Tumor-Recruited Neutrophils and Neutrophil TIMP-Free MMP-9 Regulate Coordinately the Levels of Tumor Angiogenesis and Efficiency of Malignant Cell Intravasation

Bekes, Erin M.; Schweighofer, Bernhard; Kupriyanova, Tatyana A.; Zając, Ewa; Ardi, Veronica C.; Quigley, James P.; Deryugina, Elena I.

doi:10.1016/j.ajpath.2011.05.031

Cited by 260 publications

(244 citation statements)

References 52 publications

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“…33 Recently, Bekes et al showed that tumor-associated neutrophils played a critical role in tumor angiogenesis and migration of tumor cells through secretion of TIMP-free MMP-9. 34 They also showed that the enhancement of angiogenesis was blocked by inhibition of neutrophil recruitment. Furthermore, Benelli et al showed that depletion of neutrophils intensively inhibited cytokine-induced angiogenesis in vivo.…”

Section: Discussionmentioning

confidence: 99%

G‐CSF rescues tumor growth and neo‐angiogenesis during liver metastasis under host angiopoietin‐2 deficiency

Im¹,

Tapmeier²,

Balathasan³

et al. 2012

Intl Journal of Cancer

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Suppression of neo‐angiogenesis is a clinically used anti‐tumor strategy with new targets such as angiopoietin‐2 (Ang2) being proposed. However, the functions of Ang2 in vascular remodeling, inflammation and tumor growth are not consistent. We examined effect of depletion of host Ang2 on liver colony formation using Ang2 deficient (Ang2−/−) mice. Surprisingly, the metastatic colonies formed in Ang2−/− mice were larger than those in the wild type. These colonies had greater vascular density with more pericyte coverage than the vessels in liver colonies in the wild type. Liver VEGF concentration in both genotypes was equivalent, and thus, the differences appeared VEGF independent. However, after colony formation, the serum concentration of granulocyte‐colony stimulating factor (G‐CSF) and CXCL1 in Ang2−/− mice was 12 and 6 times greater than after colony formation in wild type. Increase of these two cytokines was associated with two times greater numbers of neutrophils recruited to the liver. Two times more Tie2+/CD11b+/CD31− cells were present in the tumors in Ang2−/− than in the wild type livers. These results suggest that the depletion of host Ang2 induced compensatory VEGF‐independent angiogenic mechanisms and thus enhanced liver metastatic colony growth and colony vascularity. They further indicate organotypic differences in response to tumor metastasis. In contrast, Ang2 deficiency inhibited tumor growth during metastatic colony formation in the lung, consistent with the reports of decreased pulmonary seeding of tumor cells after pharmacological inhibition of Ang2. Further studies are thus required to assess the effects of pharmacological Ang2 blockade for cancer patients particularly in the liver.

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Section: Discussionmentioning

confidence: 99%

G‐CSF rescues tumor growth and neo‐angiogenesis during liver metastasis under host angiopoietin‐2 deficiency

Im¹,

Tapmeier²,

Balathasan³

et al. 2012

Intl Journal of Cancer

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“…One mechanism neutrophils employ to promote tumor growth is the induction of angiogenesis (Figure 3), and neutrophil depletion decreased tumor growth and microvessel density in both transplantable and spontaneous tumor models 65,85,91,[120][121][122][123] . Blocking CXCR2 signaling or transplanting cancer cell lines into CXCR2-deficient mice recapitulated these effects 58,124,125 .…”

Section: Neutrophils and Tumor Growthmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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“…IL-8 is another chemokine expressed in variety of tumors and is associated with neutrophil recruitment and activation [251]. For example, IL-8 secreted by human fibrosarcoma and prostate carcinoma cells promoted the infiltration of MMP-9 + neutrophils [252] and melanoma secreted IL-8 was shown to increase CD11b/CD18 expression on neutrophils, an indication for their activation [253,254].…”

Section: Neutrophil Activation In Cancermentioning

confidence: 99%

“…TANs were shown to support tumor growth by producing angiogenic factors and matrix-degrading enzymes [8,57,64,252,264,277]. Neutrophils were also shown to promote the acquisition of a metastatic phenotype [265] and to suppress antitumor immune responses [278].…”

Section: Neutrophils At the Primary Tumor Sitementioning

confidence: 99%

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Sionov

Fridlender

Granot

2014

Cancer Microenvironment

342

261

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Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.

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Tumor-Recruited Neutrophils and Neutrophil TIMP-Free MMP-9 Regulate Coordinately the Levels of Tumor Angiogenesis and Efficiency of Malignant Cell Intravasation

Cited by 260 publications

References 52 publications

G‐CSF rescues tumor growth and neo‐angiogenesis during liver metastasis under host angiopoietin‐2 deficiency

G‐CSF rescues tumor growth and neo‐angiogenesis during liver metastasis under host angiopoietin‐2 deficiency

Neutrophils in cancer: neutral no more

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

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