| 1. |
- Cedervall, Jessica, et al.
(författare)
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HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
- 2013
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Ingår i: Angiogenesis. - : Springer Science and Business Media LLC. - 0969-6970 .- 1573-7209. ; 16:4, s. 889-902
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Tidskriftsartikel (refereegranskat)abstract
- Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors-a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFR beta. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity.
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| 2. |
- Cedervall, Jessica, et al.
(författare)
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Immunity Gone Astray - NETs in Cancer
- 2016
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Ingår i: Trends in Cancer. - : Elsevier BV. - 2405-8025 .- 2405-8033. ; 2:11, s. 633-634
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil extracellular traps (NETs) have emerged as significant contributors to cancer-associated pathologies such as metastasis, thrombosis, and organ dysfunction in preclinical models. We review recent discoveries of the involvement of NETs in human cancers and suggest tumor-induced NET formation as an interesting potential therapeutic target in oncology.
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| 3. |
- Cedervall, Jessica, et al.
(författare)
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Injection of embryonic stem cells into scarred rabbit vocal folds enhances healing and improves viscoelasticity : short-term results
- 2007
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Ingår i: The Laryngoscope. - Philadelphia : Lippincott Williams & Wilkins. - 0023-852X .- 1531-4995. ; 117:11, s. 2075-2081
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Scarring caused by trauma; postcancer treatment, or inflammation in the vocal folds is associated with stiffness of the lamina propria and results in severe voice problems. Currently there is no effective treatment. Human embryonic stem cells (hESC) have been recognized as providing a potential resource for cell transplantations, but in the undifferentiated state, they are generally not considered for therapeutic use due to risk of inadvertent development. This study assesses the functional potential of hESC to prevent or diminish scarring and improve viscoelasticity following grafting into scarred rabbit vocal folds.Study Design: hESC were injected into 22 scarred vocal folds of New Zealand rabbits. After 1 month, the vocal folds were dissected and analyzed for persistence of hESC by fluorescence in situ hybridization using a human specific probe, and for differentiation by evaluation in hematoxylin-eosin-stained tissues. Parallel-plate rheometry was used to evaluate the functional effects, i.e., viscoelastic properties, after treatment with hESC.Results: The results revealed significantly improved viscoelasticity in the hESC-treated vs. non-treated vocal folds. An average of 5.1% engraftment of human cells was found 1 month after hESC injection. In the hESC-injected folds, development compatible with cartilage, muscle and epithelia in close proximity or inter-mixed with the appropriate native V rabbit tissue was detected in combination with less scarring and improved viscoelasticity.Conclusions: The histology and location of the surviving hESC-derived cells strongly indicate that the functional improvement was caused by the injected cells, which were regenerating scarred tissue. The findings point toward a strong impact from the host microenvironment, resulting in a regional specific in vivo hESC differentiation. and regeneration of three; types of tissue in scarred vocal folds of adult rabbits.
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| 4. |
- Cedervall, Jessica, et al.
(författare)
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Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
- 2015
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 75:13, s. 2653-2662
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Tidskriftsartikel (refereegranskat)abstract
- Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.
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| 5. |
- 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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| 6. |
- Cedervall, Jessica
(författare)
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Optimization and validation of a species-specific in vivo approach for studies on growth and progression of neural crest derived tumours
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Despite great advantages in cancer therapeutics during the last decades, therapy-resistance remains a problem in the majority of malignancies. Hence, development of more effective therapeutics is critical to enhance survival of patients with cancer. A big challenge for therapy development is low efficacy upon clinical translation; therapies proven highly effective in animal trials often exhibit a poor effect or even fail in the clinic. This indicates the need for more relevant preclinical in vivo model systems for cancer. Malignant melanoma and pediatric neuroblastoma, occurring in derivatives of the neural crest, are both exhibiting a high degree of therapy-resistance, with a high number of deaths as a consequence. These malignancies are characterized by a significant plastic developmental capacity with a tumour phenotype extensively depending on the surrounding microenvironment. Thus, they provide excellent opportunity for studies on interactions between the tumour and adjacent supportive tissue. Objective: The overall aim of this thesis is to optimize and validate a human in vivo model system, based on human embryonic stem cell derived teratomas (hEST-model), for growth and progression of neural crest derived malignancies. Further on, I aim to elucidate whether human tumours grafted in such system are having a higher resemblance to clinical tumours, as compared to conventionally used xenografts. Results: Based on a thorough kinetic study of development in hESC derived teratoma from the cell line HS181, we chose day 45 as the time