| 1. |
- Cedervall, Jessica, et al.
(författare)
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Neutrophil extracellular traps promote cancer-associated inflammation and myocardial stress.
- 2022
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Ingår i: Oncoimmunology. - : Informa UK Limited. - 2162-4011 .- 2162-402X. ; 213, s. S2-S3
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is associated with systemic pathologies that contribute to mortality, such as thrombosis and distant organ failure. The aim of this study was to investigate the potential role of neutrophil extracellular traps (NETs) in myocardial inflammation and tissue damage in treatment-naïve individuals with cancer. Mice with mammary carcinoma (MMTV-PyMT) had increased plasma levels of NETs measured as H3Cit-DNA complexes, paralleled with elevated coagulation, compared to healthy littermates. MMTV-PyMT mice displayed upregulation of pro-inflammatory markers in the heart, myocardial hypertrophy and elevated cardiac disease biomarkers in the blood, but not echocardiographic heart failure. Moreover, increased endothelial proliferation was observed in hearts from tumor-bearing mice. Removal of NETs by DNase I treatment suppressed the myocardial inflammation, expression of cardiac disease biomarkers and endothelial proliferation. Compared to a healthy control group, treatment-naïve cancer patients with different malignant disorders had increased NET formation, which correlated to plasma levels of the inflammatory marker CRP and the cardiac disease biomarkers NT-proBNP and sTNFR1, in agreement with the mouse data. Altogether, our data indicate that NETs contribute to inflammation and myocardial stress during malignancy. These findings suggest NETs as potential therapeutic targets to prevent cardiac inflammation and dysfunction in cancer patients.
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| 2. |
- Femel, Julia, 1986-, et al.
(författare)
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Vaccination against galectin-1 promotes cytotoxic T-cell infiltration in melanoma and reduces tumor burden
- 2022
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Nature. - 0340-7004 .- 1432-0851. ; 71:8, s. 2029-2040
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-1 (Gal1) is a glycan-binding protein that promotes tumor progression by several distinct mechanisms. Through direct binding to vascular endothelial growth factor (VEGF)-receptor 2, Gal1 is able to induce VEGF-like signaling, which contributes to tumor angiogenesis. Furthermore, several studies have demonstrated an immunosuppressive function of Gal1 through effects on both effector and regulatory T cells. Elevated Gal1 expression and secretion have been shown in many tumor types, and high Gal1 serum levels have been connected to poor prognosis in cancer patients. These findings suggest that therapeutic strategies directed against Gal1 would enable simultaneous targeting of angiogenesis, immune evasion and metastasis. In the current study, we have analyzed the potential of Gal1 as a cancer vaccine target. We show that it is possible to generate high anti-Gal1 antibody levels in mice immunized with a recombinant vaccine protein consisting of bacterial sequences fused to Gal1. Growth of Gal1 expressing melanomas was significantly impaired in the immunized mice compared to the control group. This was associated with improved perfusion of the tumor vasculature, as well as increased infiltration of macrophages and cytotoxic T cells (CTLs). The level of granzyme B, mainly originating from CTLs in our model, was significantly elevated in Gal1 vaccinated mice and correlated with a decrease in tumor burden. We conclude that vaccination against Gal1 is a promising pro-immunogenic approach for cancer therapy that could potentially enhance the effect of other immunotherapeutic strategies due to its ability to promote CTL influx in tumors.
