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Cancer Immunology at the Crossroads: Tumor Microenvironment
The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis
Wei Liang and Napoleone Ferrara
Wei Liang
Moores Cancer Center and Department of Pathology, University of California San Diego, La Jolla, California.
Napoleone Ferrara
For correspondence: nferrara@ucsd.edu
DOI: 10.1158/2326-6066.CIR-15-0313 Published February 2016
Chronic inflammation fosters cancer development and progression and also modulates tumor responses to anticancer therapies. Neutrophils are key effector cells in innate immunity and are known to play a critical role in various inflammatory disorders. However, the functions of neutrophils in cancer pathogenesis have been largely neglected until recently and still remain poorly characterized compared with other immune cells in the tumor microenvironment. We highlight recent findings on the mechanisms by which tumor cells, in cooperation with tumor-associated stromal cells, induce expansion, recruitment, and polarization of neutrophils. We also review the multifaceted roles that neutrophils play in different aspects of cancer development and progression, with an emphasis on tumor angiogenesis and metastasis. Cancer Immunol Res; 4(2); 83–91. ©2016 AACR.
Neutrophils are the most abundant white blood cells (WBC) in the human circulatory system and constitute an important part of the first-line defense against infection (1). Neutrophils are constantly generated through granulopoiesis in the bone marrow and are mobilized in the peripheral circulation to patrol for invading pathogens (1). Chemokines produced at the infection/inflammatory sites attract neutrophils, where they exert anti-infection/proinflammatory functions, such as phagocytosis of pathogens; release of antimicrobial products, including reactive oxygen species (ROS), antibacterial peptides, enzymes, and neutrophil extracellular traps (NET); and production of cytokines and chemokines to recruit other immune cells (1, 2).
Inflammation has been long recognized as a key aspect of cancer development, which can fuel both primary tumor growth and metastasis (3). Therefore, it is not surprising that neutrophils, a key inflammatory cell type, can be mobilized and recruited to tumors. In fact, aberrant accumulation of neutrophils has been documented in a wide variety of tumors and is often associated with poor clinical outcomes (4–11). Emerging evidence also suggests that neutrophils, in response to signals derived from cancer cells or stromal cells, can alter their phenotypes and migration routes and also release factors that act on tumor cells and other cell types (e.g., endothelial cells and immune cells), which we review in the following sections.
Deregulation of Neutrophils by the Tumor Microenvironment
The induction of granulopoiesis, a cascade of cellular events that lead to neutrophil production, is mainly regulated by granulocyte colony-stimulating factor (G-CSF) and its receptor, G-CSFR (12). G-CSF is a ∼25 kDa secreted glycoprotein encoded by the csf3 gene (13). It is produced by endothelial cells, fibroblasts, monocytes, and macrophages in response to Toll-like receptor ligands and various proinflammatory cytokines (13, 14). G-CSF binds to its receptor, expressed in neutrophils and in neutrophil progenitor cells, and activates the downstream Janus kinase (JAK)/signal transducer and activator of the transcription 3 (Stat3) pathway (15), an essential signaling pathway for cancer inflammation (16). Activation of the JAK/Stat3 signaling pathway leads to expression of genes that are required for granulopoiesis (e.g., MYC, CEBPB; ref. 17). As a result, G-CSF promotes commitment to granulocyte development, neutrophil progenitor cell proliferation, and survival of mature neutrophils (13, 14). In addition, G-CSF facilitates release of neutrophils and hematopoietic progenitor cells from the bone marrow through downregulation of the CXC-chemokine ligand 12 (CXCL12)/CXC-chemokine receptor 4 (CXCR4) axis that mediates retention/homing of neutrophils to the bone marrow (18). G-CSFR is a member of the type-1 cytokine receptor family encoded by the CSF3R gene (13). It contains a conserved cytokine receptor homologous (CRH) domain, an Ig-like domain, and three fibronectin type III–like domains in the extracellular region; a single transmembrane region; and an intracellular region without intrinsic catalytic activity (19, 20). Upon G-CSF binding, G-CSFR forms a "cross-over," 2:2 ligand:receptor complex, in which each G-CSF molecule binds to both receptors (19, 21). Expression of G-CSFR has been detected in both hematopoietic and nonhematopoietic cell types, including the placenta, neurons, endothelial cells, cardiomyocytes, and cancer cells (22). In the hematopoietic system, G-CSFR is predominantly expressed in myeloid lineage cells such as myeloid progenitor cells, granulocytes, and monocytes (22).
Mice deficient in G-CSF (23) or G-CSFR (24) manifest severe neutropenia under basal and stressed conditions (e.g., bacterial infection; ref. 25). Administration of exogenous G-CSF remains the most efficient method to induce granulopoiesis and mobilization of hematopoietic progenitor cells in humans and animals (14). Other factors, including GM-CSF, IL6, and thrombopoietin, can also contribute to granulopoiesis, although to a lesser extent than G-CSF. Knockout mice for GM-CSF (26), IL6 (27), or thrombopoietin (28) have been examined and, in contrast to G-CSF−/− (23) or G-CSFR−/− (24) mice, appear to have normal neutrophil numbers in the blood. However, mice lacking both G-CSF (or its receptor) and GM-CSF (26), IL6 (29), or thrombopoietin (ref. 28; double knockout) display more severe neutropenia than mice lacking only G-CSF (or its receptor). It is noteworthy that mice lacking all three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) can still generate macrophages and granulocytes, albeit at substantially reduced levels (30).
Elevated G-CSF, as well as GM-CSF or IL6, have been documented in human and mouse cancers and are often associated with paraneoplastic "leukemoid reactions" (PLR), characterized by high WBC counts of more than 50,000/μL (in humans), with neutrophils being the predominant cell type (16, 31–36). PLR can occur in 10% to 15% of cancer patients and are strongly predictive of poor clinical outcomes (33, 34). We have previously reported that activation of the oncogenic RAS/MEK/ERK pathway induces expression of G-CSF from tumor cells through the Ets transcription factor (37). Blockade of G-CSF release through MEK inhibition, antibody-mediated G-CSF neutralization, or targeted inactivation of the G-CSF receptor in mice, resulted in suppression of aberrant neutrophil accumulation and inhibition of tumor angiogenesis and metastasis (35, 37–39). The significance of tumor-derived GM-CSF or IL6 on neutrophil homeostasis in malignancies has been less extensively characterized. However, it has been shown that augmented expression levels of GM-CSF and IL6 in tumor-bearing mice are associated with increased myeloid-derived suppressor cells (MDSC), a heterogeneous population of monocytic and granulocytic myeloid cells that promotes cancer progression through various mechanisms (40, 41).
Mechanisms of neutrophil recruitment to the inflamed tissues have been reviewed in detail elsewhere (1, 2) and are not discussed here. Of interest, tumors do share some basic chemotaxis mechanisms that regulate recruitment of neutrophil to inflammatory sites. For example, tumor cells and stromal cells in the tumor microenvironment secrete chemokines such as CXCL1, CXCL2, CXCL5, and CXCL8 to attract neutrophils (reviewed in refs. 42, 43). G-CSF induces expression of Bv8/prokineticin-2, a protein that induces angiogenesis, and also facilitates recruitment of CD11b+Ly6Ghi neutrophils in both primary tumors and the metastatic sites (35, 38, 39). Once neutrophils arrive at tumor sites, they can be instructed by tumor-derived factors to "tune up" their tumor-supporting functions. One characteristic feature of advanced solid tumors is hypoxia. In fact, hypoxia promotes HIF-1α–dependent neutrophil survival (44, 45) but impairs the respiratory burst activity in human neutrophils (46). In addition, it has been reported that blockade of TGFβ in the tumor microenvironment drives neutrophil polarization from a protumoral "N2" phenotype to an antitumoral "N1" phenotype characterized by enhanced cytotoxic and immunostimulatory activities (47).
Tumor-Supporting Functions of Neutrophils
Growing evidence supports a protumoral role of neutrophils. In this section, we review the protumoral functions of neutrophils on tumor cells and tumor-associated stromal cells at primary tumors and metastatic sites.
Tumorigenesis, tumor cell proliferation, and survival
Neutrophils can directly act on premalignant epithelial cells to accelerate tumorigenesis. Work by Coussens and colleagues has shown that matrix metalloproteinase 9 (MMP9), supplied by bone marrow–derived cells, contributes to skin carcinogenesis (48). Among various cell types in the tumor microenvironment, neutrophils are a rich source of MMP9, yet lack expression of tissue inhibitor of metalloproteinases (TIMP), the endogenous inhibitors of MMP9. This renders neutrophil-derived MMP9 more prone to activation and participation in protumoral functions (49). Neutrophils produce ROS (through the action of myeloperoxidase and NADPH oxidase), which is known to cause DNA damage, genome instability, and gene mutation in premalignant epithelial cells and drives oncogenic transformation (50, 51). Together, these observations suggest that neutrophils recruited to chronic inflammation sites may foster tumorigenesis through multiple mechanisms.
During tumor progression, neutrophils release factors that stimulate tumor cell proliferation (Fig. 1). Neutrophil elastase (ELA2) can enter tumor cells, activate phosphoinositide 3-kinase (PI3K) through degradation of its negative regulator insulin receptor substrate-1 (IRS-1), and promote tumor cell proliferation (52). Moreover, breast cancer cells can induce neutrophils to produce oncostatin M (53), a factor known to stimulate tumor cell proliferation through activation of Stat3 (16). A recent study also shows that carcinoma-derived CXCL1/2 facilitates recruitment of S100A8/9-positive granulocytes, which induced tumor cell survival, metastasis, and resistance to chemotherapy (54).
