Tissue inhibitor of metalloproteinases (TIMP)‐1 creates a premetastatic niche in the liver through SDF‐1/CXCR4‐dependent neutrophil recruitment in mice

Seubert, Bastian; Grünwald, Barbara; Kobuch, Julia; Cui, Haissi; Schelter, Florian; Schaten, Susanne; Siveke, Jens T.; Lim, Ngee Han; Nagase, Hideaki; Simonavicius, Nicole; Heikenwälder, Mathias; Reinheckel, Thomas; Sleeman, Jonathan; Janssen, Klaus–Peter; Knolle, Percy A.; Krüger, Achim

doi:10.1002/hep.27378

Cited by 167 publications

(195 citation statements)

References 31 publications

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“…For adenoviral transduction, 3x10 9 ifu were intravenously injected, as previously described. 22 Recombinant TIMP-1 protein was applied in LPS-free PBS by a single intraperitoneal (i.p.) injection of 2 mg/kg, as previously described.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…injection of 2 mg/kg, as previously described. 22 Mice were killed with CO 2 , blood was collected from the vena cava inferior using EDTA-coated syringes, and BM cells were obtained by flushing femurs and tibias with PBS. …”

Section: Animal Experimentsmentioning

confidence: 99%

“…8,21 We have previously shown that high systemic TIMP-1 levels promote liver metastasis by altering the hepatic microenvironment, resulting in a strongly increased susceptibility of the liver towards metastasis of circulating tumor cells. 22 Neutrophils were shown to be involved in this enhanced metastasis. 22 High numbers of neutrophils are increasingly recognized to promote cancer progression, although they were originally believed to trigger cytotoxic responses against tumor cells.…”

Section: Introductionmentioning

confidence: 95%

“…22 Neutrophils were shown to be involved in this enhanced metastasis. 22 High numbers of neutrophils are increasingly recognized to promote cancer progression, although they were originally believed to trigger cytotoxic responses against tumor cells.…”

Section: Introductionmentioning

confidence: 95%

“…26 It is still unclear at which level TIMP-1 impacts on neutrophils in the context of the TIMP-1-induced pre-metastatic niche in the liver. 22 In the cur- The homeostasis of neutrophil granulocytes can affect the outcome of several inflammation-associated diseases including cancer. The regulation of this homeostasis is still not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nrent study, we investigated whether TIMP-1 affects neutrophil homeostasis. We show that TIMP-1 signaling via CD63 triggered granulopoiesis in the bone marrow (BM) resulting in increased systemic neutrophil blood counts. Our findings reveal a new function of TIMP-1 on immune cell homeostasis, and may provide a link to the frequently described correlation of high TIMP-1 levels with inflammatory diseases in the clinic. Methods Animal experimentsAnimal experiments were performed in compliance with the guidelines of the Tierschutzgesetz des Freistaates Bayern and approved by the Regierung von Oberbayern. For TIMP-1-secreting tumors, 2x10 6 HT1080 cells were subcutaneously injected into the nuchal fold of CD1 nu/nu mice and tumors were grown over ten days to a diameter of approximately 1 cm. Tumor size was monitored with a caliper. For adenoviral transduction, 3x10 9 ifu were intravenously injected, as previously described. 22 Recombinant TIMP-1 protein was applied in LPS-free PBS by a single intraperitoneal (i.p.) injection of 2 mg/kg, as previously described. 22 Mice were killed with CO 2 , blood was collected from the vena cava inferior using EDTA-coated syringes, and BM cells were obtained by flushing femurs and tibias with PBS. Flow cytometryAbsolute quantification of blood neutrophils occurred in BD trucount TM tubes according to the manufacturer´s instructions. Briefly, antibody-cocktail was mixed with 50 mL fresh blood in trucount TM tubes and incubated for 15 min at RT. Subsequently, 450 mL FACS TM lysing solution (BD Bioscience) were added and incubated for 30 min at RT to lyse erythrocytes and fix the sample. For staining of BM, femurs and tibias were flushed with PBS and the obtained cell suspension was stained as blood. Samples were measured on a FACS Canto TM II flow cytometer (BD) and analyzed using FlowJo software. Immunohistochemical staining of neutrophilsFor immunohistochemical analysis of BM, femurs were freed from tissue, fixed in 4% paraformaldehyde for 20 h, de-calcified in 0.5 M EDTA for five days, dehydrated and embedded into paraffin. Ly6G-positive cells were stained on 4 mm sections, as previously described. 22 Colony formation assayBone marrow cells were harvested from AdCtrl or AdT1-transduced mice and erythrocytes were removed with RBC lysis buffer (eBioscience). 1x10 4 BM cells were seeded in MethoCult TM medium (StemCell Technologies) containing 50 ng/mL murine rSCF, 10 ng/mL murine rIL-3, and 10 ng/mL murine rIL-6 into 6-well plates. Cells were incubated at 37°C for seven days and colonies per well were counted. For each mouse, analysis was performed in duplicates, and a total of 5 mice per group were analyzed. 32Dcl3 differentiation assay 32Dcl3 cells were seeded at a density of 8x10 5 cells/mL in IL3-free medium supplemented with 100 ng/mL murine G-CSF (Peptrotech) +/-1000 ng/mL rTIMP-1. Every two days, medium was replaced by fresh medium containing 50 ng/mL G-CSF +/-1000 ng/mL rTIMP-1. At the indicated time points, cells were c...

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Section: Animal Experimentsmentioning

confidence: 99%

Section: Animal Experimentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

et al. 2015

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FGF19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer

Chen

et al. 2023

Advanced Science

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Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

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Beyond the horizon: Neutrophils leading the way in the evolution of immunotherapy

Rajgopal,

Nakano,

Cook

2023

Cancer Medicine

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Cancer is a complex and dynamic disease, initiated by a multitude of intrinsic mutations and progressed with the assistance of the tissue microenvironment, encompassed by stromal cells including immune cell infiltration. The novel finding that tumors can evade anti‐cancer immune functions shaped the field of immunotherapy, which has been a revolutionary approach for the treatment of cancers. However, the development of predominantly T cell‐targeted immunotherapy approaches, such as immune checkpoint inhibition, also brought about an accumulation of evidence demonstrating other immune cell drivers of tumor progression, such as innate immune cells and notably, neutrophils. In the past decade, neutrophils have emerged to be primary mediators of multiple cancer types and even in recent years, are gaining attention for their potential use in the next generation of immunotherapies. Here, we review current immunotherapy strategies and thoroughly discuss the roles of neutrophils in cancer and novel neutrophil‐targeted methods for treating cancer.

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Tissue inhibitor of metalloproteinases (TIMP)‐1 creates a premetastatic niche in the liver through SDF‐1/CXCR4‐dependent neutrophil recruitment in mice

Cited by 167 publications

References 31 publications

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

FGF19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer

Beyond the horizon: Neutrophils leading the way in the evolution of immunotherapy

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