point for tumour inoculation. At this time, mature embryonic tissues are formed and human vascularisation is initiated. Also, this allows further grafting of the tumour cells without affecting the animals well-being and occurrence of necrotic areas. The capacity for teratoma formation was also explored using a subline of HS181 with altered karyotype, i.e. trisomic for chromosome 12. Results revealed that these cells are capable of forming teratomas, however with a skewed tissue contribution with higher frequency of renal formation. Cell lines from malignant melanoma and neuroblastomas were grafted in the hEST-model and compared to the corresponding xenograft. For the melanomas, striking differences in expression of markers related to melanocytic differentiation was seen, indicative of induced differentiation from the xenograft-environment. Also, a dedifferentiated and invasive subpopulation of melanoma cells was detected, but not present in the xenograft, indicating species-specific interactions upon migration and invasion into surrounding stroma. Grafting of three different neuroblastoma cell lines in the hEST-model resulted in a general finding of higher histological heterogeneity and more resemblance to clinical neuroblastomas, as compared to the xenografts. Grafting of both tumour types in the hEST-model induced an extensive neo-vascularisation of human origin in the surrounding mesenchyme indicating species-specific effects. Conclusions: The results presented in this thesis indicate that a human in vivo model system for cancer based on hESC-derived teratomas add significant importance for preclinical cancer studies. The embryonic environment of the teratoma is probably most relevant for grafting of embryonic tumours, indicated also by our results using pediatric neuroblastoma. Altogether, the hEST-model provides unique possibilities to study human tumours in a species-specific environment, and is therefore suggested a well-needed complement to current preclinical in vivo models.
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| 7. |
- Cedervall, Jessica, et al.
(författare)
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Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.
- 2017
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.
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| 8. |
- Cedervall, Jessica, et al.
(författare)
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Platelets, NETs and cancer
- 2018
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Ingår i: Thrombosis Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0049-3848 .- 1879-2472. ; 164, s. S148-S152
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Tidskriftsartikel (refereegranskat)abstract
- In addition to the central role of platelets in hemostasis, they contribute to pathological conditions such as inflammation and tumor progression. Aberrant expression and/or exposure of pro-coagulant factors in the tumor microenvironment induce platelet activation and subsequent release of growth factors from platelet granules. Cancer patients are commonly affected by thrombotic events, as a result of tumor-induced platelet activation. A novel player potentially contributing to cancer-associated thrombosis is the formation of neutrophil extracellular traps (NETs). NETs are composed of externalized DNA of nuclear or mitochondrial origin, bound to histones and granular proteases such as neutrophil elastase (NE) and myeloperoxidase (MPO). These extracellular traps help neutrophils to catch and kill pathogens such as bacteria, virus and fungi. It is now clear that NETs form also under conditions of sterile inflammation such as cancer and autoimmunity and can promote thrombosis. Recent data show that platelets play a key role in determining when and where NETs should form. This review will highlight our current insight in the role of platelets as regulators of NET formation, both during infection and sterile inflammation.
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| 9. |
- Cedervall, Jessica, et al.
(författare)
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Species-specific in vivo engraftment of the human BL melanoma cell line results in an invasive dedifferentiated phenotype not present in xenografts
- 2009
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 69:9, s. 3746-3754
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Tidskriftsartikel (refereegranskat)abstract
- For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell-derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo.
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| 10. |
- Cedervall, Jessica, et al.
(författare)
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Tumor-Induced Local and Systemic Impact on Blood Vessel Function
- 2015
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Ingår i: Mediators of Inflammation. - : Hindawi Limited. - 0962-9351 .- 1466-1861.
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Forskningsöversikt (refereegranskat)abstract
- Endothelial dysfunction plays a role in several processes that contribute to cancer-associated mortality. The vessel wall serves as a barrier for metastatic tumor cells, and the integrity and activation status of the endothelium serves as an important defense mechanism against metastasis. In addition, leukocytes, such as cytotoxic T-cells, have to travel across the vessel wall to enter the tumor tissue where they contribute to killing of cancer cells. Tumor cells can alter the characteristics of the endothelium by recruitment of leukocytes such as neutrophils andmacrophages, which further stimulate inflammation and promote tumorigenesis. Recent findings also suggest that leukocyte-mediated effects on vascular function are not limited to the primary tumor or tissues that represent metastatic sites. Peripheral organs, such as kidney and heart, also display impaired vascular function in tumor-bearing individuals, potentially contributing to organ failure. Here, we discuss how vascular function is altered in malignant tissue and distant organs in individuals with cancer and how leukocytes function as potent mediators of these tumor-induced effects.
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