Increased evidence suggests that cancer-associated inflammation supports tumor growth and progression. We have previously shown that semaphorin 4D (Sema4D), a ligand produced by different cell types, is a proangiogenic molecule that acts by binding to its receptor, plexin B1, expressed on endothelial cells (Conrotto, P., D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. 2005. Blood. 105:4321–4329). The present work highlights the role of Sema4D produced by the tumor microenvironment on neoplastic angiogenesis. We show that in an environment lacking Sema4D, the ability of cancer cells to generate tumor masses and metastases is severely impaired. This condition can be explained by a defective vascularization inside the tumor. We demonstrate that tumor-associated macrophages (TAMs) are the main cells producing Sema4D within the tumor stroma and that their ability to produce Sema4D is critical for tumor angiogenesis and vessel maturation. This study helps to explain the protumoral role of inflammatory cells of the tumor stroma and leads to the identification of an angiogenic molecule that might be a novel therapeutic target.

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Mechanisms governing stress-induced hematopoietic progenitor cell mobilization are not fully deciphered. We report that during granulocyte colony-stimulating factor-induced mobilization c-Met expression and signaling are up-regulated on immature bone marrow progenitors. Interestingly, stromal cell-derived factor 1/CXC chemokine receptor-4 signaling induced hepatocyte growth factor production and IntroductionDuring steady state conditions, adhesive interactions between the bone marrow (BM) stromal cells and primitive hematopoietic cells mostly result in stem cell retention, in a noncycling and nonmotile mode. However, low levels of progenitor cells are continuously released from the BM to the blood circulation as part of homeostasis. This process is dramatically amplified during emergency situations because of damage and cell death, as part of host defense and repair, in response to stress signals, including cytokines such as granulocyte colony-stimulating factor (G-CSF). Repetitive G-CSF stimulations are commonly used in the clinic, mimicking emergency situations to harvest stem and progenitor cells from the circulation for transplantation protocols. 1,2 The BM reservoir of immature and maturing leukocytes is dynamic, replenishing the blood with new cells on demand. These dynamic changes are achieved through a complex interplay between the immune and nervous systems, the bones and the BM microenvironment, involving cytokines, chemokines, proteolytic enzymes, and adhesion molecules. 3 In particular, oscillations in BM levels of stromal cell-derived factor 1 (SDF-1; transiently increased and subsequently degraded) and CXC chemokine receptor-4 (CXCR4) activation play a crucial role in promoting progenitor cell egress. 4,5 The cytokine hepatocyte growth factor (HGF) and its receptor c-Met control complex biologic programs known as "invasive growth" and tumor spreading. 6 Reactive oxygen species (ROS) are constantly generated during intracellular metabolism and in response to cytokines. Although excess ROS can cause oxidative damage to DNA, moderate levels have important roles in cell signaling, regulating different physiologic and pathologic cellular processes, including cell-cycle progression, migration, and invasion. 7 Finally, redox signaling has emerged as an important regulator of hematopoietic stem cell (HSC) self-renewal and lifespan. 8,9 The Forkhead Box, class O (FOXO) family of Forkhead transcription factors is a regulator of oxidative stress. 10 Loss of FOXO function in HSCs results in increased ROS levels, defective maintenance of quiescence, and reduced long-term repopulating ability. 11,12 FOXOs are a direct substrate of the protein kinase Akt, a mammalian target of rapamycin inhibition (mTOR) target, 13 which inactivates them by phosphorylation. 14 In this study, we demonstrate that c-Met expression levels on immature and maturing leukocytes in the BM reservoir are dynamic and dramatically increased when urgent requirements for enhanced leukocyte production and recruitment emerge. Moreover, full c-Me...

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