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The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, oedema and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. Recently, new insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumour lymphangiogenesis.Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies. This review highlights the recent insights and advances into the field of lymphatic vascular research, outlining the most important aspects of the embryo development, structure, specific markers and methods applied for studying lymphangiogenesis. Finally, molecular mechanisms involved in the regulation of lymphangiogenesis are described.

Inhibition by thalidomide is probably confined to the genes of active MMECs and KS. This would account for its higher efficacy in these diseases.

IntroductionMultiple myeloma (MM) remains an incurable disease, despite conventional and high-dose chemotherapies. 1 Molecules targeting not only plasma cells, but also the bone marrow (BM) microenvironment are needed to overcome drug resistance.Pathologic angiogenesis is a constant component of the MM microenvironment. 2 The vascular endothelial growth factor (VEGF)/ VEGF receptor-2 (VEGFR-2) pathway greatly contributes to MM angiogenesis and growth, 3 and mediates proliferation and capillarogenesis in MM endothelial cells (MMECs) through an autocrine loop. 4 VEGF 165 is the most abundant and effective isoform. 5 It binds simultaneously to its cognate receptors VEGFR-1 and VEGFR-2 and to the coreceptor neuropilin-1 (NRP1), a cellsurface glycoprotein expressed on axons in the developing nervous system as well. 6 NRP1 is the ligand-binding subunit of the receptor complex for class 3 semaphorins, a family of secreted proteins that mediate neuronal guidance. 7 Binding of secreted semaphorin 3A (SEMA3A) to NRP1 induces the collapse of neuronal growth cones 8 by activating the signal-transducing subunit(s) of the receptor complex, that is, class A plexins, a family of transmembrane proteins whose cytoplasmic domain is endowed with an R-Ras GAP activity that inhibits integrin function. 9 NRP1 is also expressed on ECs, 10 where it acts as an isoform-specific receptor for VEGF 165 , and enhances by 4-to 6-fold its affinity for VEGFR-2, as well as VEGF 165 -induced cell chemotaxis and proliferation. 11 By competing with VEGF 165 for binding to NRP1 12 and by activating class A plexins, 13 SEMA3A inhibits integrinbased EC adhesion and migration and capillary sprouting. Autocrine loops of endothelial SEMA3A play a self-limiting role in angiogenesis and regulate EC behavior during its physiologic development. 13 Here we analyze the expression levels of VEGF 165 , SEMA3A, and their receptors NRP1 and plexin-A1 in BM ECs isolated from patients with MM and MGUS (MMECs and MGECs), and from the human umbilical vein (HUVECs). We show that overangiogenic MMECs display a high VEGF 165 /SEMA3A ratio and behave like MGECs and HUVECs upon exposure to exogenous SEMA3A, which seems as effective as an anti-VEGFR-2 antibody. Our observations point to SEMA3A as a potential antiangiogenic Patients, materials, and methods PatientsThirty-two patients fulfilling the International Myeloma Working Group diagnostic criteria 14 for MM (n ϭ 18) and MGUS (n ϭ 14) were studied at diagnosis. The MM patients (12 male, 6 female) were aged 44 to 81 years (median 68.5 years) and staged 15 as IIA (n ϭ 4), IIB (n ϭ 2), IIIA (n ϭ 10), and IIIB (n ϭ 2); the M-component was IgG (n ϭ 12), IgA (n ϭ 4), and or (n ϭ 2). The MGUS patients (8 male, 6 female) were aged 42 to 79 years (median 70.6 years) and were IgG (n ϭ 10) or IgA (n ϭ 4). The study was approved by the local ethics committee of the University of Bari Medical School, Italy, and all patients gave their informed consent in accordance with the Declaration of Helsinki. Separation and culture of ECs and...

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Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma. [Mol Cancer Ther 2007;6(12):3256-62]

The growth of solid tumors is certainly angiogenesis dependent. However, the role of angiogenesis in the growth and survival of leukemias and other hematological malignancies has only been rendered evident since 1994 in a series of demonstrations showing that the progression of several forms is clearly related to their degree of angiogenesis. Here, we present an overview of the literature concerning the relationship between angiogenesis and disease progression in several hematological malignancies and the recent advances in antiangiogenesis in these diseases and we describe the most important active substances, preclinical and clinical data, and future perspectives.