The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment

Semaphorins are a large family of evolutionarily conserved morphogenetic molecules originally identified for their repelling role in axonal guidance. Intriguingly, semaphorins have recently been implicated in cancer progression (Neufeld, G., T. Lange, A. Varshavsky, and O. Kessler. 2007. Adv. Exp. Med. Biol. 600:118–131). In particular, semaphorin 3B (SEMA3B) is considered a putative tumor suppressor, and yet we found that it is expressed at high levels in many invasive and metastatic human cancers. By investigating experimental tumor models, we confirmed that SEMA3B expression inhibited tumor growth, whereas metastatic dissemination was surprisingly increased. We found that SEMA3B induced the production of interleukin (IL) 8 by tumor cells by activating the p38–mitogen-activated protein kinase pathway in a neuropilin 1–dependent manner. Silencing the expression of endogenous SEMA3B in tumor cells impaired IL-8 transcription. The release of IL-8, in turn, induced the recruitment of tumor-associated macrophages and metastatic dissemination to the lung, which could be rescued by blocking IL-8 with neutralizing antibodies. In conclusion, we report that SEMA3B exerts unexpected functions in cancer progression by fostering a prometastatic environment through elevated IL-8 secretion and recruitment of macrophages coupled to the suppression of tumor growth

Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models

The role of semaphorins in tumor progression is still poorly understood. In this study, we aimed at elucidating the regulatory role of semaphorin 3A (SEMA3A) in primary tumor growth and metastatic dissemination

Angiogenic growth factors : mechanism of action and function in vascular development

The mature vascular system is composed of a network of blood vessels organized into arteries, capillaries, and veins. The vessels are composed of endothelial cells surrounded by smooth muscle cells and embedded in a specialized basement membrane. The demand for oxygen during embryonal development regulates vessel formation through a process denoted vasculogenesis. These primitive vessels are further remodeled through proliferation, sprouting and migration of endothelial cells in a process denoted angiogenesis. Vasculogenesis and angiogenes are regulated by growth factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). To study vasculogenesis and angiogenesis, we employed differentiating embryonal stem cells (embryoid bodies). Vascularization of embryoid bodies follows a vascular pattern highly reminiscent of the in vivo pattern, leading to expression of a set of endothelial cell markers. Treatment of the embryoid bodies with different angiogenic growth factors led to distinct vascular morphologies. Expression of VEGF receptor-2 was an absolute demand for proper vascular development. PDGF-BB was shown to be potent in regulating vascular plexus formation in embryoid bodies. PDGF-BB induced capillary formation by promoting endothelial cell migration and differentiation. Hypoxia is a powerful inducer of angiogenic growth factors, such as VEGF-A, leading to angiogenesis. Hypoxia treatment induced an extensive vascular network that covered the entire embryoid body. Hypoxia-induced vascularization still occurred when VEGF receptor function was blocked, indicating that other pathway than VEGF/VEGF receptors may be critical for hypoxia-driven vessel formation. Heparan sulfated proteoglycans (HSPGs) are present in the vascular basement membrane and are known to modulate angiogenic growth factor effects on endothelial cells in normal and pathological conditions such as tumor growth and formation of metastases. We employed heparin as an HSPG equivalent to show that PDGF-BB stimulation of PDGF a-receptor phosphorylation was augmented by heparin, resulting in increased mitogen activated protein kinase (MAPK) and protein kinase B PKB/Akt activation, and enhanced cellular migration towards PDGF-BB