Schematic overview of the tumor-supporting functions of neutrophils. Tumor- or stroma-derived G-CSF stimulates neutrophil production in the bone marrow and subsequent release in the circulation. Circulating neutrophils, recruited into the tumor by various chemokines, locally produce factors (e.g., ELA2, OSM, and S100A8/9) that promote tumor cell proliferation, survival, and resistance to chemotherapy. Neutrophil-derived ROS can induce DNA damage in premalignant cells that facilitates oncogenic transformation. Neutrophils then support tumors through stimulation of tumor angiogenesis by releasing proangiogenic factors such as VEGF and Bv8. Neutrophils are a rich source of proteolytic enzymes, including MMPs and serine proteases, which can break down the extracellular matrix (ECM) and release the bioactive forms of growth factors and proangiogenic molecules. Additionally, neutrophils can secrete factors that induce local immunosuppression by impairing T-cell responses, inducing T-cell death, and recruiting regulatory T cells, which permits tumor development and progression. Other immune cells in turn produce factors such as IL17 derived from Th17 and γδ T cells that augment G-CSF levels and tumor-induced neutrophilia. ELA2, neutrophil elastase; OSM, oncostatin M.
Angiogenic properties of tumor-associated neutrophils
Angiogenesis is the formation of new blood vessels and involves proliferation, migration, and differentiation of endothelial cells (55). Angiogenesis is a critical step during cancer development, and it has become clear that not only tumor cells but also stromal cells in the tumor microenvironment can supply proangiogenic factors. Tumor-infiltrating neutrophils can mediate the angiogenic switch in a transgenic mouse tumor model (56). Also, tumors grow faster, become highly vascularized, and are more infiltrated by neutrophils in IFNβ-deficient mice compared with the wild-type mice; depletion of neutrophils eliminates the enhanced tumor growth and angiogenesis in IFNβ-deficient mice (57). In myxofibrosarcoma patients, elevated numbers of neutrophils positively correlated with tumor microvessel density (58). Moreover, intratumoral infiltration of neutrophils is significantly correlated with tumor grade in glioma patients (11, 59) and with acquired resistance to anti-VEGF therapy in tumor-bearing mice (59).
Vascular endothelial growth factor (VEGF)-A is a potent angiogenic factor and a validated therapeutic target for blocking tumor as well as intraocular angiogenesis (60). Tumor-associated neutrophils contain a large intracellular pool of VEGF that can be rapidly released upon stimulation (61). Moreover, de novo synthesis of VEGF mRNA has been reported in tumor-associated neutrophils, in spite of the low gene transcription in mature neutrophils (62). Accordingly, elevated amounts of VEGF are found in neutrophils isolated from the oral cavity of cancer patients compared with control subjects, and VEGF amounts in neutrophils are positively associated with disease stages (63).
MMP9 is a proteolytic enzyme that cleaves substrates within, and remodels, the extracellular matrix (ECM), facilitating endothelial cell movement. Moreover, the proteolytic activity of MMP9 releases VEGF and other growth factors that had been sequestered in an inactive form in the ECM (reviewed in refs. 64, 65). When neutrophils secrete TIMP-free MMP9, it liberates bioactive fibroblast growth factor-2 and VEGF from the ECM and induces tumor angiogenesis. Involvement of neutrophils in angiogenic switches has been illustrated in the RIP1-Tag2 transgenic pancreatic neuroendocrine mouse model by counting the number of islets undergoing angiogenesis under different conditions. When neutrophils are depleted by administration of antibodies to Gr1 (a marker on the neutrophil cell surface), the association of VEGF with its receptor is reduced, as is the number of islets undergoing angiogenesis (56). Interestingly, a recent study shows that MMP9-positive neutrophils can compensate for the loss of macrophages in tumor-bearing CCR2-null mice by supporting tumor angiogenesis and progression (66).
In an effort to identify molecular and cellular mechanisms mediating tumor refractoriness to anti-VEGF therapy, we discovered that tumor infiltration by CD11b+Gr1+ myeloid cells results in reduced responsiveness to anti-VEGF antibodies, as compared with tumor models with little or no CD11b+Gr1+ cell infiltration (67). Interestingly, a similar tumor responsiveness to anti-VEGF treatment was observed in both immunocompetent and XID mice, indicating that these effects of CD11b+Gr1+ cells do not require B-cell or T-cell function (67). Further studies identified G-CSF produced by tumor or stromal cells as a critical mediator of accumulation of CD11b+Gr1+ cells and consequent tumor refractoriness to anti-VEGF therapy (38, 39).
G-CSF is also induced when tumor-infiltrating T helper type 17 (Th17) cells secrete IL17, which in turn leads to expansion, mobilization, and tumor recruitment of myeloid cells (mostly neutrophils; ref. 68). Upon stimulation with G-CSF, neutrophils upregulate expression of Bv8/prokineticin-2 through activation of the Stat3 pathway (69–71). As noted, Bv8 stimulates endothelial cell proliferation, survival, and migration (39) and also functions as a chemoattractant for neutrophils and, in some cases, for metastatic tumor cells (35). 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). In a complementary fashion, neutrophils can also recruit Th17 cells to the inflammatory sites through secretion of CCL2 and CCL20 (72). Collectively, these results suggest that neutrophils and Th17 cells can cross-talk and work in concert to induce, among other effects, tumor resistance to antiangiogenic therapy.
Besides VEGF, MMP9, and Bv8, recent work in the field has extended the list of neutrophil-derived factors that are known to sustain tumor angiogenesis. These factors include but are not limited to chemokines and cytokines (e.g., CXCL1, CXCL8, IL1β, and IL6), oncostatin M, and urokinase-type plasminogen activator (uPA; reviewed in refs. 73, 74). Nevertheless, whether and how these factors contribute to neutrophil-mediated tumor angiogenesis remains to be determined.
The results generated in various preclinical models strongly suggest a role for neutrophils in mediating tumor angiogenesis and refractoriness to anti-VEGF therapy. 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). The same group also reported that a low baseline NLR was associated with the longest progression-free survival (PFS) in colorectal cancer patients receiving bevacizumab as a first-line therapy (76). Also, in patients with metastatic renal cell carcinoma treated with the VEGFR tyrosine kinase inhibitor sunitinib, a low NLR (NLR ≤ 3) before treatment was associated with better response rate, longer PFS, and overall survival (OS; ref. 77). Although these findings are consistent with the important roles of neutrophils in mediating tumor angiogenesis and resistance to anti-VEGF therapy (Fig. 1), more studies are clearly needed to address the following concerns: (i) the direct involvement of neutrophils in triggering angiogenesis in human tumors; (ii) the role of neutrophils in predicting the clinical outcomes in patients receiving anti-VEGF therapies; and (iii) whether blockade of the proangiogenic function of neutrophils in cancer patients can reverse resistance to anti-VEGF therapy.
Neutrophils as negative regulators of anticancer immunity
Although a comprehensive review of neutrophil immunology is beyond the scope of this article, we want to emphasize that neutrophils can initiate and engage in complex cross-talk with other immune cells throughout their development and activation. Such cross-talk can reciprocally modulate the phenotypes of neutrophils and other immune cells and thus control inflammation and immune responses under physiologic and pathologic conditions.
It is well established that tumor cells often induce an immunosuppressive microenvironment through impaired antigen presentation, release of immunosuppressive factors, induction of immunologic tolerance and recruitment of immune cells equipped with tumor-supporting machineries (78). In this context, multiple mechanisms have been proposed for the immunosuppressive features of neutrophils and granulocytic MDSCs, a heterogeneous cell population that shares remarkable features including surface markers, cell morphology, and function with tumor-associated neutrophils (79). For instance, tumor-infiltrating neutrophils produce TGFβ (80), an immunosuppressive cytokine with diverse effects on multiple lineages of immune cells.
Peripheral blood polymorphonuclear leukocytes isolated from patients with hepatocellular carcinoma release significantly more CCL2 compared with healthy subjects. This CCL2 inhibits peripheral blood mononuclear cell (PBMC) production of IFNγ, an inhibition that is abolished by antibodies that block CCL2 (81). Neutrophils also exert their immunosuppressive function through production of arginase (ARG1; ref. 82) and ROS. Arginase depletes arginine from the surrounding environment, leading to inhibition of T-cell proliferation and function (83). ROS can suppress T-cell activation and, at high concentrations, induce apoptosis in T cells (84). In addition, tumor-associated neutrophils recruit immunosuppressive regulatory T cells (Treg) into tumors through secretion of CCL17 (85). In summary, the immunosuppressive environment fostered by neutrophils facilitates tumor growth and metastasis (Fig. 1).
Neutrophils in premetastatic and metastatic microenvironments
Metastasis remains the leading cause of death for patients with cancer. The multistep process of metastasis involves tumor cell migration, invasion, and escape from primary tumor sites, survival in circulation, extravasation and seeding at secondary sites, overcoming dormancy, and initiation of metastatic outgrowth. Meanwhile, tumor cells need to be protected from attack by the host's immune system throughout the process. Emerging evidence suggests that neutrophils, in response to tumor-derived stimuli, contribute to most if not all of these steps during cancer metastasis. In this section, we highlight recent findings on the input of neutrophils to different phases of cancer metastasis.
Neutrophils produce a variety of proteins that can stimulate tumor cell migration and invasion. For example, neutrophils maintain a large intracellular pool of serine proteases and MMPs (reviewed in refs. 73, 74) that can be released upon activation, which can facilitate tumor cell migration and invasion through remodeling ECM and increasing the bioavailability of (pro-migration and pro-invasion) signaling molecules. Alveolar neutrophils secrete hepatocyte growth factor (HGF), which induces human lung cancer cell migration (86). Moreover, some neutrophil-derived proteins are known to trigger epithelial–mesenchymal transition (EMT) of tumor cells. EMT is a developmental program that allows stationary epithelial cells to lose tight cell–cell junction and obtain the ability to migrate and invade during development (87). Tumor cells are known to use this strategy to increase cell motility, invasiveness, and their ability to break/remodel basement membrane and ECM (87). EMT can also prevent circulating tumor cells from dying and facilitate extravasation and seeding at the secondary sites (87). Tumor-infiltrating neutrophils produce among other factors TGFβ (80), a primary inducer of EMT through upregulation of Snail1/2, Zeb1/2, and Twist1 (87). Neutrophil-derived TGFβ has been shown to induce EMT in lung adenocarcinoma cells (88), and a recent study suggests that neutrophil elastase can contribute to EMT by degradation of E-cadherin in tumor cells (89). Neutrophils isolated from inflammatory disorders express TNFα upon stimulation (90), which has also been shown to promote EMT (91).
