| 1. |
- Claesson-Welsh, Lena
(författare)
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How the matrix metalloproteinase MMP14 contributes to the progression of colorectal cancer : Comment
- 2020
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:3, s. 1093-1095
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Certain matrix metalloproteinase (MMP) family proteins have been associated with cell proliferation and invasion in aggressive cancers. However, attempts to target the MMPs with the hope of treating tumors have thus far failed. In this issue of the JCI, Ragusa and coworkers identified an intestinal cancer subgroup of slow-growing, chemotherapy-resistant, and very aggressive matrix-rich tumors that mimic a hard-to-treat colorectal cancer subtype in humans. These tumors showed downregulated levels of the transcription factor prospero homeobox protein 1 (PROX1), which relieved repression of the matrix metalloproteinase MMP14. Upregulated MMP14 levels correlated with blood vessel dysfunction and a lack of cytotoxic T cells. Notably, blockade of proangiogenic factors in combination with stimulation of the CD40 pathway in the mouse cancer model boosted cytotoxic T cell infiltration. The study illustrates how combinatorial treatments for aggressive, T cell-deficient cancers can launch an antitumor immune response.
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| 2. |
- Nwadozi, Emmanuel, et al.
(författare)
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Hypersensitive blood vessels in Clarkson disease
- 2024
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Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 134:10
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Idiopathic systemic capillary leak syndrome (ISCLS) is a rare, recurrent condition with dramatically increased blood vessel permeability and, therefore, induction of systemic edema, which may lead to organ damage and death. In this issue of the JCI, Ablooglu et al. showed that ISCLS vessels were hypersensitive to agents known to increase vascular permeability, using human biopsies, cell culture, and mouse models. Several endothelium-specific proteins that regulate endothelial junctions were dysregulated and thereby compromised the vascular barrier. These findings suggest that endothelium-intrinsic dysregulation underlies hyperpermeability and implicate the cytoplasmic serine/threonine protein phosphatase 2A (PP2A) as a potential drug target for the treatment of ISCLS.
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| 3. |
- Sjöberg, Elin, et al.
(författare)
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Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and antitumor immunity through eNOS/Src
- 2023
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Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:20
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial phospholipase C gamma (PLC gamma) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLC gamma was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLC gamma expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLC gamma was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLC gamma (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo-and immunotherapy. Mechanistically, pY1173/PLC gamma signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLC gamma/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLC gamma and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLC gamma pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.
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| 4. |
- Tisch, Nathalie, et al.
(författare)
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Caspase-8 modulates physiological and pathological angiogenesis during retina development
- 2019
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 129:12, s. 5092-5107
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Tidskriftsartikel (refereegranskat)abstract
- During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8-KO pups (Casp-8(ECKO)) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-8ECKO pups. Taking these data together, we show that Casp-8 acts in a cell death-independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP.
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