Mediators of Inflammation

Mediators of Inflammation / 2015 / Article
Special Issue

Macrophages and Neutrophils: Regulation of the Inflammatory Microenvironment in Autoimmunity and Cancer

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Review Article | Open Access

Volume 2015 |Article ID 701067 |

Zvi Granot, Jadwiga Jablonska, "Distinct Functions of Neutrophil in Cancer and Its Regulation", Mediators of Inflammation, vol. 2015, Article ID 701067, 11 pages, 2015.

Distinct Functions of Neutrophil in Cancer and Its Regulation

Academic Editor: Ronald Gladue
Received24 Aug 2015
Accepted27 Oct 2015
Published16 Nov 2015


Neutrophils are the most abundant of all white blood cells in the human circulation and are usually associated with inflammation and with fighting infections. In recent years the role immune cells play in cancer has been a matter of increasing interest. In this context the function of neutrophils is controversial as neutrophils were shown to possess both tumor promoting and tumor limiting properties. Here we provide an up-to-date review of the pro- and antitumor properties neutrophils possess as well as the environmental cues that regulate these distinct functions.

1. Introduction

Neutrophils are the most abundant of all white blood cells and play a key role in host protection against microbial infections and in inflammation. Chronic inflammation has been associated with increased susceptibility for cancer. Hepatitis B [1] and inflammatory bowel disease [2] are common examples for this correlation, leading to hepatocellular carcinoma and colorectal cancer, respectively. Neutrophils, as a key component in inflammation, may play a crucial role in inflammation driven tumorigenesis. This was well exemplified when neutrophils were shown to directly promote carcinogenesis in a mouse model of colitis [3]. Indeed, neutrophils at the primary tumor site were shown to provide a wide range of different tumor promoting functions. Neutrophils were shown to support angiogenesis via secretion of proangiogenic factors as well as the proteolytic activation of proangiogenic factors. Neutrophils were also implicated in promoting tumor growth through the proteolytic release of EGF, TGFβ, and PDGF from the extracellular matrix (ECM). Neutrophils express high levels of metalloproteinases which can also modify the ECM to allow tumor cell dissemination thereby promoting tumor spread. Furthermore, neutrophils were shown to recruit other tumor promoting cells to the tumor bed. Finally, immature neutrophils, also termed G-MDSC (granulocytic myeloid derived suppressor cells), were implicated in the establishment of an immunosuppressive tumor microenvironment thereby limiting antitumor immunity. On the other hand, neutrophils were shown to have antitumor properties including the capacity to kill tumor cells either through direct cytotoxicity or via antibody dependent cell cytotoxicity (ADCC) [4]. Similar conflicting reports were made as to the role neutrophils play in the premetastatic niche. Neutrophils accumulate in large numbers in premetastatic organs [57]. The fact that bone marrow derived cells were implicated in priming of the premetastatic niche prompted the hypothesis that neutrophils may be the cells that mediate this process. Indeed, neutrophils were shown to have a positive effect on tumor cell seeding in the premetastatic site [6]. In contrast, we and others have shown that neutrophils actively limit metastatic seeding by killing tumor cells [5, 7].

Interestingly, while neutrophils play a role in modulating tumor cell seeding in the metastatic site, it seems like they do not affect the growth rate of the metastatic nodules [5, 7]. This suggested that neutrophil antitumor functions are not always manifested inside the tumor and may depend on the chemokine landscape in the tumor microenvironment. This notion was further supported by findings showing that upon entering the tumor microenvironment neutrophils acquire a different set of traits. This was referred to as “polarization” of neutrophils toward a tumor promoting or an antitumor phenotype which is mediated via cytokines available in the tumor microenvironment (i.e., TGFβ and IFNs, resp.). Furthermore, recent studies suggested that neutrophils are not a homogeneous population of cells and may consist of both pro- and antitumor subpopulations [8]. Together, the observations made thus far suggest that the mere accumulation of neutrophils in the tumor site may not necessarily be indicative of their contribution or of their prognostic value. Along these lines, the ongoing efforts to correlate neutrophil counts, or the ratio between neutrophils and other immune cells, with patient prognosis and ultimate outcome are conflicting and show that neutrophil abundance may correlate with a better prognosis in some studies and with a worse prognosis in others [9].

2. Molecular Mechanisms of Neutrophil Polarization in the Tumor Microenvironment

Neutrophils were shown to have diverse functions in the tumor microenvironment including both promoting and inhibiting tumor growth. As neutrophils are quick to respond to environmental cues, the most plausible explanation for the different neutrophil phenotypes was that neutrophil function is dictated by the local chemokine milieu. Advances in our understanding of how neutrophil function is regulated in cancer have led to the realization that neutrophils may be directed towards a specific phenotype, be it tumor promoting or tumor limiting, upon entering the tumor. Here we will discuss how interferons and TGFβ polarize neutrophils in the tumor microenvironment.

2.1. Interferons

Type I interferons (IFNs) were first characterized in the process of viral interference. However, since then IFNs were found to be involved in a wide range of biological processes. In the context of cancer, IFNs show strong antitumor function as they inhibit tumor cell proliferation and promote apoptosis [10]. However, IFNs were also found to play a key role in mounting an antitumor immune response through the activation of T-cells, NK cells, and macrophages [11]. In recent years it has become apparent that IFNs also affect neutrophil function and promote antitumor processes mediated by neutrophils. Jablonska et al. have shown that IFN-β is critical for suppressing the expression of proangiogenic factors, such as VEGF and MMP9, in tumor infiltrating neutrophils leading to enhanced tumor vascularization and growth in IFN-β deficient animals [12]. Furthermore, IFN-β was found to play a significant role in regulating the recruitment of neutrophils and their longevity in the primary tumor [13, 14]. Finally, type I IFN activity was found to inhibit neutrophil-mediated formation of “fertile” premetastatic niche [15].

2.2. TGFβ

TGFβ is a multipotent molecule known to have diverse effects in cancer. One of the most explored functions of TGFβ in cancer is its role in generating an immunosuppressive tumor microenvironment. A groundbreaking study by Fridlender and colleagues [16] demonstrated that TGFβ plays a critical role in suppression of antitumor neutrophil cytotoxicity. In this study, the authors showed that blocking TGFβ signaling leads to a change in the cellular composition of the tumor and allows the influx of large numbers of neutrophils. More importantly, they showed that tumor-associated neutrophils (TANs) recruited in the absence of TGFβ signaling have an antitumor N1 phenotype. The authors concluded that TGFβ in the tumor microenvironment is involved in polarizing TAN towards N2 protumor phenotype. This concept was supported by other studies showing that TGFβ can directly block antitumor neutrophil cytotoxicity [5] and that TGFβ receptor deficient myeloid cells, including neutrophils, maintain an antitumor phenotype and limit tumor growth [17].

The conflicting effects of TGFβ and IFNs on neutrophil function in the context of cancer are an example of how neutrophils respond to cues in the microenvironment (Figure 1). While understanding the mechanisms that regulate neutrophil function is clearly important from a therapeutic point of view, the realization that neutrophils may play conflicting roles, depending on their context, is an important notion.

3. Antitumor N1 Phenotype

Antitumor N1 neutrophils act to limit tumor growth and metastatic progression. This is accomplished via distinct mechanisms including direct and antibody dependent cytotoxicity as well as through the activation of other cell types including T-cells and dendritic cells.

3.1. Direct Cytotoxicity

Direct cytotoxicity of neutrophils towards tumor cells is not a novel concept and was first observed in the early 1970s [18]. Neutrophils are highly motile phagocytic cells whose primary function is antimicrobial protection of the host. Accordingly, neutrophils generate a variety of antimicrobial molecules. However, most of these molecules are harmless to eukaryotic cells. Still, the reactive molecules generate by the NADPH oxidase complex, superoxides, H2O2, and HOCl. Indeed, these molecules were found to be directly involved in antitumor neutrophil cytotoxicity [1921]. Several studies have shown that physical contact is required for neutrophil cytotoxicity. However, stimulating cultured neutrophils with a potent agonist, such as PMA, leads to the generation and secretion of very high levels of H2O2 alleviating the need for physical contact [5].