Neutrophils in the peripheral circulation can also facilitate cancer metastasis by inducing cancer cells to adhere to endothelial cells at the extravasation sites. Circulating human melanoma cells secrete IL8, a neutrophil chemoattractant that also induces expression of β2 integrin (Mac-1) on neutrophils, which increases the binding of melanoma cells to neutrophils and endothelial cells, leading to increased metastasis (92). Another study suggests that neutrophils promote adhesion of lung cancer cells to liver sinusoids and liver metastasis and this effect is partially reversed by Mac-1 or ICAM-1 blockade (93). In addition, Cools-Lartigue and colleagues reported that neutrophil-released neutrophil extracellular traps (NET) can contribute to cancer metastasis (94). NETs are neutrophil-derived structures composed of DNA, chromatin, and granule proteins and represent a host defense mechanism by trapping and killing microorganisms (95). Circulating tumor cells become trapped within NETs, and NET trapping increases formation of liver metastasis (94). Inhibition of NET with DNase or a neutrophil elastase inhibitor impedes metastasis development (94).
A recent revisitation of Paget's classic "seed and soil" hypothesis (96) is the "premetastatic niche" (97). Lyden and colleagues reported that VEGFR1+ hematopoietic progenitor cells are recruited to the premetastatic sites and form cellular clusters before the arrival of tumor cells (97). These VEGFR1+ cells can then promote adherence and growth of metastatic tumor cells, possibly through production of MMP9 and CXCL12 (97). Our work has suggested that neutrophils, rather than VEGFR1+ cells, are the major cell type mobilized by signals derived from primary tumors (e.g., G-CSF) and recruited to metastatic sites such as lung and liver, to promote a permissive environment (35). We found that, at the metastatic sites, neutrophils express a spectrum of genes, Bv8 and S100A8 being among the most upregulated. As noted, Bv8 facilitates further recruitment of neutrophils and seeding of metastatic tumor cells (35). Accordingly, treatment with antibodies to G-CSF or Bv8 reduces aberrant accumulation of neutrophils at premetastatic organs and significantly inhibits lung metastasis (35).
It is noteworthy that several studies have confirmed and further explored the role of neutrophils in fostering metastatic niches and establishing cancer metastasis. The study by Casbon and others confirmed the presence of neutrophils in premetastatic lung tissue and found that prolonged exposure of G-CSF expanded T-cell–suppressive neutrophils, resulting in increased cancer metastasis (98). A recent study by Coffelt and colleagues found that expression of IL17 from γδ T cells induced expansion and polarization of neutrophils in mice bearing metastatic tumors (99). Tumor-induced neutrophils facilitated cancer metastasis by suppressing CD8+ cytotoxic T-cell proliferation and activation (99). This effect was dependent on the IL17/G-CSF axis as neutralization of IL17 or G-CSF prevented neutrophil accumulation, relieved cytotoxic T cells from neutrophil-mediated immunosuppression, and inhibited cancer metastasis (99).
On the other hand, mice deficient in type I IFN signaling (IFNαR1−/−) have a higher rate of metastasis after tumor implantation compared with wild-type mice (100). This effect is associated with increased G-CSF, neutrophil accumulation, and expression of prometastatic proteins like Bv8, MMP9, S100A8, and S100A9 at the metastatic sites (100). Type I IFN signaling is negatively correlated with IL17 signaling in T cells (101). It is conceivable that in IFNαR1−/− mice, IL17 signaling becomes hyperactivated, leading to G-CSF–mediated expansion and mobilization of neutrophils, as observed in this study. As mentioned previously, granulocytic myeloid cells can be recruited to the metastatic sites by tumor-derived CXCL1/2 and secrete S100A8/9, supporting metastatic tumor cell survival and chemoresistance (54). Furthermore, blockade of colony-stimulating factor-1 (CSF-1) or its receptor (CSFR1) can lead to increased lung metastasis associated with enhanced serum G-CSF, increased frequency of neutrophils at primary tumors, and metastasis to the (102). Administration of neutralizing antibodies against G-CSF receptor prevents neutrophil accumulation and metastasis promoted by blockade of CSF-1/CSF-1R (102). Additionally, a recent study confirmed the involvement of neutrophils in establishing the premetastatic lung microenvironment and indicated that neutrophil-derived leukotrienes can support colonization of metastatic tumor cells by selectively expanding a sub-pool of cancer cells with high tumorigenic potential (103). These findings are consistent with previous observations that antagonists of the leukotriene generating enzyme (104), or inhibition of leukotriene receptor (105), can suppress tumor metastasis. In summary, these findings are consistent with the hypothesis that tumor-associated neutrophils can promote cancer metastasis through multiple mechanisms that include induction of EMT and tumor cell migration and invasion, assisting extravasation, and creating the metastatic niche and the immunosuppressive microenvironment (Fig. 2).
Neutrophils promote tumor metastasis. At primary tumor sites, neutrophils secrete factors that can induce EMT of tumor cells and support their migration machinery. MMPs produced by neutrophils can break down and remodel the ECM, which in turn facilitates tumor cell migration, invasion, and intravasation. In the peripheral circulation, neutrophils may support adhesion and retention of circulating tumor cells (to the endothelium at the metastatic target sites) through multiple mechanisms. For example, NETs produced by neutrophils can entrap circulating tumor cells and induce extravasation. In addition, neutrophils can facilitate cancer metastasis by suppressing the cytotoxic T-cell–mediated immune surveillance against metastatic tumor cells. At the distant metastatic sites (e.g., lung), neutrophils, along with other bone marrow–derived cells, arrive before tumor cells and constitute the "premetastatic niche" by releasing factors such as MMP9, S100A8/9, Bv8, and leukotrienes that promote colonization, migration, and outgrowth of metastatic tumor cells.
Antitumor Effects of Neutrophils
While tumor promotion seems to be the predominant outcome of the interaction between neutrophils and tumor/stromal cells, several studies have reported antitumor functions of neutrophils. For instance, it was suggested that neutrophils can directly inhibit tumor cell proliferation and survival through production of TRAIL, a TNF superfamily member that binds to its receptor in tumor cells and induces apoptosis (106). Also, "tumor-entrained" neutrophils have been reported to have antitumor and antimetastatic effects, based on the observation that antibody-mediated depletion of neutrophils in 4T1 and MMTV-PyMT mouse tumor models results in enhancement of metastasis (107). These findings, while intriguing, are contradicted by several reports (see above; refs. 35, 98, 103), showing that, in similar tumor models, tumor-associated neutrophils have clear prometastasis functions. In a different setting, the cMet proto-oncogene is expressed in neutrophils and required for chemoattraction and nitric oxide–dependent cytotoxicity of antitumoral neutrophils (108). As a result, cMet deletion in neutrophils stimulates tumor growth and metastasis (108).
Neutrophils are essential for development, survival, and activation of other immune cells under basal condition and during induction of immune responses against invading pathogens (reviewed in refs. 1, 2). It has been shown that blockade of TGFβ polarized the protumoral, immunosuppressive "N2" neutrophils to the antitumor, immunostimulatory "N1" neutrophils (47). It remains unclear, however, whether tumor-associated neutrophils are involved in the development of anticancer immunity without any therapeutic intervention. Previous published results (47, 98, 99) suggest that it is a strong possibility that tumor-associated neutrophils are primarily immunosuppressive, due to chronic exposure to tumor-derived signals, and can be polarized to be immunostimulatory through inhibition of the immunosuppressive signals (e.g., TGFβ).
Potential Strategies to Inhibit Neutrophils
The tumor-promoting actions of neutrophils provide a rationale for the development of therapies that target such cells. However, approaches that eliminate the whole neutrophil population are expected to have major adverse effects because neutrophils constitute a vital defense mechanism against foreign pathogens and depletion of neutrophils may render patients vulnerable to infections. Such approaches might also remove the host–beneficial antitumoral neutrophils. Alternatively, other strategies may be considered: (i) blocking neutrophil mobilization and recruitment to primary tumors and metastatic sites; (ii) polarizing neutrophils from the protumoral phenotype to the antitumoral phenotype; and (iii) specifically targeting neutrophil-derived molecules with tumor-supporting functions. For instance, therapeutics that reduce the expression levels of G-CSF by tumor or stromal cells (e.g., MEK/ERK inhibitor or anti-IL17) or the downstream targets of the G-CSF/G-CSFR axis (inhibitor of the JAK/Stat3 pathway or anti-Bv8) can be used to test the first strategy. Antagonists of GM-CSF or other chemokines may also be valuable. Anti-TGFβ therapy can be used to test the second strategy. To test the third strategy, one might consider antagonists of neutrophil elastase, S100A8/9, VEGF, MMP9, oncostatin M, neutrophil-derived serine proteases, and scavengers of ROS.
Additionally, blockade of the tumor-supporting functions of neutrophils may be valuable when combined with conventional chemotherapies and other targeted therapies. This is exemplified by the combinational treatment of tumor-bearing mice using antibodies to VEGF and to G-CSF, Bv8, or IL17. Our previous studies indicated that such combination therapies reduce tumor growth in mouse tumor models that are otherwise refractory to anti-VEGF treatment (38, 39, 68).
Concluding Remarks and Perspectives
Emerging evidence supports an important yet complex role of neutrophils during tumor initiation, growth, angiogenesis, evasion from immunosurveillance and metastasis. Still, much remains unknown, and further characterization of neutrophil functions in the context of cancer and cancer-related inflammation is needed (see Box 1). The knowledge gained by addressing such questions is expected to advance our understanding of neutrophil recruitment, heterogeneity, programming, and functional plasticity, in response to signals derived from tumors and possibly other pathologic conditions. It should also facilitate identification of the most efficient strategies to block the tumor-supporting functions of neutrophils while preserving or even boosting the antitumoral functions.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Box 1. Outstanding Questions
Considering the difference between mouse and human neutrophils, to what extent can knowledge generated from mouse tumor models be applied to human cancer patients?
