Neutrophils and cancer: guilt by association

Jenne, Craig N.; Kubes, Paul

doi:10.1038/nrgastro.2016.90

Cited by 5 publications

(4 citation statements)

References 10 publications

(8 reference statements)

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“…TINs can be found in almost every type of malignancies. Although their presence is undeniable, their prognostic value is controversial (2,3). Positive (35), negative (36), or no (37) association between TINs and patient prognosis have been reported, highlighting their heterogeneity and diversity.…”

Section: Discussionmentioning

confidence: 99%

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Tumor-Contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine–Paracrine Loop

Wang

Chen

Yang

et al. 2019

Clinical Cancer Research

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Purpose: The different prognostic values of tumor-infiltrating neutrophils (TIN) in different tissue compartments are unknown. In this study, we investigated their different prognostic roles and the underlying mechanism. Experimental Design: We evaluated CD66b þ neutrophils in primary tumors from 341 patients with breast cancer from Sun Yat-sen Memorial Hospital by IHC. The association between stromal and parenchymal neutrophil counts and clinical outcomes was assessed in a training set (170 samples), validated in an internal validation set (171 samples), and further confirmed in an external validation set (105 samples). In addition, we isolated TINs from clinical samples and screened the cytokine profile by antibody microarray. The interaction between neutrophils and tumor cells was investigated in transwell and 3D Matrigel coculture systems. The therapeutic potential of indicated cytokines was evaluated in tumor-bearing immunocompetent mice. Results: We observed that the neutrophils in tumor parenchyma, rather than those in stroma, were an independent poor prognostic factor in the training [HR = 5.00, 95% confidence interval (CI): 2.88-8.68, P < 0.001], internal validation (HR ¼ 3.56, 95% CI: 2.07-6.14, P < 0.001), and external validation set (HR ¼ 5.07, 95% CI: 2.27-11.33, P < 0.001). The mechanistic study revealed that neutrophils induced breast cancer epithelialmesenchymal transition (EMT) via tissue inhibitor of matrix metalloprotease (TIMP-1). Reciprocally, breast cancer cells undergoing EMT enhanced neutrophils' TIMP-1 secretion by CD90 in a cell-contact manner. In vivo, TIMP-1 neutralization or CD90 blockade significantly reduced metastasis. More importantly, TIMP-1 and CD90 were positively correlated in breast cancer (r 2 ¼ 0.6079; P < 0.001) and associated with poor prognosis of patients. Conclusions: Our findings unravel a location-dictated interaction between tumor cells and neutrophils and provide a rationale for new antimetastasis treatments.

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Section: Discussionmentioning

confidence: 99%

“…Neutrophils are the most prevalent white blood cells in human blood and constitute a significant proportion of inflammatory cells in tumor microenvironment of various types of malignancies (1)(2)(3). In mouse models, their role in cancer metastasis is controversial.…”

Section: Introductionmentioning

confidence: 99%

Tumor-Contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine–Paracrine Loop

Wang

Chen

Yang

et al. 2019

Clinical Cancer Research

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“…Tumor-infiltrating neutrophils (TINs) are the neutrophils that interact with cancer cells in the tumor microenvironment (TME) [ 11 , 18 ]. Wang et al demonstrated that high levels of TINs are associated with advanced histologic grade and tumor stage as well as the TNBC subtype.…”

Section: Introductionmentioning

confidence: 99%

Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance

Chen

et al. 2023

Breast Cancer Res

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Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with limited therapeutic options readily available. Immunotherapy such as immune checkpoint inhibition has been investigated in TNBC but still encounters low overall response. Neutrophils, the most abundant leukocytes in the body, are increasingly recognized as an active cancer-modulating entity. In the bloodstream, neutrophils escort circulating tumor cells to promote their survival and stimulate their proliferation and metastasis. In the tumor microenvironment, neutrophils modulate the immune milieu through polarization between the anti-tumor and the pro-tumor phenotypes. Through a comprehensive review of recently published literature, it is evident that neutrophils are an important player in TNBC immunobiology and can be used as an important prognostic marker of TNBC. Particularly, in their pro-tumor form, neutrophils facilitate TNBC metastasis through formation of neutrophil extracellular traps and the pre-metastatic niche. These findings will help advance the potential utilization of neutrophils as a therapeutic target in TNBC.

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“…Processing of the zymogen is mainly performed by other proteases that remove N- and/or C-terminal signaling peptides in the protease structure. If all of the control points fail, the uncontrolled activity of serine proteases led to the undiserable hydrolysis of peptides that is associated with diseases, such as chronic obstructive pulmonary disease (COPD), cancer progression, and metastasis ( Jenne and Kubes, 2016 ; Pandey et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Peptidyl Activity-Based Probes for Imaging Serine Proteases

Kasperkiewicz

2021

Front. Chem.

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Proteases catalyze the hydrolysis of peptide bonds. Products of this breakdown mediate signaling in an enormous number of biological processes. Serine proteases constitute the most numerous group of proteases, accounting for 40%, and they are prevalent in many physiological functions, both normal and disease-related functions, making them one of the most important enzymes in humans. The activity of proteases is controlled at the expression level by posttranslational modifications and/or endogenous inhibitors. The study of serine proteases requires specific reagents not only for detecting their activity but also for their imaging. Such tools include inhibitors or substrate-related chemical molecules that allow the detection of proteolysis and visual observation of active enzymes, thus facilitating the characterization of the activity of proteases in the complex proteome. Peptidyl activity-based probes (ABPs) have been extensively studied recently, and this review describes the basic principles in the design of peptide-based imaging agents for serine proteases, provides examples of activity-based probe applications and critically discusses their strengths, weaknesses, challenges and limitations.

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Neutrophils and cancer: guilt by association

Cited by 5 publications

References 10 publications

Tumor-Contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine–Paracrine Loop

Tumor-Contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine–Paracrine Loop

Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance

Peptidyl Activity-Based Probes for Imaging Serine Proteases

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