3.2. ADCC

Antibody dependent cell-mediated cytotoxicity (ADCC) is another mechanism for neutrophil antitumor cytotoxicity. Tumor cell-specific antibodies may be successfully used as an anticancer therapy. Antibody labeled cells are susceptible to destruction by immune cells expressing Fc receptors (FcR). Neutrophils express several FcRs that can mediate ADCC including FcγRI (CD64), FcγRIIa (CD32), FcγRIIIa (CD16a), and FcγRIIIb (CD16b) [2224]. Indeed, neutrophils were shown to take part in ADCC in several types of cancer including glioma, squamous cell, and ovarian carcinoma. Neutrophils were also shown to contribute to the antitumor ADCC in Non-Hodgkin’s Lymphoma [25], in breast cancer using [26], and in B-cell lymphoma [27].

3.3. Stimulation of T-Cells and DCs

Neutrophils, on top of having a role in killing tumor cells directly, can also stimulate adaptive antitumor immune responses. This was well exemplified by experiments showing that neutrophils are required for proper antitumor CD8+ T-cell immune response [16, 2830]. Stimulation of adaptive antitumor immunity by neutrophils has two arms, the recruitment of other immune cells and their antigen presenting abilities.

(a) Recruitment of Immune Cells. Neutrophils secrete several cytokines including TNFα, Cathepsin G, and neutrophil elastase which have a direct effect on T-cells and promote their proliferation and cytokine production. Neutrophils, under these conditions, act to recruit and activate T-cells and enhance the overall adaptive immune antitumor response. Specifically, TAN were shown to stimulate T-cell proliferation and IFNγ secretion in early stage lung cancer patients [31].

(b) Neutrophil Extracellular Traps (NETs). Production of extracellular traps by neutrophils is an interesting feature in neutrophil biology. These NETs are composed of chromatin fibers decorated with histones and other proteins and are considered as an additional tool in neutrophils’ arsenal of antimicrobial properties. However, Tillack and colleagues showed that NETs may also be utilized to prime T-cells [32]. This was also linked to a possible role of NETs in immunoediting in cancer and the propagation of antitumor immune responses [33].

(c) Antigen Presentation. For a long time antigen presentation was thought to be exclusively mediated by macrophages and more so by dendritic cells (DCs). However, in 2007 Beauvillain and colleagues demonstrated that neutrophils can efficiently process and present antigens to directly stimulate T-cell immune responses [34]. While this does not directly link neutrophil presentation of antigens to antitumor cytotoxicity, Fridlender and colleagues showed in 2009 that N1 TANs require T-cells for their antitumor activity in the primary tumor [16], an observation that may be explained by neutrophils’ ability to present tumor antigens to stimulate T-cells.

4. Protumor N2 Phenotype

Neutrophils have been traditionally considered as guards of the host immune system. However, in the context of tumor, the function of these cells is frequently modified to act against the host and promote tumor growth and metastasis formation. A possible reason for this could be tumor-secreted factors that elicit wound-repair responses by neutrophils that in turn inadvertently stimulate tumor progression [35]. Moreover, wound-infiltrating neutrophils are rapidly diverted from a wound to preneoplastic cells and such interactions lead to increased proliferation of the preneoplastic cells. Prostaglandin E2 (PGE2) seems to be the factor responsible for this process [36]. These results have shown that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Along these lines, several studies have shown that infiltration of tumors by neutrophils is associated with poor clinical outcome. Tumor-associated neutrophils (TANs) have been shown to promote tumor growth and progression via a variety of mechanisms, including extracellular matrix remodeling, promotion of tumor cell invasion and metastasis, angiogenesis, lymphangiogenesis, and immune suppression [12, 13, 15].

4.1. Protumor Cytokines

One of the mechanisms responsible for neutrophil-mediated tumor angiogenesis, growth, and metastasis is the secretion of protumor cytokines by these cells [37]. Depending on the cytokine milieu, neutrophils are able to secrete multiple growth factors such as EGF, TGFβ, PDGF, HGF, VEGF, and oncostatin M [12, 3841].

Evidence suggests that EGF and its receptor EGFR are involved in the pathogenesis and progression of different carcinoma types [42]. Amplification of the EGFR gene and mutations of the EGFR tyrosine kinase domain have been recently demonstrated to occur in carcinoma patients. EGFR causes neoangiogenesis but also increased proliferation, decreased apoptosis, and enhanced tumor cell motility [43] since its receptor (EGFR; HER1; erbB1) is highly expressed on variety of human tumors including non-small cell lung cancer (NSCLC) and breast, head and neck, gastric, colorectal, esophageal, prostate, bladder, renal, pancreatic, and ovarian cancers [42, 44].

TGFβ is frequently upregulated in human cancers [45] and has been linked to the regulation of tumor initiation, progression, and metastasis [46]. Tumor-secreted TGFβ is usually sequestered to the extracellular matrix as an inactive complex and becomes activated through enzymes such as neutrophil-derived elastase and MMP9 [46]. Furthermore, reactive oxygen free radicals produced by activated neutrophils can activate latent TGFβ [47]. Thus, activated neutrophils, through production of elastase, MMP9, and ROS, may contribute to TGFβ-mediated immunosuppression [9]. Furthermore, TGFβ has been shown to be a potent chemoattractant for neutrophils facilitating their recruitment to sites of inflammation [48, 49] and to promote their protumor N2 phenotype, as mentioned above [16].

Another important neutrophil-derived growth factor is platelet-derived growth factor (PDGF). Interestingly, this growth factor was shown to be chemotactic for monocytes and neutrophils [50]. It was recently established that PDGF stimulation cooperates with genetic changes caused by retroviral insertions in induction of fully malignant tumor phenotype [51]. Moreover, the autocrine PDGF signaling seems to play a role in the growth and metastasis of epithelial cancers.

VEGF is a very potent proangiogenic factor but also serves as a potent chemoattractant for neutrophils. It has been implicated as the key endothelial cell-specific factor required for pathological angiogenesis, including tumor neovascularization. Inhibition of the VEGF signaling blocks angiogenesis in growing tumors, leading to regression of tumor growth [52]. The function of vascular endothelial growth factor (VEGF) in cancer is not limited to angiogenesis and vascular permeability [53]. VEGF-mediated signaling occurs in tumor cells, and this signaling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumor initiation [54]. Autocrine VEGF signaling can promote the growth, survival, migration, and invasion of cancer cells [5557].

Oncostatin M is another pleiotropic cytokine that is secreted by neutrophils [58]. It has been shown to exert proinflammatory effects by inducing adhesion and chemotaxis of neutrophils and chemokine production by endothelial cells [59]. Although oncostatin M was originally identified as an inhibitor of tumor cell growth in vitro [60, 61], it is increasingly apparent that this cytokine plays a role in breast cancer cell detachment [62] and angiogenesis [41].

In addition to growth factors, neutrophils are able to secrete other cytokines that influence tumor development and spreading. For instance, neutrophil delivered TNFα, IL-6, and IL-17 were shown to promote tumor growth by modifying the function of stromal cells surrounding the tumor [63, 64]. TNFα produced by tumor cells or inflammatory cells in the tumor microenvironment can promote tumor cell survival through the induction of NFκB-dependent antiapoptotic molecules [65]. TNFα was also shown to promote angiogenesis [66] and induce the expression of VEGF and HIF-1α in tumor cells [67]. IL-6 promotes angiogenesis and the expression of VEGF [68] through JAK2/STAT3 signaling [64] and the tumor promoting effects of IL-17 are in part mediated through upregulation of IL-6 [63, 64].