What are the most efficient and reliable methods to identify and isolate neutrophils from mouse tumor models, and more importantly, human cancer patients?
What is the developmental status of neutrophils recruited to primary tumors and metastatic sites?
How do neutrophils interact with other cell types that are recruited to/constitute the metastatic niche? How does this interaction regulate cancer metastasis? What are the relative contributions of immunosuppression and direct stimulation of angiogenesis or tumor cell growth to neutrophil-induced tumor promotion? Are they tumor-type or tumor-stage dependent?
Are the protumoral and antitumoral neutrophils fundamentally different neutrophil subsets? Or do they simply represent different developmental stages or activation states of neutrophils? Can the protumoral and antitumoral neutrophils coexist in the same tumor tissue? What surface/intracellular markers can be used to distinguish them? Which signaling pathways determine differentiation toward protumoral versus antitumoral phenotypes of neutrophils? How can we develp therapies to target such signaling pathways in order to suppress the protumoral while promoting the antitumoral effects?
Amulic B,
Cazalet C,
Hayes GL,
Metzler KD,
Zychlinsky A
. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012;30:459–89.
Kolaczkowska E,
Kubes P
. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013;13:159–75.
Balkwill F,
Mantovani A
. Inflammation and cancer: back to Virchow? Lancet 2001;357:539–45.
Walsh SR,
Cook EJ,
Goulder F,
Justin TA,
Keeling NJ
. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005;91:181–4.
Carus A,
Ladekarl M,
Hager H,
Nedergaard BS,
Donskov F
. Tumour-associated CD66b +neutrophil count is an independent prognostic factor for recurrence in localised cervical cancer. Br J Cancer 2013;108:2116–22.
Stotz M,
Gerger A,
Eisner F,
Szkandera J,
Loibner H,
Ress AL,
Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J cancer 2013;109:416–21.
Cho IR,
Park JC,
Park CH,
Jo JH,
Lee HJ,
Kim S,
Pre-treatment neutrophil to lymphocyte ratio as a prognostic marker to predict chemotherapeutic response and survival outcomes in metastatic advanced gastric cancer. Gastric Cancer 2014;17:703–10.
Xue TC,
Xie XY,
Ge NL,
Li LX,
Zhang BH,
Prognostic significance of the neutrophil-to-lymphocyte ratio in primary liver cancer: a meta-analysis. PLoS One 2014;9:e96072.
Kang MH,
Go SI,
Song HN,
Lee A,
Kim SH,
Kang JH,
The prognostic impact of the neutrophil-to-lymphocyte ratio in patients with small-cell lung cancer. Br J Cancer 2014;111:452–60.
Koh CH,
Bhoo-Pathy N,
Ng KL,
Jabir RS,
Tan GH,
See MH,
Utility of pre-treatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as prognostic factors in breast cancer. Br J Cancer 2015;113:150–8.
Fossati G,
Ricevuti G,
Edwards SW,
Walker C,
Dalton A,
Rossi ML
. Neutrophil infiltration into human gliomas. Acta Neuropathol 1999;98:349–54.
Bugl S,
Wirths S,
Muller MR,
Radsak MP,
Kopp HG
. Current insights into neutrophil homeostasis. Ann N Y Acad Sci 2012;1266:171–8.
Roberts AW
. G-CSF: a key regulator of neutrophil production, but that's not all! Growth Factors 2005;23:33–41.
Bendall LJ,
Bradstock KF
. G-CSF: from granulopoietic stimulant to bone marrow stem cell mobilizing agent. Cytokine Growth Factor Rev 2014;25:355–67.
Tian SS,
Lamb P,
Seidel HM,
Stein RB,
Rosen J
. Rapid activation of the ST A T3 transcription factor by granulocyte colony-stimulating factor. Blood 1994;84:1760–4.
Yu H,
Lee H,
Herrmann A,
Buettner R,
Jove R
. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014;14:736–46.
Zhang H,
Nguyen-Jackson H,
Panopoulos AD,
Li HS,
Murray PJ,
Watowich SS
. STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 2010;116:2462–71.
Petit I,
Szyper-Kravitz M,
Nagler A,
Lahav M,
Peled A,
Habler L,
G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002;3:687–94.
Larsen A,
Davis T,
Curtis BM,
Gimpel S,
Sims JE,
Cosman D,
Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains. J Exp Med 1990;172:1559–70.
Fukunaga R,
Ishizaka-Ikeda E,
Seto Y,
Nagata S
. Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Cell 1990;61:341–50.
Tamada T,
Honjo E,
Maeda Y,
Okamoto T,
Ishibashi M,
Tokunaga M,
Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex. Proc Natl Acad Sci U S A 2006;103:3135–40.
Molineux G,
Foote M,
Arvedson T
Watowich S
. G-CSF receptor structure, function, and intracellular signal transduction. In: Molineux G, Foote M, Arvedson T , editors. Twenty years of G-CSF clinical and nonclinical discoveries. New York: Springer; 2012. p 83–105.
Lieschke GJ,
Grail D,
Hodgson G,
Metcalf D,
Stanley E,
Cheers C,
Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 1994;84:1737–46.
Wu HY,
Wesselschmidt R,
Kornaga T,
Link DC
. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 1996;5:491–501.
Basu S,
Dunn A,
Ward A
. G-CSF: function and modes of action (Review). Int J Mol Med 2002;10:3–10.
Seymour JF,
Quilici C,
Dunn AR
. Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood 1997;90:3037–49.
Dalrymple SA,
Lucian LA,
Slattery R,
McNeil T,
Aud DM,
Fuchino S,
Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia. Infect Immun 1995;63:2262–8.
Kaushansky K,
Fox N,
Lin NL,
Liles WC
. Lineage-specific growth factors can compensate for stem and progenitor cell deficiencies at the postprogenitor cell level: an analysis of doubly TPO- and G-CSF receptor-deficient mice. Blood 2002;99:3573–8.
Poursine-Laurent J,
. Interleukin-6 and the granulocyte colony- stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood 1997;90:2583–90.
Hibbs ML,
Kountouri N,
Armes JE,
Burgess AW,
Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis. J Immunol 2007;178:6435–43.
Aliper AM,
Frieden-Korovkina VP,
Buzdin A,
Roumiantsev SA,
Zhavoronkov A
. A role for G- CSF and GM-CSF in nonmyeloid cancers. Cancer Med 2014;3:737–46.
Kasuga I,
Makino S,
Kiyokawa H,
Katoh H,
Ebihara Y,
Ohyashiki K
. Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer 2001;92:2399–405.
Chakraborty S,
Keenportz B,
Woodward S,
Anderson J,
Colan D
. Paraneoplastic leukemoid reaction in solid tumors. Am J Clin Oncol 2015;38:326–30.
Granger JM,
Kontoyiannis DP
. Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study. Cancer 2009;115:3919–23.
Kowanetz M,
Wu X,
Lee J,
Tan M,
Hagenbeek T,
Qu X,
Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A 2010;107:21248–55.
Stathopoulos GP,
Armakolas A,
Tranga T,
Marinou H,
Stathopoulos J,
Chandrinou H
. Granulocyte colony-stimulating factor expression as a prognostic biomarker in non-small cell lung cancer. Oncol Rep 2011;25:1541–4.
Phan VT,
Cheng JH,
Sheng RX,
Chung AS,
Zhuang G,
Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc Natl Acad Sci U S A 2013;110:6079–84.
Shojaei F,
G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A 2009;106:6742–7.
Zhong C,
Liang XH,
Yao J,
Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 2007;450:825–31.
Lechner MG,
Liebertz DJ,
Epstein AL
. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol 2010;185:2273–84.
Marvel D,
Gabrilovich DI
. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 2015;125:3356–64.
Fridlender ZG,
Albelda SM
. Tumor-associated neutrophils: friend or foe? Carcinogenesis 2012;33:949–55.
Dumitru CA,
Lang S,
Brandau S
. Modulation of neutrophil granulocytes in the tumor microenvironment: mechanisms and consequences for tumor progression. Semin Cancer Biol 2013;23:141–8.
Hannah S,
Mecklenburgh K,
Rahman I,
Bellingan GJ,
Greening A,
Haslett C,
Hypoxia prolongs neutrophil survival in vitro. FEBS Lett 1995;372:233–7.
Walmsley SR,
Print C,
Farahi N,
Peyssonnaux C,
Johnson RS,
Cramer T,
Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 2005;201:105–15.
McGovern NN,
Cowburn AS,
Porter L,
Summers C,
Thompson AA,
Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils. J Immunol 2011;186:453–63.
Sun J,
Kapoor V,
Cheng G,
Ling L,
Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 2009;16:183–94.
Coussens LM,
Tinkle CL,
Hanahan D,
Werb Z
. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 2000;103:481–90.
Ardi VC,
Kupriyanova TA,
Deryugina EI,
Quigley JP
. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A 2007;104:20262–7.
Knaapen AM,
Schins RP,
Polat D,
Becker A,
Borm PJ
. Mechanisms of neutrophil-induced DNA damage in respiratory tract epithelial cells. Mol Cell Biochem 2002;234–235:143–51.
Gungor N,
Borm PJ,
Van Schooten FJ
. Neutrophils and respiratory tract DNA damage and mutagenesis: a review. Mutagenesis 2006;21:225–36.
Houghton AM,
Rzymkiewicz DM,
Ji H,
Gregory AD,
Egea EE,
Metz HE,
Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 2010;16:219–23.
Queen MM,
Ryan RE,
Holzer RG,
Keller-Peck CR,
Jorcyk CL
. Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression. Cancer Res 2005;65:8896–904.
Acharyya S,
Oskarsson T,
Vanharanta S,
Malladi S,
Kim J,
Morris PG,
A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 2012;150:165–78.
Ferrara N
. Developmental and pathological angiogenesis. Annu Rev Cell Dev Biol 2011;27:563–84.
Nozawa H,
Chiu C,
Hanahan D
. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 2006;103:12493–8.
