Plasticity in Tumor-Promoting Inflammation: Impairment of Macrophage Recruitment Evokes a Compensatory Neutrophil Response

Pahler, Jessica C.; Tazzyman, Simon; Erez, Neta; Yy, Chen; Murdoch, Craig; Nozawa, Hiroaki; Lewis, Claire E.; Hanahan, Douglas

doi:10.1593/neo.07871

Cited by 192 publications

(175 citation statements)

References 36 publications

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“…Data from a genetically engineered skin cancer model and transplantable mammary tumor models indicate that neutrophil infiltration into tumors and their systemic expansion is increased following macrophage blockade via CSF1R or CCR2 signaling 200,201 . Given the tight interplay between neutrophils and macrophages 131 , neutrophils may be expected to promote resistance to macrophage-targeting therapies.…”

Section: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning

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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Section: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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“…The increase in neutrophils and circulating Ly6C hi monocytes following CSF-1R (AFS-98) or CSF-1 neutralization in 4T1.2 and EMT6.5 tumors was unexpected, although compensatory increases in neutrophils have been reported in infections of macrophage-deficient Csf1 op /Csf1 op mice (54), and after reduction of macrophages in a murine cervical cancer model (55). Using a similar protocol in non-tumor-bearing mice in the steady state or during inflammation, we and others found that AFS-98 antibody has no effect on these cell populations (35,56).…”

Section: Neutrophils Macrophagesmentioning

confidence: 99%

The Promotion of Breast Cancer Metastasis Caused by Inhibition of CSF-1R/CSF-1 Signaling Is Blocked by Targeting the G-CSF Receptor

Swierczak

Cook

Lenzo

et al. 2014

Cancer Immunology Research

101

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Treatment options are limited for patients with breast cancer presenting with metastatic disease. Targeting of tumor-associated macrophages through the inhibition of colony-stimulating factor-1 receptor (CSF-1R), a key macrophage signaling pathway, has been reported to reduce tumor growth and metastasis, and these treatments are now in clinical trials. Here, we report that, surprisingly, treatment with neutralizing anti-CSF-1R and anti-CSF-1 antibodies, or with two different small-molecule inhibitors of CSF-1R, could actually increase spontaneous metastasis without altering primary tumor growth in mice bearing two independently derived mammary tumors. The blockade of CSF-1R or CSF-1 led to increased levels of serum G-CSF, increased frequency of neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased numbers of neutrophils and Ly6C hi monocytes in the peripheral blood. Neutralizing antibody against the G-CSF receptor, which regulates neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers that resulted from CSF-1R blockade. These results indicate that the role of the CSF-1R/CSF-1 system in breast cancer is far more complex than originally proposed, and requires further investigation as a therapeutic target. Cancer Immunol Res; 2(8); 765-76. Ó2014 AACR.

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“…If TAM accumulation is suppressed, neutrophils are recruited to the tumor providing a secondary source of MMP-9. Therefore, in the absence of TAMs, TANs provide alternative paracrine support for tumor angiogenesis and progression [171]. Hence, the elimination of TAMs alone may be insufficient to eradicate myeloid cell support to tumor growth.…”

Section: Therapeutic Approaches Targeting Tamcsmentioning

confidence: 99%

Origin and Functions of Tumor-Associated Myeloid Cells (TAMCs)

Sica

Porta

Morlacchi

et al. 2011

Cancer Microenvironment

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The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote the expansion and the recruitment of leukocyte populations, among which tumor-associated myeloid cells (TAMCs) represent a paradigm for cancer-promoting inflammation. TAMCs group heterogeneous phagocytic populations stemming from a common myeloid progenitor (CMP), that orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses; immunosuppression; cell growth; angiogenesis; matrix deposition and remodelling; construction of a metastatic niche and actual metastasis. Several evidence indicate that TAMCs show plasticity and/or functional heterogeneity, suggesting that tumour-derived factors promote their functional "reprogramming" towards protumoral activities. While recent studies have attempted to address the role of microenvironment signals, the interplay between cancer cells, innate and adaptive immunity is now emerging as a crucial step of the TAMCs reprogramming. Here we discuss the evidence for the differentiation of TAMCs during the course of tumor progression and the molecular mechanisms that regulate such event.

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Plasticity in Tumor-Promoting Inflammation: Impairment of Macrophage Recruitment Evokes a Compensatory Neutrophil Response

Cited by 192 publications

References 36 publications

Neutrophils in cancer: neutral no more

Neutrophils in cancer: neutral no more

The Promotion of Breast Cancer Metastasis Caused by Inhibition of CSF-1R/CSF-1 Signaling Is Blocked by Targeting the G-CSF Receptor

Origin and Functions of Tumor-Associated Myeloid Cells (TAMCs)

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