Soluble Molecules 41 Vascular Endothelial Growth Factor and Angiogenesis

In the last few years, a considerable amount of work has been dedicated to elucidating the relationship between angiogenesis and tumor growth. It has been established that the expansion and dissemination of primary solid tumors is supported by the ability of tumor cells to generate vascularization intimately connected to the tumor (133,134). The release of pro-angiogenic vascular factors is essential in this process. Although the role of angiogenesis in hematopoietic malignancies is less clear, several recent observations have suggested that the release of angio-genic growth factors and abnormal angiogenesis may be intimately related to the leukemic process (135-137).

In CLL, there is growing experimental evidence that various angiogenic molecules and receptors may be linked to the pathogenesis of the disease. The expression of vascular factors and their receptors by leukemic CLL B-cells could be essential to induce the tumor vasculature required for disease progression in the bone marrow and in secondary lymphoid tissues. Even more intriguing is the question of whether it could also result in the generation of autocrine or paracrine loops that directly modulate the biology of the leukemic clone, through modifications of CLL cell survival or acquisition of drug resistance.

An abnormal angiogenesis, with increased microvessel density compared with normal controls, has been described in the bone marrow of CLL patients (138). A recent study also demonstrated a high blood vessel density in lymph nodes infiltrated by CLL cells, and this abnormal vasculature was reported to be intimately connected to the leukemic CLL infiltration (139). In the same report, CLL B-cells were reported to be capable of inducing the proliferation of endothelial cells and of enhancing angiogenesis in vitro. Thus, in CLL, the leukemic clone appears to be able to induce the genesis of the blood vessels required to supply oxygen and nutrients to the tumor tissue, through the secretion of vascular growth factors.

Among the several molecules with angiogenic or endothelial cell-activating properties, vascular endothelial growth factor (VEGF) is considered one of the most relevant, and many studies on the role of angiogenesis in CLL have chosen to focus on this molecule (Fig. 3). VEGF is a multifunctional protein that, upon binding to its receptors on endothelial cells, affects vascular permeability and cell proliferation, migration, and survival, all of which are required for angio-genesis (140,141). Serum levels of VEGF have been reported to be abnormally elevated in CLL, with higher values more frequently detected in advanced clinical stage patients and capable of predicting the risk of disease progression in early CLL (142). VEGF is produced by the leukemic B-cells (139,143), which also express the VEGF-specific receptors Flt1 and Tie1 (144). Recently, peripheral blood CLL cells were also found to express higher than normal levels of another VEGF receptor, VEGFR-2, also termed KDR (145). These findings are interesting in that they raise the question of a possible autocrine VEGF pathway, with several biological implications for CLL cell survival and proliferation. In fact, higher levels of Tie1 and KDR were both found to be associated with a significantly shorter survival in CLL patients, suggesting a possible role in the proliferation of leukemic CLL cells (144,145).

Endothelial cells are capable of secreting several CSFs in response to cytokines such as IL-1 (146). In the study of Bellamy et al. (147), human endothelial cells exposed to VEGF were found to be capable of increasing the message for a number of hematopoietic growth factors, including G-CSF, M-CSF, IL-6, and stem cell factor (SCF). The role of some of these cytokines in the pathogenesis and clinical course of CLL has already been discussed. Thus, it is possible that endothelial cells may, in response to angiogenic factors, release cytokines capable of influencing the growth and survival of the leukemic CLL clone. The possible autocrine and paracrine pathways associated with the release of vascular growth factors in CLL need to be elucidated by future studies, as does the possibility that modulation of vascular growth factor synthesis could be helpful in the management of these patients.

AUTOCRINE LOOP?

Fig. 3. Vascular endothelium-derived growth factor (VEGF): role in CLL-induced neo-angiogenesis and CLL cell survival. VEGF released by CLL neoplastic cells can induce the proliferation of endothelial cells and enhance angiogenesis in vivo. In addition, it might be involved in autocrine and paracrine loops: CLL cells express surface receptors for VEGF itself and for several VEGF-induced cytokines released by endothelial cells. G-CSF, granulocyte colony-stimulating factor; IL-6, interleukin-6; M-CSF, macrophage colony-stimulating factor.

ENDOTHELIAL CELLS

AUTOCRINE LOOP?

Fig. 3. Vascular endothelium-derived growth factor (VEGF): role in CLL-induced neo-angiogenesis and CLL cell survival. VEGF released by CLL neoplastic cells can induce the proliferation of endothelial cells and enhance angiogenesis in vivo. In addition, it might be involved in autocrine and paracrine loops: CLL cells express surface receptors for VEGF itself and for several VEGF-induced cytokines released by endothelial cells. G-CSF, granulocyte colony-stimulating factor; IL-6, interleukin-6; M-CSF, macrophage colony-stimulating factor.

The importance of the mechanisms regulating lymphocyte trafficking and adhesion in the pathogenesis of CLL is underlined by well-known clinical observations (in patients with CLL, the marrow is invariably infiltrated with leukemia cells, and the extent of marrow infiltration correlates with clinical stage and prognosis) (148,149), as well as by more recent experimental data. The results of a study in which cDNA microarrays were employed to compare gene expression profiles with clinical features in CLL have been recently published. The authors were able to identify genes whose expression levels correlated significantly with patient survival and/or with clinical staging. Surprisingly, most of these genes coded either for cell adhesion molecules or for factors inducing cell adhesion molecules, suggesting that prognosis of this disease may be related to a defect in lymphocyte trafficking (59).

The superfamily of chemokines consists of an array of chemoattractant proteins capable of regulating the trafficking of immune cells during hematopoiesis and inflammatory responses. In addition, they also stimulate leukocyte degranulation, have a pivotal role in the signaling of integrin activation, and promote angiogenesis or angiostasis (150,151). Evidence is increasing that through binding to their specific membrane receptors, chemokines may regulate many aspects of immune responses, in part because cell migration is intimately related to lymphocyte function (152,153). Like to their normal counterparts, it is conceivable that the functional behavior of CLL B-cells may be influenced by chemokine and chemokine receptor expression.

Most of the recent studies investigating the relationship between chemokines and CLL have focused on the mechanisms of extravasation of leukemic cells and of bone marrow infiltration.

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