Jablonska J,
Leschner S,
Westphal K,
Lienenklaus S,
Weiss S
. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 2010;120:1151–64.
Mentzel T,
Brown LF,
Dvorak HF,
Kuhnen C,
Stiller KJ,
Katenkamp D,
The association between tumour progression and vascularity in myxofibrosarcoma and myxoid/round cell liposarcoma. Virchows Archiv 2001;438:13–22.
Liang J,
Piao Y,
Holmes L,
Fuller GN,
Henry V,
Tiao N,
Neutrophils promote the malignant glioma phenotype through S100A4. Clin Cancer Res 2014;20:187–98.
. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795–803.
Gaudry M,
Bregerie O,
Andrieu V,
El Benna J,
Pocidalo MA,
Hakim J
. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood 1997;90:4153–61.
Webb NJ,
Myers CR,
Watson CJ,
Bottomley MJ,
Brenchley PE
. Activated human neutrophils express vascular endothelial growth factor (VEGF). Cytokine 1998;10:254–7.
Jablonska E,
Piotrowski L,
Jablonski J,
Grabowska Z
. VEGF in the culture of PMN and the serum in oral cavity cancer patients. Oral Oncol 2002;38:605–9.
Stetler-Stevenson WG
. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 1999;103:1237–41.
. Matrix metalloproteinases and the development of cancer. Chem Biol 1996;3:895–904.
Pahler JC,
Tazzyman S,
Erez N,
Chen YY,
Murdoch C,
Plasticity in tumor- promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 2008;10:329–40.
Malik AK,
Baldwin ME,
Schanz S,
Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 2007;25:911–20.
Ngu H,
Kasman I,
Zhang J,
An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 2013;19:1114–23.
Meng G,
. Induction of Bv8 expression by granulocyte colony- stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. J Biol Chem 2012;287:19574–84.
Xin H,
Lu R,
Zhang W,
Zhang C,
Deng J,
G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells. J Biol Chem 2013;288:13842–9.
Meng YG,
. Characterization and regulation of bv8 in human blood cells. Clin Cancer Res 2009;15:2675–84.
Pelletier M,
Maggi L,
Micheletti A,
Lazzeri E,
Tamassia N,
Costantini C,
Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 2010;115:335–43.
Cassatella MA
. Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol 1999;73:369–509.
Borregaard N,
Sorensen OE,
Theilgaard-Monch K
. Neutrophil granules: a library of innate immunity proteins. Trends Immunol 2007;28:340–5.
Botta C,
Barbieri V,
Ciliberto D,
Rossi A,
Rocco D,
Addeo R,
Systemic inflammatory status at baseline predicts bevacizumab benefit in advanced non-small cell lung cancer patients. Cancer Biol Ther 2013;14:469–75.
Mazzanti R,
Cusi MG,
Vincenzi B,
Mantovani G,
Licchetta A,
Baseline inflammatory status defined by neutrophil to lymphocyte cell count ratio (NLR) predicts progression free survival (PFS) in metastatic colorectal cancer patients (mCRC) undergoing bevacizumab based biochemotherapy. Eur J Cancer 2011;47:S174–75.
Keizman D,
Ish-Shalom M,
Huang P,
Eisenberger MA,
Pili R,
Hammers H,
The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma. Eur J Cancer 2012;48:202–8.
Dranoff G,
Fearon D
. Tumour immunology. Curr Opin Immunol 2013;25:189–91.
Youn JI,
Collazo M,
Shalova IN,
Biswas SK,
. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol 2012;91:167–81.
Aoyagi Y,
Oda T,
Kinoshita T,
Nakahashi C,
Hasebe T,
Ohkohchi N,
Overexpression of TGF-beta by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer. Br J Cancer 2004;91:1316–26.
Tsuda Y,
Fukui H,
Asai A,
Fukunishi S,
Miyaji K,
Fujiwara S,
An immunosuppressive subtype of neutrophils identified in patients with hepatocellular carcinoma. J Clin Biochem Nutr 2012;51:204–12.
Jacobsen LC,
Theilgaard-Monch K,
Christensen EI,
Borregaard N
. Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils. Blood 2007;109:3084–7.
Bronte V,
Zanovello P
. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005;5:641–54.
Lu T,
. Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res 2012;18:4877–82.
Mishalian I,
Bayuh R,
Eruslanov E,
Michaeli J,
Levy L,
Zolotarov L,
Neutrophils recruit regulatory T-cells into tumors via secretion of CCL17–a new mechanism of impaired antitumor immunity. Int J Cancer 2014;135:1178–86.
Wislez M,
Rabbe N,
Marchal J,
Milleron B,
Crestani B,
Mayaud C,
Hepatocyte growth factor production by neutrophils infiltrating bronchioloalveolar subtype pulmonary adenocarcinoma: role in tumor progression and death. Cancer Res 2003;63:1405–12.
Kalluri R,
Weinberg RA
. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420–8.
Hu P,
Shen M,
Zheng C,
Pang Z,
Zhu L,
Intratumoral neutrophil granulocytes contribute to epithelial-mesenchymal transition in lung adenocarcinoma cells. Tumour Biol 2015;36:7789–96.
Grosse-Steffen T,
Giese T,
Giese N,
Longerich T,
Schirmacher P,
Hansch GM,
Epithelial- to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase. Clin Dev Immunol 2012;2012:720768.
Dubravec DB,
Spriggs DR,
Mannick JA,
Rodrick ML
. Circulating human peripheral blood granulocytes synthesize and secrete tumor necrosis factor alpha. Proc Natl Acad Sci U S A 1990;87:6758–61.
Bates RC,
Mercurio AM
. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell 2003;14:1790–800.
Huh SJ,
Liang S,
Sharma A,
Dong C,
Robertson GP
. Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development. Cancer Res 2010;70:6071–82.
Spicer JD,
McDonald B,
Cools-Lartigue JJ,
Chow SC,
Giannias B,
Kubes P,
Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells. Cancer Res 2012;72:3919–27.
Cools-Lartigue J,
Spicer J,
Gowing S,
Chow S,
Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest 2013;123:3446–58.
Najmeh S,
Ferri L
. Neutrophil extracellular traps in cancer progression. Cell Mol Life Sci 2014;71:4179–94.
Paget S
. The distribution of secondary growths in cancer of the breast 1889. Cancer Metastasis Rev 1989;8:98–101.
Kaplan RN,
Riba RD,
Zacharoulis S,
Bramley AH,
Vincent L,
Costa C,
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005;438:820–7.
Casbon AJ,
Reynaud D,
Park C,
Khuc E,
Gan DD,
Schepers K,
Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci U S A 2015;112:E566–75.
Coffelt SB,
Kersten K,
Doornebal CW,
Weiden J,
Vrijland K,
Hau CS,
IL17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 2015;522:345–8.
100.↵
Wu CF,
Andzinski L,
Kasnitz N,
Kroger A,
Klawonn F,
The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung. Int J Cancer 2015;137:837–47.
Trinchieri G
. Type I interferon: friend or foe? J Exp Med 2010;207:2053–63.
Swierczak A,
Cook AD,
Lenzo JC,
Restall CM,
Doherty JP,
Anderson RL,
The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor. Cancer Immunol Res 2014;2:765–76.
Wculek SK,
Malanchi I
. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 2015;528:413–7.
Meng Z,
Cao R,
Liu T,
. Inhibitor of 5-lipoxygenase, zileuton, suppresses prostate cancer metastasis by upregulating E-cadherin and paxillin. Urology 2013;82:1452 e7–14.
Kim EY,
Seo JM,
Kim C,
Lee JE,
Lee KM,
Kim JH
. BLT2 promotes the invasion and metastasis of aggressive bladder cancer cells through a reactive oxygen species-linked pathway. Free Radic Biol Med 2010;49:1072–81.
Koga Y,
Matsuzaki A,
Suminoe A,
Hattori H,
Hara T
. Neutrophil-derived related apoptosis- inducing ligand (TRAIL): a novel mechanism of antitumor effect by neutrophils. Cancer Res 2004;64:1037–43.
Granot Z,
Henke E,
Comen EA,
King TA,
Norton L,
Benezra R
. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 2011;20:300–14.
Finisguerra V,
Di Conza G,
Di Matteo M,
Serneels J,
Costa S,
MET is required for the recruitment of anti-tumoural neutrophils. Nature 2015;522:349–53.
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Here's why you shouldn't shy away from investing, even if you only have a small amount of money – CNBC
Robert G. Allen, author of several best-selling personal finance books once asked, "How many millionaires do you know who have become wealthy by investing in savings accounts? I rest my case."
Using a savings account and an emergency fund for short-term expenses is important, but investing for retirement and the future is arguably just as crucial. While it may feel pointless to start investing if you don't have much money, it can still be incredibly worthwhile. Think of it this way: few, if any, start investing with a large sum of money. For many, growing your wealth happens over years and years and is a slow and steady process.
By starting slow, even with a small amount of cash, you can begin to establish the habit of investing regularly, which will hopefully lead to a large nest egg in the future.
Select details why you should start investing today, even if you don't have a large amount of money to start with.
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Why you should start investing today
Investing can be an intimidating word and concept for many reasons. There are a large amount of terms, tax implications, planning and investments to understand — along with knowing there will be market fluctuations making your net worth go up and down. But by understanding the mere basics, you can begin to grow your wealth quickly.
Corbin Blackwell CFP, senior financial planner at wealth management app Betterment, told Select that, "Investing is one of the best ways to grow your long-term wealth and reach major goals for things like retirement, buying a home and college funds."
He also said that beginning the investing journey is often the most difficult part, as growth will be limited at first. He added that, "Tools available today, like digital investment advisors, make it easier than ever to get started."
And by getting started today, you have the best asset that any investor can have on their side: time.
By letting your money sit in the market longer, you allow for compound interest to take over — which is when your interest and gains stack on top of one another. Blackwell gives an excellent example of the power of compound interest:
"Let's say you invested just $100 today and saw a 5% annual return – thanks to the power of compound interest, if you don't touch your investment, in 30 years you'd have $430."