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| 5. |
- Herre, Melanie, 1991-
(författare)
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Neutrophil extracellular traps as potential therapeutic targets to prevent tumor-induced organ failure and metastasis
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer does not only affect surrounding tissues, but also leads to complications at distant sites. The reason for this is that tumors secrete factors and prime cells that travel through the body, making cancer a systemic disease. In fact, cancer death is mostly caused by systemic complications such as metastasis, organ failure or thrombosis. However, surprisingly little is known about the effect of cancer on distant organs that are not sites of tumor growth.Neutrophil extracellular traps (NETs) are web-like structures consisting of neutrophil DNA and granular proteins that are released from the neutrophil in response to a stimulus. NETs are not only formed in bacterial infections but also in noninfectious inflammatory disorders like cancer. While NETs can be beneficial for the host in severe infections they come with a cost. NETs are pro-thrombotic, cause damage to the vessel-lining endothelial cells, are involved in metastasis formation and impair organ function. The removal of NETs by DNase I an enzyme that breaks the NET backbone can therefore be of use as a therapy for certain conditions.The aim of this thesis was to investigate the mechanisms leading to systemic effects of cancer and potential therapeutic strategies with a special focus on NETs.In paper I we investigated how the presence of a primary tumor affected heart function. We conclude that tumor-induced NETs contribute to inflammation and myocardial strain in malignant disease and identify NETs as potential therapeutic targets in cancer patients to prevent cardiac inflammation and dysfunction.In paper II we investigated if the long-term removal of NETs by the use of a murine DNase I expressing adeno-associated virus vector was possible and how this affected organ function and metastasis formation in tumor-bearing mice. We conclude that long-term, species-specific expression of DNase I is possible. Elevated DNase I expression improved kidney function and reduced the proportion of mice with metastasis.In paper III we investigated how cancer and cancer-associated NETs affect endothelial gene expression in distant organs. We found that the number of differentially expressed genes increased with tumor size and that it was higher in metastatic organs. In response to a tumor, the kidney vasculature showed signs of renal hepatization, a state of kidney stress. In conclusion, this study gives a global overview of the gene expression changes that take place in the vasculature of distant organs in individuals with cancer and the potential role of NETs.
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| 6. |
- Herre, Melanie, et al.
(författare)
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Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases
- 2023
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Ingår i: Physiological Reviews. - : American Physical Society. - 0031-9333 .- 1522-1210. ; 103:1, s. 277-312
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Forskningsöversikt (refereegranskat)abstract
- Neutrophil extracellular trap (NET) formation, first described in 2004 as a previously unknown strategy of neutrophils to fight microbes, has attracted an increasing interest in the research community. NETs are formed when neutrophils externalize their decondensed chromatin together with content from their azurophilic granules. In addition to their role in defense against microbes, NETs have been implicated as mediators of pathology in sterile inflammation, such as cancer and autoimmunity, and their potential as therapeutic targets is actively explored. However, targeting of NETs is challenging since the beneficial effects of their removal need to be balanced against the potential harmful loss of their function in microbial defense. Moreover, depending on the stimuli or species, NETs can be formed via distinct mechanisms and are not always made up of the same components, making direct comparisons between various studies challenging. This review focuses on the role of NETs in cancer-associated pathology, such as thrombosis, organ dysfunction, and metastasis. Different strategies to target NETs, by either preventing their formation or degrading existing ones, are also discussed.
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| 7. |
- Yau, Anthony C. Y., et al.
(författare)
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Inflammation and neutrophil extracellular traps in cerebral cavernous malformation
- 2022
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Nature. - 1420-682X .- 1420-9071. ; 79:4
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3(iECKO)), we show that endothelial cells from Ccm3(iECKO) mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3(iECKO) mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3(iECKO) mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas of patients with CCM confirms the clinical relevance of NETs in CCM.
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| 9. |
- Zhang, Yanyu, et al.
(författare)
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Platelet-Derived PDGFB Promotes Recruitment of Cancer-Associated Fibroblasts, Deposition of Extracellular Matrix and Tgf beta Signaling in the Tumor Microenvironment
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:8
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Tidskriftsartikel (refereegranskat)abstract
- Platelets constitute a major reservoir of platelet-derived growth factor B (PDGFB) and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. To address the specific role of platelet-derived PDGFB in the tumor microenvironment, we have created a mouse model with conditional knockout of PDGFB in platelets (pl-PDGFB KO). Lack of PDGFB in platelets resulted in 10-fold lower PDGFB concentration in the tumor microenvironment, fewer cancer-associated fibroblasts and reduced deposition of the extracellular matrix (ECM) molecules fibronectin and collagen I in the orthotopic RIP1-Tag2 model for pancreatic neuroendocrine cancer. Myosin light chain phosphorylation, promoting cell contraction and, consequently, the mechano-induced release of active transforming growth factor (TGF) beta from extracellular compartments, was reduced in tumors from pl-PDGFB KO mice. In agreement, TGF beta signaling, measured as phosphorylated Smad2, was significantly hampered in tumors from mice lacking PDGFB in their platelets, providing a plausible explanation for the reduced deposition of extracellular matrix. These findings indicate a major contribution of platelet-derived PDGFB to a malignant transformation of the tumor microenvironment and address for the first time the role of PDGFB released specifically from platelets in the remodeling of the ECM in tumors.
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| 10. |
- Zhang, Yanyu, et al.
(författare)
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Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis
- 2020
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 80:16, s. 3345-3358
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor b-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for platelet-derived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes. Significance: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis.
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