4.2. Angiogenesis and Modulation of the ECM

Angiogenesis is one of the hallmarks of the development of malignant neoplasias. Primary tumors of a certain size require the growth of new blood vessels in order to be supplied with nutrients and oxygen. Accordingly, at a size of 1-2 mm3, tumors alter their angiogenic phenotype and support continuous proliferation of endothelial cells. This “angiogenic switch” is activated by disturbed balance between endogenous pro- and antiangiogenic factors. It leads to the uncontrolled growth of blood vessels, mainly via stimulation of VEGF. Importantly, experimental in vivo models of angiogenesis have demonstrated that neutrophils affect neovascularization in the tissues [69]. Accordingly, Gr-1-mediated neutrophil depletion was found to significantly reduce tumor angiogenesis [70, 71]. Notably, in patients with myxofibrosarcoma, elevated numbers of neutrophils were observed in high-grade malignant tumors and this correlated positively with increased intratumoral microvessel density [72]. The mechanism by which tumor-associated neutrophils modulate tumor angiogenesis has not been fully elucidated. Activated neutrophils can release a variety of proteases that can degrade and remodel the ECM, a process that is crucial for angiogenesis. These cells have recently been shown to express high amounts of VEGF and MMP9 that is known to be responsible for initiation of the angiogenic switch and to support vessel growth in tumors [12]. MMP9 has been shown to have the most profound effects in mediating tumor angiogenesis [73]. Proteolysis of the ECM by this MMP releases such potent angiogenic factors such as vascular endothelial growth factor (VEGF) and FGF2 that are usually sequestered in an inactivated form to the ECM [74, 75]. MMP9 is also involved in the regulation of leukocytosis, for example, by potentiating proangiogenic and neutrophil attracting IL-8 expression [76] and by the release of hematopoietic progenitor cells from the bone marrow [77]. Huang et al. could show that MMP9-deficient mice display significantly reduced tumor microvessel density, compared with wild-type mice [78]. Neutrophil-derived MMP9 has also been shown to contribute to tumor angiogenesis and progression of squamous cell carcinoma [74]. Finally, Bv8, a potent proangiogenic factor, was shown to be upregulated in neutrophils in the context of cancer and to directly contribute to tumor angiogenesis and progression [79, 80].

4.3. Tumor Cell Dissemination

Metastasis is a highly complex process requiring tumor cell detachment from the primary tumor and migration to secondary target organs through the lymphatic or blood circulatory systems [81]. Neutrophils can exhibit both pro- and antimetastatic properties under certain conditions [8285]. In prometastatic state neutrophils secrete soluble factors, including proteases and cytokines, that activate endothelium and parenchymal cells, leading to improvement of adhesion of circulating tumor cells in distant sites [74, 83, 86] and enhanced metastasis formation. Moreover, contact-dependent mechanisms, whereby neutrophils act as a bridge, tethering circulating tumor cells (CTCs) to target organ endothelium, have been described [87]. Such interaction is mediated by the binding of β2 integrins on neutrophils to ICAM-1 on tumor cells and was described for lung and liver metastasis model [84, 88]. In studies by Spicer et al. neutrophils promote cancer cell adhesion within liver sinusoids and their depletion before cancer cell inoculation resulted in decreased number of metastases in an intrasplenic model of liver metastasis [84]. Another interesting study showed that neutrophils can support lung metastasis development through physical interaction and anchoring of circulating tumor cells to endothelium [89]. It is not clear if this process supports tumor cell extravasation into target organ or neutrophils hold melanoma cells in the capillaries until they grow into a secondary tumor [89].

In addition to the mechanisms proposed thus far, novel aspects of neutrophil biology recently got attention as possible mechanism that contributes to cancer progression and metastasis. Recent studies suggest that NETs are able to trap tumor cells and depending on neutrophil activation such sequestered tumor cells can be destroyed by ROS that results in inhibition of metastasis formation [82] or be kept in place thus supporting early adhesion of tumor cells to distant organ sites and metastatic processes [90].

In the recent work of Wu et al. an inhibitory role of endogenous type I IFNs on neutrophil-mediated metastasis formation could be shown. The lack of endogenous type I IFNs drives neutrophils to prometastatic phenotype at least in two ways, supporting neutrophil migration and the formation of the premetastatic niche in the lung and inhibiting neutrophil cytotoxicity against tumor cells in circulation.

4.4. Formation of the Premetastatic Niche

Tumor induced changes in the microenvironment of distal organs make tissues more receptive to colonization of migrating tumor cells [91, 92]. Consequently, bone marrow derived cells, including neutrophils, are mobilized and accumulate in the future site of metastasis [93] where they participate in the formation of supportive metastatic microenvironment termed “premetastatic niche” [9496]. These cells are recruited by Bv8, MMP9, S100A8, and S100A9 [6, 97] and this process seems to be strongly dependent on granulocyte colony-stimulating factor (G-CSF) [6].

Recent studies have shown that neutrophils make up the main cell population involved in formation of premetastatic niche [82]. This process seems to be enhanced by the absence of type I interferons that results in upregulation of CXCR2 expression on neutrophils from these mice. Moreover, prometastatic molecules like S100A8, S100A9, Bv8, and MMP9 are upregulated in lungs of Ifnar1−/− mice. Both S100A8 and S100A9 are known to influence tumor cell proliferation, survival, and migration [97, 98] but also to stimulate migration and proliferation of neutrophils. Bv8, next to induction of tumor cell extravasation [6], increases neutrophil accumulation within premetastatic tissue. MMP9 is responsible for formation of leaky vasculature in the premetastatic lung [99] and support of tumor cells survival in this organ [100].

4.5. Recruitment of Other Cells and Immune Evasion

The immune regulatory functions of neutrophils are recently getting growing attention. Interactions between neutrophils and other immune cells obviously are regulating many inflammatory processes, including tumorigenesis. There is evidence that activated neutrophils can interact with T-cells in dichotomous ways. Several studies have shown that neutrophils can present antigens and provide accessory signals for T-cell activation [101103]. Other studies have suggested that neutrophils can suppress antigen-nonspecific T-cell proliferation [104, 105]. The suppressive function of granulocytic cells in cancer patients has generally been attributed to a circulating low-density granulocytic myeloid derived suppressor cell (G-MDSC) population [6062]. However, there is some uncertainty about whether G-MDSCs do exist in humans. In mice this heterogeneous group of cells consists mainly of immature neutrophils and monocytes.

Neutrophil-mediated T-cell suppression requires arginase 1 or ROS [105107]. In humans with metastatic cancer disease, arginase 1-mediated suppression of lymphocytes was reported [108, 109]. Lately, mature blood neutrophil subset was shown to suppress T-cell activation in cancer [8] and during severe inflammation [104]. This suppression requires release of H2O2 into the immunological synapse in a Mac-1 (CD11b/CD18) dependent manner.

Very recent studies show that neutrophils cooperate with γδ T-cells in promotion of breast cancer metastasis [110]. Neutrophil depletion in the highly aggressive metastatic breast cancer mouse model KEP results in significant reduction of both spontaneous pulmonary and lymph node metastasis [110]. Moreover, combined depletion of both neutrophils and CD8+ cells results in inhibition of metastasis formation, implicating cooperation of these cells during this process.

5. Recruitment of Neutrophils into Tumor and Premetastatic Sites

Neutrophils make up substantial population of cells infiltrating tumors and premetastatic niche, in mice and human [12, 15, 111]. Many cell subtypes, including tumor cells, produce chemokines that attract neutrophils, for example, CXCL1 or CXCL2.