That's an ok return, but imagine if you invested $100 monthly for 30 years into a common index fund. An index fund is a fund that has a group of companies within it, and tracks the performance of the entire group. These groups can range in focus including the size of each company, the respective industries, location of the companies, type of investment and more. One of the most popular indices, the S&P 500, consists of the 500 largest companies in the United States, making it a relatively safe investment because of its exposure to hundreds of companies and dozens of industries.
Many consider this a 'boring investment,' but the results the index has produced are nothing to balk at.
The average yearly return of the S&P 500 over the last 30 years is 10.7%, but even at a conservative return of 8%, you would have over $146,000 if you invest $100 a month for 30 years. The impressive part is that your total contributions would be $36,000, which means your money would have quadrupled in value in 30 years (note that past performance does not guarantee future success).
In short, the more money and more time you have in the market, the more likely you are to grow your investment funds.
S&P 500 Index performance during the Covid-19 pandemic
The S&P 500 index, a key benchmark for Wall Street, took a beating from the economic fallout of the Covid-19 pandemic. From Jan. 1, 2020 to Mar. 23, 2020, the S&P 500 index dropped 33% in value. Since then, the index has grown over 110% in value.
It's important to remember that the market will have ups and downs, but riding the waves over the long term will garner the largest return. Trying to time the market is nearly impossible.
How to begin investing
If growing your net worth is your goal, you can get started in just a few minutes. Here are a few things to consider:
Build a budget that works for you
Starting to invest with a small amount of money isn't an issue. However, it's important to know how much you can afford to invest, as you don't want to harm your personal finances in the process. Blackwell urged, "as long as you aren't using money [to invest] that you need to cover day to day expenses such as food, rent and high interest debt payments, I recommend you start investing."
A budget gives you a way to see where your money is going each month, where you can possibly cut back and how much you can invest each month. You can set up a budget for yourself using a budgeting app, a spreadsheet or even a simple pen and paper. I use Personal Capital to manage my budget because I'm able to track my expenses and monitor the performance of my investments in one convenient app.
Regardless of which budgeting method works best for you, it's important to have an established budget to understand how much you can invest each month without cutting into the money allocated towards your monthly essentials.
Select an investing "bucket" and investments
There are many different buckets you can fill with money, such as a Roth IRA, HSA, 529 or taxable brokerage account. Each of these accounts serve a different purpose and have different tax implications, so be sure to select one that makes sense for you. For example, a Roth IRA is great if you plan on being in a higher tax bracket when you retire — you'll contribute after-tax income but all gains are tax-free after 59 and a half years old.
Once you select the type of account you want to invest within, you then must decide what type of investment to put your money into. This is the puzzling part for many, as there are an abundance of options, from ETFs to viral meme stocks to index funds and many more in-between.
For long term investors, index funds are a great solution as they have low fees, are low maintenance, provide wide exposure and many provide stable returns. In fact, John Bogle, the founder of Vanguard, summarizes the effectiveness of index funds in one analogy: "Don't look for the needle in the haystack. Just buy the haystack."
Regardless of which investment you choose, it's important to evaluate your risk-tolerance and understand what you're investing in. Be sure to do your own research, and potentially connect with an accredited financial advisor to discuss the best options.
Automate your investing
Once you determine how much you can and want to invest each month, it's important to turn on auto-investing.
This is where money is taken out of your checking account each month and automatically deposited into your choice of investments. Choosing this option is important because it takes the leg work away from needing to invest each month. Additionally, studies show that we are built for 'present bias' — which is the idea that the farther away something is, the less important it is. Essentially, it's much easier to spend now, rather than save for later. Automating transfers from your checking account or paycheck into an investment account will help ensure you don't spend money that you were planning on investing.
By automating your investments, you will be passively growing your nest egg and getting yourself closer to reaching your financial goals.
You may also want to consider a robo-advisor like Betterment or Wealthfront. Robo-advisors work by gathering information from you on your financial situation and investing goals to suggest investments that fit your needs and risk tolerance. After supplying this information, the robo-advisor will build you a portfolio based on your answers through computer algorithms and advanced software, with little to no work on your end. Plus, it will rebalance your investments over time based on your goals and changes in the market.
Best brokerages to get started
To begin investing, you'll need to select a brokerage account provider. These brokerages serve as the intermediary between you and the seller of the stock or security you want to purchase.
When deciding on the best brokerage for you, be sure to consider these factors:
Fees: These can range from minimum deposits, stock trade fees, mutual fund trade fees and more. Be sure to select a no- or low-fee brokerage.
Ease of use: Each brokerage has a different website and mobile app. While this is much more subjective, it's advantageous to use a brokerage with a web interface and experience you understand and enjoy.
Promotions: From time to time, brokerages will offer bonuses to new users. For example, I recently signed up for a Fidelity brokerage account and earned a $100 bonus after depositing $50.
Below are a few of our favorite online brokerages:
Information about Fidelity accounts has been collected independently by Select and has not been reviewed or provided by the issuer prior to publication.
$0 for stocks, ETFs, options and some mutual funds
Account minimum
Stocks, bonds, fractional shares, ETFs, mutual funds, options
Some ETFs don't have expense ratios
Mobile app is easy to use
No commissions on many types of securities
No futures or forex trading
High fees for broker assisted trades
$0 commission on stocks, options and ETFs
Includes stocks, bonds, mutual funds, ETFs, options, Forex, and futures
Intuitive trading platform
Large selection of mutual funds
Some mutual funds charge high commissions
Free research may not all be relevant to novice investors
Doesn't offer fractional shares of stocks
Information about the Vanguard accounts has been collected independently by Select and has not been reviewed or provided by the issuer prior to publication.
Stocks, bonds, ETFs, mutual funds, options, CDs
One of the largest ETF and mutual funds offerings around
Large number of no-transaction-fee mutual funds
$20 annual fee for IRAs and brokerage accounts, though investors can waive this fee by opting into paperless statements
Basic trading platform only
No robust research and data tools
Peel Hunt Reports Record First-Half Investment Banking Revenue – BNN
Increased scrutiny will make greenwashing tougher – Investment Executive
Bitcoin investors dig in for long haul in 'staggering' shift
As bitcoin heads into 2022, a growing cohort of long-term investors is doubling down on its stashes of the cryptocurrency, hoping a December dip was merely a festive blip.
Some industry watchers point to the underlying stability of such long-term investments as potentially promising indicators for the capricious cryptocurrency.
Since last July, for example, the amount of bitcoin held in digital wallets with no outflows for more than five months has been steadily increasing, according to digital currency brokerage Genesis Trading.
In addition, the amount of the bitcoin held in "illiquid" wallets – which spend less than quarter of their inflows – is also rising, meaning fewer coin are being actively traded, it added, citing wallet data across several exchanges.
"The number of bitcoins that haven't moved in over a year has been climbing since July," said Noelle Acheson, head of market insights at Genesis Trading. "That's pretty staggering."
Many investors were nonetheless sent diving for cover in December when the world's most popular cryptocurrency sunk almost 20%, roughly the same as the second-biggest coin ether, with risk appetite hit by inflation fears and a quicker pace of interest rate hikes from the U.S. Federal Reserve.
While bitcoin and ether both posted gains last week – up 2.9% to $43,107 and up 6.3% to $3,350, respectively – they are still some way off their 2021 highs of $69,000 and $4,868
'STRONG HANDS'
Many cryptocurrency experts caution that no one has been known to reliably predict bitcoin's characteristically wild price swings. In 2017, for example, it went from about $1,000 to around $20,000. In early 2020, it sunk below $4,000 at one point before beginning a dizzying rise.
Yet advocates of bitcoin and other coins say the increasing acceptance of cryptocurrencies in mainstream financial and investing in recent years has shored up the sector.
Cryptocurrency research firm Delphi Digital said their research showed a similar shift towards bitcoin being held for longer period by investors, which it said "illustrates a transference from shorter-term 'weak hands' to long-term 'strong hands'."
Crypto data platform Coinglass's bitcoin Fear & Greed index, has wavered between 10 and 29 since the start of the year, which could be an indicator of a possible market bottom and buying opportunities, according to Will Hamilton, head of trading & research at Trovio Capital Management.
"Previous market bottoms in July 2021 and March 2020 correlated with Fear and Greed scores of 19 and 10 respectively," he added.
For the uninitiated, 0 indicates "extreme fear" and 100 is "extreme greed"
MUSK AND DOGE
There were, meanwhile, more headlines for cryptocurrencies last week.
Meme-based dogecoin stole the spotlight after Tesla CEO Elon Musk tweeted that the company would accept it as payment for select merchandise.
The tweet sent dogecoin up nearly 12%.
"If more people are looking to buy Tesla merchandise with dogecoin then there's more demand," Acheson said, adding that this move could improve fundamental factors for dogecoin.
Cryptocurrency Solana was another altcoin in focus, with Bank of America analysts saying the Solana blockchain could pull market share away from ethereum and "could become the Visa of the digital asset ecosystem".
Elsewhere, bitcoin miners bounced back from mining crackdowns in China and the recent unrest in Kazakhstan, one of the world's primary centres for bitcoin mining.
Bitcoin's mean "hash rate" a measure of the power of the bitcoin computing network, touched an all time high of over 215 million terahashes per second on Thursday, according to blockchain data provider Glassnode.
(Reporting by Medha Singh and Lisa Mattackal in Bengaluru; Editing by Vidya Ranganathan and Pravin Char) (more…)
Foreign investment in Canadian securities
$30.1 billion
Canadian investment in foreign securities
Foreign investors acquired $30.1 billion of Canadian securities in November, the largest investment since April 2020. At the same time, Canadian investors increased their holdings of foreign securities by $17.5 billion, led by purchases of US shares.
As a result, international transactions in securities generated a net inflow of funds of $12.6 billion in the Canadian economy in November.
