Characterization and Regulation of Bv8 in Human Blood Cells

Abstract

Purpose: Bv8, also known as prokineticin 2, has been recently shown to be a mediator of myeloid cell^dependent tumor angiogenesis in mouse models. We wished to determine whether these findings might be potentially relevant to human disease. Experimental Design: We characterized Bv8 expression in human blood cells in vitro and in vivo, and did Bv8 immunohistochemistry in human tumor sections. We also partially purified Bv8 from human neutrophils and tested its bioactivity. Results: We found that Bv8 expression is regulated by several cytokines in a cell type^specific fashion. Both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor induced Bv8 expression in neutrophils and bone marrow cells, whereas interleukin 10 up-regulated Bv8 expression in monocytes and lymphocytes. Bv8 potently promoted neutrophil chemotaxis. Bv8 protein isolated from human neutrophils was found to be biologically active. Of the two receptors for Bv8 [prokineticin receptor 1(PKR1)/endocrine gland^derived vascular endothelial growth factor receptor 1 (EG-VEGFR1) and PKR2/EG-VEGFR2], only PKR2/EG-VEGFR2 was detectable in human neutrophils. Also, we found a marked up-regulation of Bv8 mRNA and protein in peripheral blood mononuclear cells from G-CSF^trea-ted donors compared with those from untreated individuals, verifying our in vitro observations. Finally, immunohistochemistry showed Bv8 expression in neutrophils infiltrating human tumors. Conclusions: These results provide the basis for further investigation of the pathophysiologic role of Bv8 in human tumors and inflammatory disorders and, potentially, for therapeutic application of Bv8 inhibitors.

The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis

“…Importantly, Bv8 upregulation in response to G-CSF (and GM-CSF) has been reported in human neutrophils (71). The immunohistochemical localization of Bv8 protein in human tumor-infiltrating neutrophils has also been reported (71). In a complementary fashion, neutrophils can also recruit Th17 cells to the inflammatory sites through secretion of CCL2 and CCL20 (72).…”

“…Blockade of IL17/IL17 receptor, G-CSF/G-CSF receptor, or Bv8-through genetic and pharmacologic approaches-inhibits intratumoral infiltration of neutrophils, tumor angiogenesis, and tumor growth (38,39,68). Importantly, Bv8 upregulation in response to G-CSF (and GM-CSF) has been reported in human neutrophils (71). The immunohistochemical localization of Bv8 protein in human tumor-infiltrating neutrophils has also been reported (71).…”

“…The clinical evidence supporting this notion, although still relatively limited, is growing (58,63,71). For example, in a study that investigated the role of inflammatory cells in predicting the clinical outcome in advanced nonsquamous non-small cell lung cancer patients treated with chemotherapy with or without bevacizumab, the authors found that a high number of circulating neutrophils and monocytes and a high neutrophil-to-lymphocyte ratio (NLR) are associated with poor clinical outcome only in patients treated with chemotherapy plus bevacizumab, but not in those treated with chemotherapy alone (75).…”

Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes

“…S12C). Bv8 has been shown to promote migration of myeloid cells (31). Therefore, we considered the possibility that Bv8 might also promote migration of metastatic tumor cells.…”

Immune and inflammatory gene expressions are different in Behçet’s disease compared to those in Familial Mediterranean Fever

“…PROK2 is a chemokine with five disulfide bonds and was shown to be expressed in inflamed tissues (17). It was observed that the secretion of PROK2 from lymphocytes stimulate IL-10 and this process causes an increase in angiogenesis (18). An increase in PROK2 may play a role in BD neoangiogenesis with a vascular pattern.…”