5.1. Factors That Mediate Neutrophil Recruitment

The migration of neutrophils into solid tumors depends on chemotactic factors. There are several chemotactic factors that may stimulate the migration of neutrophils, but the most potent are members of the CXCL chemokine family. Human CXCL8 (IL-8) is one of the best studied neutrophil chemoattractants with respect to tumor biology and is overexpressed in different human carcinomas and tumor cell lines including breast, colon, cervical, lung, brain, prostate, ovarian, and renal cell carcinomas, acute myelogenous and B-cell lymphocytic leukemia, melanoma, and Hodgkin’s disease [112]. Importantly, both stromal and tumor cells can produce CXCL8. Other human chemokines such as CCL3 (MIP-1α) and CXCL6 (huGCP-2) or murine chemokines CXCL1, CXCL2, and CXCL5 are potent chemoattractants and activators for neutrophils [12] and are produced by many tumors [113116]. Recent study on hepatocellular carcinoma indicated importance of CXCL16 and its receptor CXCR6 in neutrophil recruitment and tumor progression, due to its ability to stimulate tumor cells to release CXCL8. Another recent study shows that human metastatic melanoma cells entrapped in the lungs secrete IL-8 to attract neutrophils, which promotes tumor cell tethering to the vascular endothelium. Prolonged cell retention in the lungs facilitated transendothelial migration and metastasis development [89]. Experiments have shown that inhibition of neutrophil migration, for example, by blocking of chemokine receptor CXCR2 or CXCR2−/− in mice, leads to reduced tumor angiogenesis and growth in B16F10 melanoma [14, 117] and Lewis lung carcinoma model [107]. Inhibited myeloid cell infiltration due to the loss of CXCR2 was also shown to be responsible for significantly suppressed chronic colonic inflammation and colitis-associated tumorigenesis [118].

A number of additional mediators might serve as chemoattractants for neutrophil recruitment to the tumor tissue. It has been shown that bioactive lipids, such as sphingosine-1-phosphate (S1P), could promote neutrophil activation and chemotaxis [119, 120]. Similarly, the hypoxia-inducible factor 1-α and its downstream products like CXCL12, VEGF, or MMP9 are involved in recruitment and retention of neutrophils in angiogenic environments [12, 121]. VEGF, in addition to its proangiogenic role during tumor growth, is also capable of inducing neutrophil adhesion to postcapillary venules followed by homing to tissues of its high expression, for example, tumor or premetastatic niche [122, 123].

Recent studies suggest that the myeloid-related proteins (MRPs) are also involved in neutrophil migration. The MRPs S100A8 and S100A9 are strongly expressed by tumors and in the premetastatic niche and act as strong chemoattractants for neutrophils into these sites [82, 97, 124]. However, the exact mechanism of MRPs mediated neutrophil mobilization is not clear and still needs to be investigated.

5.2. Survival of Neutrophils in Tumor Microenvironment

Due to their proinflammatory functions and potential toxicity against host tissue, the neutrophil life span is strictly regulated [125]. In the absence of inflammatory stimuli, neutrophils are removed from circulation shortly after their mobilization from the bone marrow, mainly by apoptosis. Importantly, several proinflammatory cytokines have been shown to influence the longevity of neutrophils [126]. Recent observations of Andzinski et al. [13] show that the life span of tumor-associated neutrophils is remarkably prolonged in tumor-bearing IFN-β deficient (Ifnb1−/−) mice, compared to wild-type controls. This is apparently due to the fact that IFN-β is able to influence both the extrinsic and the intrinsic apoptosis pathways of neutrophilic granulocytes. Lower expression of Fas, reactive oxygen species, active Caspases 3 and 9, as well as a change in expression pattern of proapoptotic and antiapoptotic members of the Bcl-2 family and the major apoptosome constituent Apaf-1, is observed under such conditions. The death receptor Fas on neutrophils has been shown to be involved in spontaneous extrinsic cell death signaling [127]. Fas has been shown to play a role in type I IFN-induced apoptosis in several types of neoplasias such as melanoma, multiple myeloma, and chronic myeloid leukemia cells [128, 129].

ROS production by neutrophils might also play an important role in regulation of life span of neutrophils. For example, a delayed spontaneous apoptosis was shown in patients deficient for NADPH oxidase [130, 131]. It has also been shown that hypoxia or pharmacological inhibition of NADPH oxidase and hydrogen peroxide scavengers decreases the rate of neutrophil apoptosis [132]. Recent data indicate that spontaneous production of ROS is diminished in the absence of endogenous IFN-β, potentially contributing to the delayed apoptosis of tumor infiltrating neutrophils in Ifnb1−/− mice [13]. G-CSF is one of the major survival factors of neutrophilic granulocytes and has been reported to reduce Bax expression and redistribution [133] and restore its phosphorylation status thus leading to its inactivation. This mechanism is responsible for G-CSF-mediated repression of Caspase activation [134]. Regulation of G-CSF expression is responsible for altered neutrophils survival in tumors.

6. Concluding Remarks

Neutrophil function in cancer has long been a matter of debate as these cells were shown to possess a range of tumor promoting as well as tumor limiting properties. We propose that these conflicting observations stem from the fact that neutrophils are not a homogeneous population of cells. Neutrophil heterogeneity stems from two facts that are not mutually exclusive and have to do with the changes in the chemokine milieu in the context of cancer: The first is the fact that neutrophils are highly responsive to cues in their microenvironment and may adopt a protumor phenotype in certain conditions and an antitumor phenotype in others. The second is the fact that there are distinct neutrophil subsets which differ in their contribution in the context of cancer. Together, these observations support the notion that neutrophil function in cancer may be dictated in a context dependent fashion (Figure 1). These observations also identify potential elements which may be therapeutically targeted to enhance antitumor neutrophil activity while limiting their protumor properties.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