Canada's international transactions in securities
The largest foreign investment in Canadian securities since April 2020
Foreign acquisitions of Canadian securities totalled $30.1 billion in November, the largest investment since April 2020, during the first wave of the COVID-19 pandemic in Canada. In November, foreign investment targeted federal government debt securities, and to a lesser extent, private corporate debt securities. A foreign divestment in Canadian equities moderated the overall acquisition activity in the month.
Foreign investors added $31.4 billion of debt securities to their portfolios in November, up from a $20.4 billion investment in October. This activity mainly reflected purchases of federal government debt securities, both bonds ($8.6 billion) and money market instruments ($6.5 billion). In addition, investors added $9.8 billion of private corporate debt securities to their holdings in November, a seventh consecutive monthly investment, for a total of $87.6 billion. In November, Canadian long-term interest rates rose to the highest level since February 2019. Meanwhile, the Canadian dollar depreciated against the US dollar.
Foreign investment in Canadian debt securities, by sector of issuer
Non-resident investors reduced their overall exposure to the Canadian equity market by $1.3 billion in November, after three consecutive months of investment. The reduction reflected retirements of Canadian portfolio shares resulting from cross-border merger and acquisition activities. Foreign purchases of Canadian shares on the secondary market, led by shares of chartered banks, moderated the overall reduction in the month. Canadian share prices, as measured by the Standard and Poor's/TSX composite index, were down by 1.8% in November after reaching a record-high level in October.
Canadian investment in foreign securities rebounds
Canadian acquisitions of foreign securities reached $17.5 billion in November, up from a $5.4 billion investment in October and similar to the average investment observed in August and September. The investment activity in November was led by acquisitions of US shares.
Canadian investors added $7.4 billion of US shares to their holdings in November, following an investment of $652 million in October. The activity in November focused on shares of large capitalization technology firms and investment fund shares tracking broad market indices. US stock prices, as measured by the Standard and Poor's 500 composite index, were down by 0.8% in November. In addition, Canadian investors purchased $4.0 billion of non-US foreign shares, after a divestment of $2.5 billion in October. November's investment mainly targeted British companies' shares.
Canadian investment in foreign equity and investment fund shares
Meanwhile, Canadian investors added $6.1 billion of foreign debt securities to their portfolios, mainly in US dollar-denominated instruments. This activity represented the 10th straight month of investment in foreign debt securities for a total of $47.4 billion. Investment in November mainly focused on US corporate bonds ($2.8 billion) and US government bonds ($1.6 billion). In November, Canadian long-term interest rates exceeded their US counterpart with the largest value increase since August 2011.
Canadian investment in foreign bonds
The data series on international transactions in securities covers portfolio transactions in equity and investment fund shares, bonds and money market instruments for both Canadian and foreign issues. This activity excludes transactions in equity and debt instruments between affiliated enterprises, which are classified as foreign direct investment in international accounts.
Equity and investment fund shares include common and preferred equities, as well as units or shares of investment funds. For the sake of brevity, the terms "shares" and "equity and investment fund shares" have the same meaning.
Debt securities include bonds and money market instruments.
Bonds have an original term to maturity of more than one year.
Money market instruments have an original term to maturity of one year or less.
Government of Canada paper includes Treasury bills and US-dollar Canada bills.
All values in this release are net transactions unless otherwise stated.
Data on Canada's international transactions in securities for December 2021 will be released on February 17, 2022.
The Methodological Guide: Canadian System of Macroeconomic Accounts (Catalogue number13-607-X) is available.
The User Guide: Canadian System of Macroeconomic Accounts (Catalogue number13-606-G) is also available.
The data visualization product "Securities statistics," part of the series Statistics Canada – Data Visualization Products (Catalogue number71-607-X), is available online.
The Canada and the World Statistics Hub (Catalogue number13-609-X) is available online. This product illustrates the nature and extent of Canada's economic and financial relationship with the world using interactive graphs and tables. This product provides easy access to information on trade, investment, employment and travel between Canada and a number of countries, including the United States, the United Kingdom, Mexico, China and Japan.
For more information, or to enquire about the concepts, methods or data quality of this release, contact us (toll-free 1-800-263-1136; 514-283-8300; infostats@statcan.gc.ca) or Media Relations (statcan.mediahotline-ligneinfomedias.statcan@statcan.gc.ca).
Singapore REITs Double Their Overseas Investment to $12 Billion – BNN
(Bloomberg) — Singapore's property managers are accelerating their push abroad as a slow reopening and diminishing returns at home force them to look for growth opportunities elsewhere.
Foreign acquisitions by real estate investment trusts in the city-state jumped to an all-time high of 61 last year, data compiled by Bloomberg show. The total value of such deals also more than doubled from 2020 to $12.3 billion.
Property managers in Singapore — which boasts the most REITs in Asia outside of Japan — have long shown global ambitions, with overseas investments picking up during the pandemic. But a limited reopening coupled with the anticipated omicron surge is adding impetus to this drive, even as investor concerns over a slowing recovery grow.
"Singapore's commercial REITs may continue to rely on overseas M&A to achieve income growth in 2022, especially if omicron brings more uncertainty on further easing of social and traveling curbs to boost retail and office leasing demand in the country," said Bloomberg Intelligence analyst Patrick Wong.
A $3.1 billion merger of Mapletree Commercial Trust with Mapletree North Asia Commercial Trust proposed last month is the latest in a series of moves that have seen managers long comfortable with a domestic presence favor a more global footprint. Also in December, another REIT targeting retail outlets in the city-state, CapitaLand Integrated Commercial Trust, made a foray into its second overseas market with office acquisitions in Australia.
Investors like the stability a local focus can offer, Sharon Lim, the chief executive officer of the manager of Mapletree Commercial to told reporters last month, but her trust needs to be better placed to take on new opportunities overseas and achieve "meaningful long-term expansion." Lim's REIT, which she described as the "last of the Mohicans" with only Singapore-centric assets will see its domestic holdings shrink to 51% within the new merged entity.
Increased Risks
Overseas diversification may alienate some investors, however, with Mapletree Commercial's shares having declined more than 8% since the merger was announced. "Investors whose mandate demands only Singapore exposure may look at other counters," said Krishna Guha, a senior analyst at Jefferies Financial Group Inc, adding that execution and foreign exchange risks may rise.
Still, while the CEO of Singapore's tourism board Keith Tan has warned that a full recovery in visitor numbers is unlikely until 2025, a reopening dividend might yet emerge. Officials in the financial center have affirmed their determination to live with the virus and keep its borders open, while easing some restrictions, including allowing some workers back into offices.
Singapore's latest property investment manager Capitaland Investment Ltd. — a spinoff of one of the country's largest developers — said it will remain committed to local investments despite a growing foreign portfolio.
Singapore will continue to be a "core market" and is attracting strong interest from wealthy individuals, including a growing number of family offices, said CEO Lee Chee Koon in an emailed response to questions about its plans. "But given the physical growth constraints, the relative size of our Singapore business within our portfolio will become smaller over time, as we expand and deepen our interests in overseas markets."
Investors have validated this strategy so far, with Capitaland Investment emerging as the second-best performer on the benchmark Straits Times Index since its trading debut in September last year, having advanced by over 21%.
The overseas growth fervor is unlikely to dim. A limited pool of good quality assets as well as increasing competition from global funds have also pushed yields lower, said Vijay Natarajan, a real estate analyst at RHB Research Institute. Capitaland's Lee also expects stronger Asian-based competition to emerge over time.
Instead, deep liquidity pools in overseas markets like the U.K., U.S. and Australia, as well as more alluring freehold and longer lease terms will maintain the draw of markets abroad, said Natarajan. "We expect this trend of overseas acquisitions to continue."
Footnotes to second chart:
Chart displays % of foreign AUM of top eight REITs by market capitalization
Excluded names are Capitaland Integrated Commercial Trust, created through a merger in 2020, while Mapletree Commercial Trust and Frasers Logistics & Commercial Trust are pure geographical plays
Mapletree REITs' financial years end in March (E.g. For FY 2020: March 2021 rather than Dec. 2020)
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redpajama_set_name: RedPajamaCommonCrawl


CBN cancels N100 charge on inter-bank ATM transactions - TSB.com.ng!
The Central Bank of Nigeria and the Bankers Committee on Tuesday agreed to put a stop to all charges associated with the use of Automated Teller Machines nationwide.The committee also agreed to boost liquidity in the mortgage sector as well as come up with a relief package that would help ameliorate the sufferings of flood victims.
Some good news, I must say! The banks are making too much money from the citizenry and giving back nothing in return – only outlandish charges for loans and mediocre services!
Previous articleBREAKING: Dr. Olusola Saraki is dead!
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#597 - Peace & Life: SCOTUS Nominees - February 4, 2022
Potential Supreme Court Nominees on Our Issues
Every time there's a new nominee to the U.S. Supreme Court, we offer an edition detailing their experience on our issues. We need help, since online searches only go so far. Information on any of the women speculated as possible nominees can be sent to CLNeditors@gmail.com.
What we do know: Ketanji Brown Jackson got the endorsement of NARAL Pro Choice America for appellate judge, and filed an amicus brief in McGuire v. Reilly supporting a floating 6-foot buffer around those approaching abortion facilities. But she also sat on the board of a Maryland school that opposes abortion. On the death penalty, she served on a sentencing commission, but googling doesn't yet show what happened there. She clerked for Stephen Breyer, who opposes the death penalty.
Leondra Kruger got several appeals of death penalty cases in her position on the California Supreme Court, and most resulted in unanimous decisions to let the execution go forward.
This is a little information on just two of the suggested candidates, so we'll be on the lookout for more.
Top contenders, according to speculation:
Top: Ketanji Brown Jackson, Leondra Kruger. Bottom: J. Michelle Childs
Not the First Potential Black Woman Nominee
See stories in The Washington Post and Newsweek, among others: When George W. Bush had an opening, he was considering Janice Rogers Brown (pictured). But her nomination was blocked by a threatened filibuster by then-Senator Joe Biden. Samuel Alito was chosen instead. This tarnishes Biden's bragging about appointing the first Black woman; we might have had one 15 years earlier.
