| 1. |
- Xie, Yuan, et al.
(författare)
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Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma
- 2023
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 25:6, s. 1073-1084
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Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed.Methods: Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms.Results: We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice.Conclusions: These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.
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| 2. |
- Xie, Yuan, et al.
(författare)
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Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing
- 2021
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Ingår i: JCI Insight. - : American Society For Clinical Investigation. - 2379-3708. ; 6:15
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Tidskriftsartikel (refereegranskat)abstract
- Passage of systemically delivered pharmacological agents into the brain is largely blocked by the blood-brain-barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). Tumor vessels in glioblastoma (GBM), the most common malignant brain tumor in humans, are abnormally permeable, but this phenotype is heterogeneous and may differ between the tumor's center and invasive front. Here, through single-cell RNA sequencing (scRNA-seq) of freshly isolated ECs from human glioblastoma and paired tumor peripheral tissues, we have constructed a molecular atlas of human brain ECs providing unprecedented molecular insight into the heterogeneity of the human BBB and its molecular alteration in glioblastoma. We identified 5 distinct EC phenotypes representing different states of EC activation and BBB impairment, and associated with different anatomical locations within and around the tumor. This unique data resource provides key information for designing rational therapeutic regimens and optimizing drug delivery.
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| 3. |
- 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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| 4. |
- Zhang, Yanyu, et al.
(författare)
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1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas
- 2021
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Ingår i: Cellular Oncology. - : Springer. - 2211-3428 .- 2211-3436. ; 44:1, s. 193-204
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Tidskriftsartikel (refereegranskat)abstract
- Background Tumor-associated macrophages (TAM)s are critical regulators of glioma progression. As yet, however, TAMs in isocitrate dehydrogenase (IDH) mutated lower-grade gliomas (LGGs) have not been thoroughly investigated. The aim of this study was to determine whether 1p/19q co-deletion status affects the TAM phenotype or its prevalence in IDH mutated LGGs. Methods TAMs in IDH mutated LGGs were analyzed using transcriptome data from 230 samples in the TCGA database in combination with transcriptome data from single-cell RNA sequencing of IDH-mutated LGGs. Proteins potentially involved in TAM regulation were examined by immuno-staining in primary LGG samples harboring IDH mutations. Essential signaling pathways regulating TAM phenotypes were investigated in a glioma mouse model using small molecule inhibitors. Results Most of the TAMs in IDH-mutated LGGs expressed the M1 activation markers CD86 and TNF, whereas a subset of individual TAMs co-expressed both M1 and M2-related markers. Bioinformatics analysis in combination with immuno-staining of IDH-mutated patient samples revealed higher amounts of TAMs expressing M2-related markers in 1p/19q non-codeletion IDH-mutated LGGs compared to 1p/19q codeletion LGGs. The levels of transforming growth factor beta 1 (TGF beta 1) and macrophage colony-stimulating factor (M-CSF) were significantly higher in 1p/19q non-codeletion LGGs than in 1p/19q codeletion LGGs. M-CSF and TGF beta 1 signal inhibition decreased tumor growth and modulated the TAM phenotype in a glioma mouse model. Conclusions Our data indicate that 1p/19q co-deletion status relates to distinct TAM infiltration in gliomas, which is likely mediated by M-CSF and TGF beta 1 signaling. M-CSF and TGF beta 1 signaling may play a pivotal role in regulating the TAM phenotype in glioma.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- Cedervall, Jessica, et al.
(författare)
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Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure
- 2016
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:15, s. 4311-4315
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Forskningsöversikt (refereegranskat)abstract
- A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. One example is acute renal failure, a major cause of morbidity and mortality in cancer patients. Surprisingly, however, little is known about the situation in organs that are not targets for metastasis or affected by the primary tumor. Recently, neutrophil extracellular traps (NET) were implicated in tumor-induced effects on distant organs unaffected by the actual tumor cells. Formation of NETs (NETosis) was identified a decade ago as amechanismby which the innate immune system protects us from infections, especially in situations with sepsis. NETs are formed when neutrophils externalize their nuclear DNA together with antimicrobial granule proteins and form a web-like structure that can trap and kill microbes. It is now becoming increasingly clear that NETs also form under noninfectious inflammatory conditions like cancer, thrombosis, autoimmunity, and diabetes and significantly contribute to disease development. The existence of NET-dissolving drugs like heparin and DNase I, already in clinical use, and recent development of specific inhibitors of proteinarginine deiminase 4 (PAD4), an enzyme required for NET formation, should enable clinical targeting of NETosis. Preventing NETosis in cancer could provide a strategy to counteract tumor-induced thrombosis and organ failure as well as to suppress metastasis.
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| 8. |
- Liu, Linpeng, et al.
(författare)
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Ni and Fe catalyzed cascade radical reactions of oxime esters with diselenides
- 2022
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Ingår i: Organic Chemistry Frontiers. - : Royal Society of Chemistry (RSC). - 2052-4129. ; 9:13, s. 3480-3485
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Tidskriftsartikel (refereegranskat)abstract
- A radical cyclization and ring-opening of oxime esters with diselenides was developed. Both Ni(0) and Fe(II) catalysts could be employed for the selenylation of olefin-containing and cyclic oxime ester derivatives. With this method, a variety of functionalized pyrrolines and alkyl nitriles were synthesized in good yields. Moreover, a mechanism involving iminyl radical and carbon-centered radical intermediates was proposed.
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| 9. |
- Yanyu, Zhang, et al.
(författare)
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Platelet-specific ablation of PDGFB impairs vascular function and pericyte recruitment in tumors and promotes metastasis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Platelet-derived growth factor B (PDGFB) plays a crucial role in recuitment of PDGF-receptor b positive pericytes to blood vessels and the endothelium is an essential source of PDGFB in this process. PDGFB was originally isolated from platelets, which consitute a major reservoir of this growth factor. Under physiological conditions, platelets are not activated unless there is a wound, which then leads to rapid activation and degranulation of the platelet content. However, in the tumor microenvironment platelets are continuously activated, exposing tumors to the plethora of growth factors contained in platelet granules. In the current study we address the role of platelet-derived PDGFB in vascular function and pericyte recruitment in tumors by creating a platelet-specific knock-out of PDGFB. We find that mice with PDGFB-deficient platelets are viable and fertile. Furthermore, vascular function and pericyte recruitment to healthy vessels were unaffected by the lack of PDGFB in platelets. In contrast, tumor vascular function, as well as pericyte coverage, is significantly impaired in mice with PDGFB-deficient platelets. Moreover, lack of PDGFB in platelets leads to enhanced spontaneous liver metastasis in a model for pancreatic neuroendocrine carcinoma, further indicating that platelet-derived PDGFB contributes to maintain vascular integrity in the tumor microenvironment where extensive vascular remodeling is ongoing. With this finding we identify a previously unknown role for platelet-derived PDGFB.
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| 10. |
- 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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