic stem cells, megakaryocytes, and platelets, and VEGF/VPF was shown to protect stem cells from apoptosis induced by gamma irradiation (Katoh et al., 1995). VEGF/VPF was also shown to synergize with some cytokines to suppress the proliferation of myeloid progenitor cells, suggesting that it may contribute to the regulation of hematopoiesis (Broxmeyer et al., 1995; 1996). VEGFr2/Flt2/ Flk1/KDR was also observed on some leukemic cell lines, and it was shown to protect at least one of these cell lines from irradiation-induced apoptosis (Katoh et al., 1995). In clinical samples, 60-70% of AML cell lines were shown to express VEGF/VPF, which may contribute to paracrine growth regulation by inducing endothelial cells to secrete GM-CSF (Fiedler et al., 1997). VEGFrl/Flil was also expressed by 50-60% of AML cells from patients, and 20-25% of them expressed VEGFr2/Flt2/Flk1/KDR (Fiedler et al., 1997). The observation of both ligand and receptor suggests the possibility that an autocrine loop may contribute to AML pathology; perhaps by protecting these cells from apoptosis.

Kaposi's Sarcoma

Kaposi's sarcoma (KS) is the most prevalent form of cancer associated with AIDS. Proliferation of KS spindle cells is accompanied by proliferation of endothelial cells, angiogenesis, and enhanced vascular permeability as a result of VEGF/VPF and FGF2/bFGF secretion from the KS spindle cells (Sama-niego et al., 1998). KS spindle cells also express VEGFr1/Flt1 and VEGFr2/ Flt2/Flk1/KDR (Masood et al., 1997; Samaniego et al. 1998), suggesting that they may have a functional autocrine loop. Antisense oligonucleotides appeared specifically to inhibit the proliferation of KS cells in culture as well as in vivo suggesting that VEGF/VPF may be an autocrine growth factor for these cells (Masood et al., 1997). However, this observation has not yet been confirmed, and at least one group has reported that the autocrine loop may not be functional (Samaniego et al., 1998). Thus, further studies are needed to determine if VEGF receptors contribute to the pathology of the KS cell.

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