Here we have a subtle form of racism: a Black woman is a fine pick if she follows your judicial philosophy, but if you have to tolerate someone who has different ideas, then better it be a White man representing them than a Black woman.
There were undoubtedly judicial decisions where we would have disagreed with how Brown ruled, but the demographic features of a judge makes no difference on that point.
Inasmuch as being against Roe v. Wade was a concern, a prevalent view among Roe proponents was that Black women shouldn't be involved in overturning or limiting it. Better to keep the pro-life perspective seen as a white male imposition.
Women Deserve Better
Our member group Feminists for Life has new entries into its series of practical tips for mothers:
Your Pregnancy Test Is Positive: Now What?
Worse Than Morning Sickness: When You Have Hyperemesis Gravidarum
Top Remote Jobs Today
Intro to Aquaponics
Our Latest Blog Post
Lisa Stiller shares her personal journey in Life as a Pro-life Progressive.
Quotation of the Week
Michael Sean Winters
Clinging to a consistent ethic of life remains a moral imperative
National Catholic Reporter, January 21, 2022
Here is a challenge for our conservative friends: Acknowledge that poverty remains the leading abortifacient in our country and throughout the world, and bring forward policies that will ameliorate it.
How can a morally serious person give credence to the theological piffle offered by groups like Catholics for Choice? It is astonishing that they seem not to notice the moral laziness of the slogan "my body, my choice" after watching anti-vaxxers embrace the very same slogan for two years. . .
Here is a challenge for our liberal friends: Liberals rightly have been keen to call out historic racism and demand a reckoning. Why is the racist eugenicism of Margaret Sanger, the founder of Planned Parenthood, overlooked? . . .
We can witness to the consistency of our moral beliefs by clinging to the consistent ethic of life, the only, repeat only, morally and intellectually serious position I have encountered in researching and writing about the issue of abortion for 25 years.
Send to CLNeditors@googlegroups.com.


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home > brands > random-house
Here are the latest posts about Random House on The Write News:
Random House Digital Sales are Booming
Publisher's Weekly reports on the letter Random House sent to its employees at year end. (December 20, 2010)
NewsMax And Random House Announce Book Deal
NewsMax Media and Random House's Prima Publishing have agreed to a joint venture for the purposes of publishing and marketing books, it was announced by Christopher Ruddy, NewsMax CEO and President. (April 5, 2002)
Random House Children's Books to Relaunch Seussville
Random House Children's Books has announced the relaunch of Seussville, the official website of Dr. (March 1, 2002)
HealthGate Acquires Random House's The Natural Pharmacist
HealthGate Data Corp. (February 15, 2002)
Random House Launches Children's Ebooks
Random House Children's Books announced the debut of its ebook publishing program Random View Books. (October 31, 2001)
Random House Denied Injunction Against RosettaBooks
U. (July 12, 2001)
Still Waiting for Outcome of Ebook Rights Suit
Random House and RosettaBooks are still waiting for a decision from New York federal District Court Judge Sidney Stein in a major electronic rights case. (May 29, 2001)
Random House to Acquire Prima Communications
Prima Communications, Inc. (March 27, 2001)
Lycos and Random House Launch Ebook Marketplace
Terra Lycos S. (November 10, 2000)
Reciprocal, Random House To Sell Ebook Classics
Reciprocal, Inc. (November 3, 2000)
Random House to Promote Books With Internet Greeting Cards
Blab Media Inc. (October 26, 2000)
Random House Announces Ebook Imprint
Random House has announced a new ebook imprint which will include an editorial list of original electronic books. (July 31, 2000)
Random House, Inc. and Audible, Inc. Create Imprint
Random House, Inc. (May 17, 2000)
Disney Publishing and Random House Announce Licensing Agreement
Disney Publishing Worldwide and Random House Inc. (May 10, 2000)
Random House Purchases Minority Stake in Xlibris
Random House Ventures, the investment subsidiary of Random House, Inc. (April 4, 2000)
The New York Times and Random House, Inc. Sign New Book Publishing Agreement
The New York Times and Random House, Inc. (January 28, 2000)
National Poetry Month Gets High Tech Boost
Knopf Publishing Group (a division of Random House) launched its first large electronic distribution of poems to readers across the world and celebrates the opening of the Knopf Poetry Center and National Poetry Month. (April 1, 1999)
Discovery Communications and Random House to Create Discovery Channel Books
Discovery Communications, Inc. (September 2, 1998)
Random House Children's Publishing and First Book Announce Reading Hero Award
Random House Children's Publishing and First Book have partnered to create the Reading Hero Awards, a program to honor the inspiring work of teachers, tutors, mentors, and volunteers throughout the nation, who have made a difference in the literacy lives of children, it was announced by Harold Clarke, President of Random House Children's Publishing and Kyle Zimmer, President of First Book. (August 13, 1998)
Random House Children's Publishing Launches Author Chat Series
Random House Children's Publishing has announced they will sponsor an online Children's Author Chat Series. (March 13, 1998)
Next Random House Stories


The Fruit Entomology lab representing at the UGA College of Agricultural and Environmental Sciences Holiday Luncheon. I just may have convinced Santa to join our lab. He liked the sound of Dr. Santa Claus and he is usually free during the summer, so I think things might just work out. Fingers crossed!
I had a great time at the 2016 Georgia Vineyard Update in Dahlonega educating growers on the common insect pests of grapes and the best management practices for mites in the south. I definitely learned a lot and talked with some great people!


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British Travel Awards 2019 Consumer Voting Goes Live
Kanyu Kisbe
Jul 5, 2019 • 1 min read
The British Travel Awards (Pic: BTA)
Daily Star Online is proud to work with The British Travel Awards, an independent organisation, verified by leading global business practitioners Deloitte and the only travel industry accolade voted for exclusively by the travelling public.
The Awards serve to recognise all that is great about travel, as experienced by you the travelling consumer.
This year there are 83 award categories covering a comprehensive range of products and services experienced by customers when planning, booking and taking their holidays; but don't worry you don't have to vote in every category, you can dip in and out for as many or as few as you want, right through to 30 September.
And as a thank you for taking the trouble to go online and vote you'll be entered into a prize draw with more than £30,000 worth of travel prizes to be won, including holiday vouchers, for example, a £2,000 James Villa Holidays voucher; cruises including a Viking River Cruise 8 day cruise for two: and package holidays including a Ionian and Agean Island Holidays villa holiday, including flights on the stunning island of Kefalonia.
Last year a massive 334,522 leisure travellers voted, making the BTAs the largest consumer voted award programme in the UK.
The 2019 British Travel Awards' winners will be announced at a Gala ceremony in London on November 27.
BTA CEO Lorraine Barnes Burton said: "It's now more than ten years since the BTAs became the largest consumer voted awards ceremony in travel. Our core values of integrity, transparency and credibility have made the BTAs the most recognised and valued awards programme for both the travel industry and the all-important voting consumers. Our continued development of rigorous vote collation procedures is enhanced year on year via our partnership with awards verification partners and scrutineers, Deloitte."
To vote go to www.britishtravelawards.com
Top Seven Coaching Jobs in the NFL for 2022
I know there are more than seven openings, but as the Las Vegas Raiders are in the playoffs, perhaps their "interim" coach, doesn't really count. Special thanks to teamrankings.com and overthecap.com for their stats. Houston Texans2021 Record: 4-14 Scoring offense points per game= 16.5, 30th ranked
Stephen Lewis Jan 18, 2022 • 3 min read
FIFPro World XI Voting Rules for the Men and Women
Lionel Messi and Cristiano Ronaldo have been named in the FIFA FIFA Pro XI of the year. However, PSG star Neymar, Mbabane and Mohamed Salah, who are in the top three in the race of the year, did not get a place in the list of the best. The 'Best
Nikel Hemron Jan 18, 2022 • 1 min read
Men's Basketball Suffers Seven-Point Loss to Mount St. Mary's
The Merrimack College men's basketball team lost its second Northeast Conference (NEC) game of the season to Mount St. Mary's on Monday afternoon. Jordan Minor led the way for the Warriors scoring 15 points and pulling down seven rebounds. Malik Edmead dropped a second best 12 points and also had
Kristina Miranda Jan 18, 2022 • 2 min read
World News Updates © 2022
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Perhaps you've noticed that the once highly prolific drone duo Nadja has not released a proper full-length album in over two years... I know I have. Some terrific collaboration LPs with Galena, Picastro, and Vampillia, along with a 2xCD compilation have come out, but Dagdrøm will be the first full-length since 2010's Sky Burial LP.
You'll notice right of the bat that this features a more rhythmic, even rock-ish approach to their signature heavy, spacey, even shoegazey drone stylings. Indeed, some of the heaviness that has come to define the band's earlier sound seems to have been sacrificed in favor of what some might call a more structured, focused sound, and while I might have scoffed if you had told me that two or three years ago, I really think it works now. The more rhythmic approach to this record comes courtesy of live drums from The Jesus Lizard's Mac MacNeily, who I've always thought was one of the most criminally unheralded drummers. His contribution to the record certainly seems to have ushered in a new era for Nadja, if not aesthetically, then at least sonically.
Make no mistake, though, this album is still very heavy, and the spacey, cutting guitar tones are as killer as ever. Even if the sound is not as bombastic as it once was, the textured drones are every bit as mesmerizing, and can still easily wash over a room. Honestly, the point is still communicated, so there isn't really a need for the songs to be as crushing as, say, something on Bliss Torn from Emptiness or Thaumogenesis.
I think long-time Nadja fans will really like this record, and I think it's plausible that if you haven't been a Nadja fan in the past, giving this one a shot might change your perspective on the band. The sounds have changed a bit, but the intensity is there in spades.
The standard LP, CD, and download editions are coming soon from the band's own Broken Spine Productions (while a special 2xCD will be available from Japan's Daymare Recordings), but if you want to get in on the action early, you can pre-order a special limited edition green vinyl which will be numbered and signed by Aidan and Leah. If you want to stream the record, you can do so at the band's Bandcamp page.