  1. Y. Nakamoto, L. G. Guidotti, C. V. Kuhlen, P. Fowler, and F. V. Chisari, “Immune pathogenesis of hepatocellular carcinoma,” Journal of Experimental Medicine, vol. 188, no. 2, pp. 341–350, 1998. View at: Publisher Site | Google Scholar
  2. G. Rogler, “Chronic ulcerative colitis and colorectal cancer,” Cancer Letters, vol. 345, no. 2, pp. 235–241, 2014. View at: Publisher Site | Google Scholar
  3. K. Shang, Y.-P. Bai, C. Wang et al., “Crucial involvement of tumor-associated neutrophils in the regulation of chronic colitis-associated carcinogenesis in mice,” PLoS ONE, vol. 7, no. 12, Article ID e51848, 2012. View at: Publisher Site | Google Scholar
  4. M. van Egmond and J. E. Bakema, “Neutrophils as effector cells for antibody-based immunotherapy of cancer,” Seminars in Cancer Biology, vol. 23, no. 3, pp. 190–199, 2013. View at: Publisher Site | Google Scholar
  5. Z. Granot, E. Henke, E. A. Comen, T. A. King, L. Norton, and R. Benezra, “Tumor entrained neutrophils inhibit seeding in the premetastatic lung,” Cancer Cell, vol. 20, no. 3, pp. 300–314, 2011. View at: Publisher Site | Google Scholar
  6. M. Kowanetz, X. Wu, J. Lee et al., “Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21248–21255, 2010. View at: Publisher Site | Google Scholar
  7. M. A. López-Lago, S. Posner, V. J. Thodima, A. M. Molina, R. J. Motzer, and R. S. K. Chaganti, “Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression,” Oncogene, vol. 32, no. 14, pp. 1752–1760, 2013. View at: Publisher Site | Google Scholar
  8. J. Y. Sagiv, J. Michaeli, S. Assi et al., “Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer,” Cell Reports, vol. 10, no. 4, pp. 562–573, 2015. View at: Publisher Site | Google Scholar
  9. R. V. Sionov, Z. G. Fridlender, and Z. Granot, “The multifaceted roles neutrophils play in the tumor microenvironment,” Cancer Microenvironment, pp. 1–34, 2014. View at: Publisher Site | Google Scholar
  10. D. V. Kalvakolanu, “Interferons and cell growth control,” Histology and Histopathology, vol. 15, no. 2, pp. 523–537, 2000. View at: Google Scholar
  11. M. M. Brierley and E. N. Fish, “Review: IFN-α/β receptor interactions to biologic outcomes: understanding the circuitry,” Journal of Interferon and Cytokine Research, vol. 22, no. 8, pp. 835–845, 2002. View at: Publisher Site | Google Scholar
  12. J. Jablonska, S. Leschner, K. Westphal, S. Lienenklaus, and S. Weiss, “Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1151–1164, 2010. View at: Publisher Site | Google Scholar
  13. L. Andzinski, C.-F. Wu, S. Lienenklaus, A. Kröger, S. Weiss, and J. Jablonska, “Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN-β,” International Journal of Cancer, vol. 136, no. 3, pp. 572–583, 2015. View at: Publisher Site | Google Scholar
  14. J. Jablonska, C.-F. Wu, L. Andzinski, S. Leschner, and S. Weiss, “CXCR2-mediated tumor-associated neutrophil recruitment is regulated by IFN-beta,” International Journal of Cancer, vol. 134, no. 6, pp. 1346–1358, 2014. View at: Publisher Site | Google Scholar
  15. C.-F. Wu, L. Andzinski, N. Kasnitz et al., “The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung,” International Journal of Cancer, vol. 137, no. 4, pp. 837–847, 2015. View at: Publisher Site | Google Scholar
  16. Z. G. Fridlender, J. Sun, S. Kim et al., “Polarization of tumor-associated neutrophil phenotype by TGF-β: ‘N1’ versus ‘N2’ TAN,” Cancer Cell, vol. 16, no. 3, pp. 183–194, 2009. View at: Publisher Site | Google Scholar
  17. S. V. Novitskiy, M. W. Pickup, A. Chytil, D. Polosukhina, P. Owens, and H. L. Moses, “Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties,” Journal of Leukocyte Biology, vol. 92, no. 3, pp. 641–651, 2012. View at: Publisher Site | Google Scholar
  18. J. Bubeník, P. Perlmann, K. Helmstein, and G. Moberger, “Cellular and humoral immune responses to human urinary bladder carcinomas,” International Journal of Cancer, vol. 5, no. 3, pp. 310–319, 1970. View at: Publisher Site | Google Scholar
  19. J. Dissemond, T. K. Weimann, L. A. Schneider et al., “Activated neutrophils exert antitumor activity against human melanoma cells: reactive oxygen species-induced mechanisms and their modulation by granulocyte-macrophage-colony-stimulating factor,” Journal of Investigative Dermatology, vol. 121, no. 4, pp. 936–938, 2003. View at: Publisher Site | Google Scholar
  20. M. Zivkovic, M. Poljak-Blazi, G. Egger, S. B. Sunjic, R. J. Schaur, and N. Zarkovic, “Oxidative burst and anticancer activities of rat neutrophils,” BioFactors, vol. 24, no. 1–4, pp. 305–312, 2005. View at: Publisher Site | Google Scholar
  21. R. A. Clark and S. J. Klebanoff, “Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system,” Journal of Experimental Medicine, vol. 141, no. 6, pp. 1442–1447, 1975. View at: Publisher Site | Google Scholar
  22. B. H. Kushner and N.-K. V. Cheung, “Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity,” Blood, vol. 79, no. 6, pp. 1484–1490, 1992. View at: Google Scholar
  23. D. Iliopoulos, C. Ernst, Z. Steplewski et al., “Inhibition of metastases of a human melanoma xenograft by monoclonal antibody to the GD2/GD3 gangliosides,” Journal of the National Cancer Institute, vol. 81, no. 6, pp. 440–444, 1989. View at: Publisher Site | Google Scholar
  24. T. Valerius, R. Repp, T. P. M. de Wit et al., “Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy,” Blood, vol. 82, no. 3, pp. 931–939, 1993. View at: Google Scholar
  25. F. J. Hernandez-Ilizaliturri, V. Jupudy, J. Ostberg et al., “Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model,” Clinical Cancer Research, vol. 9, no. 16, part 1, pp. 5866–5873, 2003. View at: Google Scholar
  26. P. Hubert, A. Heitzmann, S. Viel et al., “Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy,” Cancer Research, vol. 71, no. 15, pp. 5134–5143, 2011. View at: Publisher Site | Google Scholar
  27. Y. Guettinger, K. Barbin, M. Peipp et al., “A recombinant bispecific single-chain fragment variable specific for HLA class II and FcαRI (CD89) recruits polymorphonuclear neutrophils for efficient lysis of malignant B lymphoid cells,” Journal of Immunology, vol. 184, no. 3, pp. 1210–1217, 2010. View at: Publisher Site | Google Scholar
  28. F. Fioretti, D. Fradelizi, A. Stoppacciaro et al., “Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor,” Journal of Immunology, vol. 161, no. 1, pp. 342–346, 1998. View at: Google Scholar
  29. A. Stoppacciaro, C. Melani, M. Parenza et al., “Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon γ,” Journal of Experimental Medicine, vol. 178, no. 1, pp. 151–161, 1993. View at: Publisher Site | Google Scholar
  30. F. Cavallo, M. Giovarelli, A. Gulino et al., “Role of neutrophils and CD4+ T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene,” The Journal of Immunology, vol. 149, no. 11, pp. 3627–3635, 1992. View at: Google Scholar
  31. E. B. Eruslanov, P. S. Bhojnagarwala, J. G. Quatromoni et al., “Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer,” Journal of Clinical Investigation, vol. 124, no. 12, pp. 5466–5480, 2014. View at: Publisher Site | Google Scholar
  32. K. Tillack, P. Breiden, R. Martin, and M. Sospedra, “T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses,” Journal of Immunology, vol. 188, no. 7, pp. 3150–3159, 2012. View at: Publisher Site | Google Scholar
  33. S. Berger-Achituv, V. Brinkmann, U. A. Abed et al., “A proposed role for neutrophil extracellular traps in cancer immunoediting,” Frontiers in Immunology, vol. 4, article 48, 2013. View at: Publisher Site | Google Scholar
  34. C. Beauvillain, Y. Delneste, M. Scotet et al., “Neutrophils efficiently cross-prime naive T cells in vivo,” Blood, vol. 110, no. 8, pp. 2965–2973, 2007. View at: Publisher Site | Google Scholar
  35. G. F. Whalen, “Solid tumours and wounds: transformed cells misunderstood as injured tissue?” The Lancet, vol. 336, no. 8729, pp. 1489–1492, 1990. View at: Publisher Site | Google Scholar
  36. N. Antonio, M. L. Bonnelykke-Behrndtz, L. C. Ward et al., “The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer,” The EMBO Journal, vol. 34, no. 17, pp. 2219–2236, 2015. View at: Publisher Site | Google Scholar
  37. C. Tecchio, P. Scapini, G. Pizzolo, and M. A. Cassatella, “On the cytokines produced by human neutrophils in tumors,” Seminars in Cancer Biology, vol. 23, no. 3, pp. 159–170, 2013. View at: Publisher Site | Google Scholar
  38. M. A. Cassatella, “Neutrophil-derived proteins: selling cytokines by the pound,” Advances in Immunology, vol. 73, pp. 369–509, 1999. View at: Publisher Site | Google Scholar
  39. G. R. Grotendorst, G. Smale, and D. Pencev, “Production of transforming growth factor beta by human peripheral blood monocytes and neutrophils,” Journal of Cellular Physiology, vol. 140, no. 2, pp. 396–402, 1989. View at: Publisher Site | Google Scholar
  40. M. McCourt, J. H. Wang, S. Sookhai, and H. P. Redmond, “Activated human neutrophils release hepatocyte growth factor/scatter factor,” European Journal of Surgical Oncology, vol. 27, no. 4, pp. 396–403, 2001. View at: Publisher Site | Google Scholar
  41. M. M. Queen, R. E. Ryan, R. G. Holzer, C. R. Keller-Peck, and C. L. Jorcyk, “Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression,” Cancer Research, vol. 65, no. 19, pp. 8896–8904, 2005. View at: Publisher Site | Google Scholar
  42. N. Normanno, A. De Luca, C. Bianco et al., “Epidermal growth factor receptor (EGFR) signaling in cancer,” Gene, vol. 366, no. 1, pp. 2–16, 2006. View at: Publisher Site | Google Scholar
  43. C. L. Arteaga, “Epidermal growth factor receptor dependence in human tumors: more than just expression?” Oncologist, vol. 7, supplement 4, pp. 31–39, 2002. View at: Publisher Site | Google Scholar
  44. D. S. Salomon, R. Brandt, F. Ciardiello, and N. Normanno, “Epidermal growth factor-related peptides and their receptors in human malignancies,” Critical Reviews in Oncology and Hematology, vol. 19, no. 3, pp. 183–232, 1995. View at: Publisher Site | Google Scholar
  45. S. Wojtowicz-Praga, “Reversal of tumor-induced immunosuppression by TGF-β inhibitors,” Investigational New Drugs, vol. 21, no. 1, pp. 21–32, 2003. View at: Publisher Site | Google Scholar
  46. B. Bierie and H. L. Moses, “Transforming growth factor beta (TGF-β) and inflammation in cancer,” Cytokine and Growth Factor Reviews, vol. 21, no. 1, pp. 49–59, 2010. View at: Publisher Site | Google Scholar
  47. M. H. Barcellos-Hoff and T. A. Dix, “Redox-mediated activation of latent transforming growth factor-β1,” Molecular Endocrinology, vol. 10, no. 9, pp. 1077–1083, 1996. View at: Publisher Site | Google Scholar
  48. T. Parekh, B. Saxena, J. Reibman, B. N. Cronstein, and L. I. Gold, “Neutrophil chemotaxis in response to TGF-beta isoforms (TGF-beta 1, TGF-beta 2, TGF-beta 3) is mediated by fibronectin,” The Journal of Immunology, vol. 152, no. 5, pp. 2456–2466, 1994. View at: Google Scholar
  49. J. Reibman, S. Meixler, T. C. Lee et al., “Transforming growth factor beta 1, a potent chemoattractant for human neutrophils, bypasses classic signal-transduction pathways,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 15, pp. 6805–6809, 1991. View at: Publisher Site | Google Scholar
  50. T. F. Deuel, R. M. Senior, J. S. Huang, and G. L. Griffin, “Chemotaxis of monocytes and neutrophils to platelet-derived growth factor,” The Journal of Clinical Investigation, vol. 69, no. 4, pp. 1046–1049, 1982. View at: Publisher Site | Google Scholar
  51. L. Uhrbom, G. Hesselager, M. Nistér, and B. Westermark, “Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus,” Cancer Research, vol. 58, no. 23, pp. 5275–5279, 1998. View at: Google Scholar
  52. G. McMahon, “VEGF receptor signaling in tumor angiogenesis,” Oncologist, vol. 5, supplement 1, pp. 3–10, 2000. View at: Publisher Site | Google Scholar
  53. D. R. Senger, “Vascular endothelial growth factor: much more than an angiogenesis factor,” Molecular Biology of the Cell, vol. 21, no. 3, pp. 377–379, 2010. View at: Publisher Site | Google Scholar
  54. H. L. Goel and A. M. Mercurio, “VEGF targets the tumour cell,” Nature Reviews Cancer, vol. 13, no. 12, pp. 871–882, 2013. View at: Publisher Site | Google Scholar
  55. R. C. Bates, J. D. Goldsmith, R. E. Bachelder et al., “Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids,” Current Biology, vol. 13, no. 19, pp. 1721–1727, 2003. View at: Publisher Site | Google Scholar
  56. R. E. Bachelder, A. Crago, J. Chung et al., “Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells,” Cancer Research, vol. 61, no. 15, pp. 5736–5740, 2001. View at: Google Scholar
  57. M. J. Barr, D. J. Bouchier-Hayes, and J. H. Harmey, “Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia,” International Journal of Oncology, vol. 32, no. 1, pp. 41–48, 2008. View at: Google Scholar
  58. A. Grenier, M. Dehoux, A. Boutten et al., “Oncostatin M production and regulation by human polymorphonuclear neutrophils,” Blood, vol. 93, no. 4, pp. 1413–1421, 1999. View at: Google Scholar
  59. S. M. Kerfoot, E. Raharjo, M. Ho et al., “Exclusive neutrophil recruitment with oncostatin M in a human system,” The American Journal of Pathology, vol. 159, no. 4, pp. 1531–1539, 2001. View at: Publisher Site | Google Scholar
  60. J. M. Zarling, M. Shoyab, H. Marquardt, M. B. Hanson, M. N. Lioubin, and G. J. Todaro, “Oncostatin M: a growth regulator produced by differentiated histiocytic lymphoma cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 24, pp. 9739–9743, 1986. View at: Publisher Site | Google Scholar
  61. J. Liu, N. Hadjokas, B. Mosley, Z. Estrov, M. J. Spence, and R. E. Vestal, “Oncostatin M-specific receptor expression and function in regulating cell proliferation of normal and malignant mammary epithelial cells,” Cytokine, vol. 10, no. 4, pp. 295–302, 1998. View at: Publisher Site | Google Scholar
  62. R. G. Holzer, R. E. Ryan, M. Tommack, E. Schlekeway, and C. L. Jorcyk, “Oncostatin M stimulates the detachment of a reservoir of invasive mammary carcinoma cells: role of cyclooxygenase-2,” Clinical and Experimental Metastasis, vol. 21, no. 2, pp. 167–176, 2004. View at: Publisher Site | Google Scholar
  63. R. J. Moore, D. M. Owens, G. Stamp et al., “Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis,” Nature Medicine, vol. 5, no. 7, pp. 828–831, 1999. View at: Publisher Site | Google Scholar
  64. F.-M. Gu, Q.-L. Li, Q. Gao et al., “IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma,” Molecular Cancer, vol. 10, article 150, 2011. View at: Publisher Site | Google Scholar
  65. J.-L. Luo, S. Maeda, L.-C. Hsu, H. Yagita, and M. Karin, “Inhibition of NF-κB in cancer cells converts inflammation- induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression,” Cancer Cell, vol. 6, no. 3, pp. 297–305, 2004. View at: Publisher Site | Google Scholar
  66. R. C. A. Sainson, D. A. Johnston, H. C. Chu et al., “TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype,” Blood, vol. 111, no. 10, pp. 4997–5007, 2008. View at: Publisher Site | Google Scholar
  67. Y. Jing, N. Ma, T. Fan et al., “Tumor necrosis factor-alpha promotes tumor growth by inducing vascular endothelial growth factor,” Cancer Investigation, vol. 29, no. 7, pp. 485–493, 2011. View at: Publisher Site | Google Scholar
  68. H.-E. Tzeng, C.-H. Tsai, Z.-L. Chang et al., “Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma,” Biochemical Pharmacology, vol. 85, no. 4, pp. 531–540, 2013. View at: Publisher Site | Google Scholar
  69. H. Nozawa, C. Chiu, and D. Hanahan, “Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 33, pp. 12493–12498, 2006. View at: Publisher Site | Google Scholar
  70. R. Benelli, M. Morini, F. Carrozzino et al., “Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation,” The FASEB Journal, vol. 16, no. 2, pp. 267–269, 2002. View at: Google Scholar
  71. J. P. Shaw, N. Chuang, H. Yee, and P. Shamamian, “Polymorphonuclear neutrophils promote rFGF-2-induced angiogenesis in vivo,” Journal of Surgical Research, vol. 109, no. 1, pp. 37–42, 2003. View at: Publisher Site | Google Scholar
  72. T. Mentzel, L. F. Brown, H. F. Dvorak et al., “The association between tumour progression and vascularity in myxofibrosarcoma and myxoid/round cell liposarcoma,” Virchows Archiv, vol. 438, no. 1, pp. 13–22, 2001. View at: Publisher Site | Google Scholar
  73. P. E. Van Den Steen, B. Dubois, I. Nelissen, P. M. Rudd, R. A. Dwek, and G. Opdenakker, “Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9),” Critical Reviews in Biochemistry and Molecular Biology, vol. 37, no. 6, pp. 375–536, 2002. View at: Publisher Site | Google Scholar
  74. L. M. Coussens, C. L. Tinkle, D. Hanahan, and Z. Werb, “MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis,” Cell, vol. 103, no. 3, pp. 481–490, 2000. View at: Publisher Site | Google Scholar
  75. G. Bergers, R. Brekken, G. McMahon et al., “Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis,” Nature Cell Biology, vol. 2, no. 10, pp. 737–744, 2000. View at: Publisher Site | Google Scholar
  76. P. E. Van den Steen, P. Proost, A. Wuyts, J. Van Damme, and G. Opdenakker, “Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact,” Blood, vol. 96, no. 8, pp. 2673–2681, 2000. View at: Google Scholar
  77. B. Heissig, K. Hattori, S. Dias et al., “Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand,” Cell, vol. 109, no. 5, pp. 625–637, 2002. View at: Publisher Site | Google Scholar
  78. S. Huang, M. Van Arsdall, S. Tedjarati et al., “Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice,” Journal of the National Cancer Institute, vol. 94, no. 15, pp. 1134–1142, 2002. View at: Publisher Site | Google Scholar
  79. F. Shojaei, M. Singh, J. D. Thompson, and N. Ferrara, “Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 7, pp. 2640–2645, 2008. View at: Publisher Site | Google Scholar
  80. F. Shojaei, X. Wu, C. Zhong et al., “Bv8 regulates myeloid-cell-dependent tumour angiogenesis,” Nature, vol. 450, no. 7171, pp. 825–831, 2007. View at: Publisher Site | Google Scholar
  81. G. P. Gupta and J. Massagué, “Cancer metastasis: building a framework,” Cell, vol. 127, no. 4, pp. 679–695, 2006. View at: Publisher Site | Google Scholar
  82. C.-F. Wu, W.-C. Chiang, C.-F. Lai et al., “Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis,” American Journal of Pathology, vol. 182, no. 1, pp. 118–131, 2013. View at: Publisher Site | Google Scholar
  83. J. E. De Larco, B. R. K. Wuertz, and L. T. Furcht, “The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8,” Clinical Cancer Research, vol. 10, no. 15, pp. 4895–4900, 2004. View at: Publisher Site | Google Scholar
  84. J. D. Spicer, B. McDonald, J. J. Cools-Lartigue et al., “Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells,” Cancer Research, vol. 72, no. 16, pp. 3919–3927, 2012. View at: Publisher Site | Google Scholar
  85. Z. G. Fridlender and S. M. Albelda, “Tumor-associated neutrophils: friend or foe?” Carcinogenesis, vol. 33, no. 5, pp. 949–955, 2012. View at: Publisher Site | Google Scholar
  86. A. M. Houghton, D. M. Rzymkiewicz, H. Ji et al., “Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth,” Nature Medicine, vol. 16, no. 2, pp. 219–223, 2010. View at: Publisher Site | Google Scholar
  87. P. Auguste, S. Lemiere, F. Larrieu-Lahargue, and A. Bikfalvi, “Molecular mechanisms of tumor vascularization,” Critical Reviews in Oncology/Hematology, vol. 54, no. 1, pp. 53–61, 2005. View at: Publisher Site | Google Scholar
  88. M. J. Slattery and C. Dong, “Neutrophils influence melanoma adhesion and migration under flow conditions,” International Journal of Cancer, vol. 106, no. 5, pp. 713–722, 2003. View at: Publisher Site | Google Scholar
  89. S. J. Huh, S. Liang, A. Sharma, C. Dong, and G. P. Robertson, “Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development,” Cancer Research, vol. 70, no. 14, pp. 6071–6082, 2010. View at: Publisher Site | Google Scholar
  90. J. Cools-Lartigue, J. Spicer, B. McDonald et al., “Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis,” Journal of Clinical Investigation, vol. 123, no. 8, pp. 3446–3458, 2013. View at: Publisher Site | Google Scholar
  91. J. A. Joyce and J. W. Pollard, “Microenvironmental regulation of metastasis,” Nature Reviews Cancer, vol. 9, no. 4, pp. 239–252, 2009. View at: Publisher Site | Google Scholar
  92. J. T. Erler, K. L. Bennewith, T. R. Cox et al., “Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche,” Cancer Cell, vol. 15, no. 1, pp. 35–44, 2009. View at: Publisher Site | Google Scholar
  93. R. N. Kaplan, R. D. Riba, S. Zacharoulis et al., “VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche,” Nature, vol. 438, no. 7069, pp. 820–827, 2005. View at: Publisher Site | Google Scholar
  94. R. N. Kaplan, S. Rafii, and D. Lyden, “Preparing the ‘soil’: the premetastatic niche,” Cancer Research, vol. 66, no. 23, pp. 11089–11093, 2006. View at: Publisher Site | Google Scholar
  95. J. P. Sleeman, “The metastatic niche and stromal progression,” Cancer and Metastasis Reviews, vol. 31, no. 3-4, pp. 429–440, 2012. View at: Publisher Site | Google Scholar
  96. J. Sceneay, M. J. Smyth, and A. Möller, “The pre-metastatic niche: finding common ground,” Cancer and Metastasis Reviews, vol. 32, no. 3-4, pp. 449–464, 2013. View at: Publisher Site | Google Scholar
  97. S. Hiratsuka, A. Watanabe, H. Aburatani, and Y. Maru, “Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis,” Nature Cell Biology, vol. 8, no. 12, pp. 1369–1375, 2006. View at: Publisher Site | Google Scholar
  98. S. Hiratsuka, A. Watanabe, Y. Sakurai et al., “The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase,” Nature Cell Biology, vol. 10, no. 11, pp. 1349–1355, 2008. View at: Publisher Site | Google Scholar
  99. H. H. Yan, M. Pickup, Y. Pang et al., “Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung,” Cancer Research, vol. 70, no. 15, pp. 6139–6149, 2010. View at: Publisher Site | Google Scholar
  100. H. B. Acuff, K. J. Carter, B. Fingleton, D. L. Gorden, and L. M. Matrisian, “Matrix metalloproteinase-9 from bone marrow-derived cells contributes to survival but not growth of tumor cells in the lung microenvironment,” Cancer Research, vol. 66, no. 1, pp. 259–266, 2006. View at: Publisher Site | Google Scholar
  101. M. Radsak, C. Iking-Konert, S. Stegmaier, K. Andrassy, and G. M. Hänsch, “Polymorphonuclear neutrophils as accessory cells for T-cell activation: major histocompatibility complex class II restricted antigen-dependent induction of T-cell proliferation,” Immunology, vol. 101, no. 4, pp. 521–530, 2000. View at: Publisher Site | Google Scholar
  102. N. S. Potter and C. V. Harding, “Neutrophils process exogenous bacteria via an alternate class I MHC processing pathway for presentation of peptides to T lymphocytes,” Journal of Immunology, vol. 167, no. 5, pp. 2538–2546, 2001. View at: Publisher Site | Google Scholar
  103. E. Reali, R. Guerrini, S. Moretti et al., “Polymorphonuclear neutrophils pulsed with synthetic peptides efficiently activate memory cytotoxic T lymphocytes,” Journal of Leukocyte Biology, vol. 60, no. 2, pp. 207–213, 1996. View at: Google Scholar
  104. J. Pillay, V. M. Kamp, E. Van Hoffen et al., “A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1,” Journal of Clinical Investigation, vol. 122, no. 1, pp. 327–336, 2012. View at: Publisher Site | Google Scholar
  105. M. Munder, F. Mollinedo, J. Calafat et al., “Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity,” Blood, vol. 105, no. 6, pp. 2549–2556, 2005. View at: Publisher Site | Google Scholar
  106. J.-I. Youn, S. Nagaraj, M. Collazo, and D. I. Gabrilovich, “Subsets of myeloid-derived suppressor cells in tumor-bearing mice,” Journal of Immunology, vol. 181, no. 8, pp. 5791–5802, 2008. View at: Publisher Site | Google Scholar
  107. L. C. Jacobsen, K. Theilgaard-Mönch, E. I. Christensen, and N. Borregaard, “Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils,” Blood, vol. 109, no. 7, pp. 3084–3087, 2007. View at: Publisher Site | Google Scholar
  108. P. C. Rodriguez, M. S. Ernstoff, C. Hernandez et al., “Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes,” Cancer Research, vol. 69, no. 4, pp. 1553–1560, 2009. View at: Publisher Site | Google Scholar
  109. A. H. Zea, P. C. Rodriguez, M. B. Atkins et al., “Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion,” Cancer Research, vol. 65, no. 8, pp. 3044–3048, 2005. View at: Google Scholar
  110. S. B. Coffelt, K. Kersten, C. W. Doornebal et al., “IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis,” Nature, vol. 522, no. 7556, pp. 345–348, 2015. View at: Publisher Site | Google Scholar
  111. H. K. Jensen, F. Donskov, N. Marcussen, M. Nordsmark, F. Lundbeck, and H. von der Maase, “Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma,” Journal of Clinical Oncology, vol. 27, no. 28, pp. 4709–4717, 2009. View at: Publisher Site | Google Scholar
  112. K. Xie, “Interleukin-8 and human cancer biology,” Cytokine and Growth Factor Reviews, vol. 12, no. 4, pp. 375–391, 2001. View at: Publisher Site | Google Scholar
  113. A. Bellocq, M. Antoine, A. Flahault et al., “Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome,” American Journal of Pathology, vol. 152, no. 1, pp. 83–92, 1998. View at: Google Scholar
  114. L.-F. Lee, R. P. Hellendall, Y. Wang et al., “IL-8 reduced tumorigenicity of human ovarian cancer in vivo due to neutrophil infiltration,” Journal of Immunology, vol. 164, no. 5, pp. 2769–2775, 2000. View at: Publisher Site | Google Scholar
  115. H. Schaider, M. Oka, T. Bogenrieder et al., “Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8,” International Journal of Cancer, vol. 103, no. 3, pp. 335–343, 2003. View at: Publisher Site | Google Scholar
  116. G. Opdenakker and J. Van Damme, “The countercurrent principle in invasion and metastasis of cancer cells. Recent insights on the roles of chemokines,” International Journal of Developmental Biology, vol. 48, no. 5-6, pp. 519–527, 2004. View at: Publisher Site | Google Scholar
  117. M. P. Keane, J. A. Belperio, Y. Y. Xue, M. D. Burdick, and R. M. Strieter, “Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer,” Journal of Immunology, vol. 172, no. 5, pp. 2853–2860, 2004. View at: Publisher Site | Google Scholar
  118. H. Katoh, D. Wang, T. Daikoku, H. Sun, S. K. Dey, and R. N. DuBois, “CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis,” Cancer Cell, vol. 24, no. 5, pp. 631–644, 2013. View at: Publisher Site | Google Scholar
  119. J. Arnold, E. C. De Boer, M. A. O'Donnell, A. Böhle, and S. Brandau, “Immunotherapy of experimental bladder cancer with recombinant BCG expressing interferon-γ,” Journal of Immunotherapy, vol. 27, no. 2, pp. 116–123, 2004. View at: Publisher Site | Google Scholar
  120. O. Florey and D. O. Haskard, “Sphingosine 1-phosphate enhances Fcγ receptor-mediated neutrophil activation and recruitment under flow conditions,” The Journal of Immunology, vol. 183, no. 4, pp. 2330–2336, 2009. View at: Publisher Site | Google Scholar
  121. R. H. Wenger, “Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression,” The FASEB Journal, vol. 16, no. 10, pp. 1151–1162, 2002. View at: Publisher Site | Google Scholar
  122. G. Christoffersson, E. Vågesjö, J. Vandooren et al., “VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue,” Blood, vol. 120, no. 23, pp. 4653–4662, 2012. View at: Publisher Site | Google Scholar
  123. M. Grunewald, I. Avraham, Y. Dor et al., “VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells,” Cell, vol. 124, no. 1, pp. 175–189, 2006. View at: Publisher Site | Google Scholar
  124. J. M. Devery, N. J. C. King, and C. L. Geczy, “Acute inflammatory activity of the S100 protein CP-10. Activation of neutrophils in vivo and in vitro,” Journal of Immunology, vol. 152, no. 4, pp. 1888–1897, 1994. View at: Google Scholar
  125. B. Amulic, C. Cazalet, G. L. Hayes, K. D. Metzler, and A. Zychlinsky, “Neutrophil function: from mechanisms to disease,” Annual Review of Immunology, vol. 30, pp. 459–489, 2012. View at: Publisher Site | Google Scholar
  126. M. L. Gabelloni, A. S. Trevani, J. Sabatté, and J. Geffner, “Mechanisms regulating neutrophil survival and cell death,” Seminars in Immunopathology, vol. 35, no. 4, pp. 423–437, 2013. View at: Publisher Site | Google Scholar
  127. W. C. Liles, P. A. Kiener, J. A. Ledbetter, A. Aruffo, and S. J. Klebanoff, “Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: implications for the regulation of apoptosis in neutrophils,” Journal of Experimental Medicine, vol. 184, no. 2, pp. 429–440, 1996. View at: Publisher Site | Google Scholar
  128. M. Chawla-Sarkar, D. W. Leaman, and E. C. Borden, “Preferential induction of apoptosis by interferon (IFN)-beta compared with IFN-alpha2: correlation with TRAIL/Apo2L induction in melanoma cell lines,” Clinical Cancer Research, vol. 7, no. 6, pp. 1821–1831, 2001. View at: Google Scholar
  129. C. Selleri, T. Sato, L. Del Vecchio et al., “Involvement of fas-mediated apoptosis in the inhibitory effects of interferon-α in chronic myelogenous leukemia,” Blood, vol. 89, no. 3, pp. 957–964, 1997. View at: Google Scholar
  130. T. Kuijpers and R. Lutter, “Inflammation and repeated infections in CGD: two sides of a coin,” Cellular and Molecular Life Sciences, vol. 69, no. 1, pp. 7–15, 2012. View at: Publisher Site | Google Scholar
  131. Y. Kasahara, K. Iwai, A. Yachie et al., “Involvement of reactive oxygen intermediates in spontaneous and CD95 (Fas/APO-1)-mediated apoptosis of neutrophils,” Blood, vol. 89, no. 5, pp. 1748–1753, 1997. View at: Google Scholar
  132. H. Lundqvist-Gustafsson and T. Bengtsson, “Activation of the granule pool of the NADPH oxidase accelerates apoptosis in human neutrophils,” Journal of Leukocyte Biology, vol. 65, no. 2, pp. 196–204, 1999. View at: Google Scholar
  133. B. Dibbert, M. Weber, W. H. Nikolaizik et al., “Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 23, pp. 13330–13335, 1999. View at: Publisher Site | Google Scholar
  134. N. A. Maianski, D. Roos, and T. W. Kuijpers, “Bid truncation, Bid/Bax targeting to the mitochondria, and caspase activation associated with neutrophil apoptosis are inhibited by granulocyte colony-stimulating factor,” Journal of Immunology, vol. 172, no. 11, pp. 7024–7030, 2004. View at: Publisher Site | Google Scholar

Copyright © 2015 Zvi Granot and Jadwiga Jablonska. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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