| 1. |
- Dahl Jensen, Lasse, et al.
(författare)
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Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish
- 2012
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Ingår i: Cell Reports. - : Elsevier (Cell Press). - 2211-1247. ; 2:2, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms underlying circadian-regulated physiological processes remain largely unknown. Here, we show that disruption of the circadian clock by both constant exposure to light and genetic manipulation of key genes in zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. Using a promoter-reporter system consisting of various deleted vegf-promoter mutants, we show that Bmal1 directly binds to and activates the vegf promoter via E-boxes. Additionally, we provide evidence that knockdown of Bmal1 leads to impaired Notch-inhibition-induced vascular sprouting. These results shed mechanistic insight on the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis.
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| 2. |
- Hosaka, Kayoko, et al.
(författare)
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Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis
- 2013
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Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 4:2129
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Tidskriftsartikel (refereegranskat)abstract
- Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dose-dependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-beta signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-beta and inactivation of the PDGF-beta signalling decreases integrin alpha 1 beta 1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.
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| 3. |
- Iwamoto, Hideki, et al.
(författare)
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PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors
- 2015
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Ingår i: Science Advances. - : AMER ASSOC ADVANCEMENT SCIENCE. - 2375-2548. ; 1:3
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors.
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| 4. |
- Jensen, Lasse, et al.
(författare)
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VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish
- 2015
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 112:44, s. E5944-E5953
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Tidskriftsartikel (refereegranskat)abstract
- Physiological functions of vascular endothelial growth factor (VEGF)-B remain an enigma, and deletion of the Vegfb gene in mice lacks an overt phenotype. Here we show that knockdown of Vegfba, but not Vegfbb, in zebrafish embryos by specific morpholinos produced a lethal phenotype owing to vascular and neuronal defects in the brain. Vegfba morpholinos also markedly prevented development of hyaloid vasculatures in the retina, but had little effects on peripheral vascular development. Consistent with phenotypic defects, Vegfba, but not Vegfaa, mRNA was primarily expressed in the brain of developing zebrafish embryos. Interestingly, in situ detection of Neuropilin1 (Nrp1) mRNA showed an overlapping expression pattern with Vegfba, and knockdown of Nrp1 produced a nearly identically lethal phenotype as Vegfba knockdown. Furthermore, zebrafish VEGF-Ba protein directly bound to NRP1. Importantly, gain-of-function by exogenous delivery of mRNAs coding for NRP1-binding ligands VEGF-B or VEGF-A to the zebrafish embryos rescued the lethal phenotype by normalizing vascular development. Similarly, exposure of zebrafish embryos to hypoxia also rescued the Vegfba morpholino-induced vascular defects in the brain by increasing VEGF-A expression. Independent evidence of VEGF-A gain-of-function was provided by using a functionally defective Vhl-mutant zebrafish strain, which again rescued the Vegfba morpholino-induced vascular defects. These findings show that VEGF-B is spatiotemporally required for vascular development in zebrafish embryos and that NRP1, but not VEGFR1, mediates the essential signaling.
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| 5. |
- Ji, Hong, et al.
(författare)
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TNFR1 mediates TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
- 2014
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Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 5:4944
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation and lymphangiogenesis are two cohesively coupled processes that promote tumour growth and invasion. Here we report that TNF-alpha markedly promotes tumour lymphangiogenesis and lymphatic metastasis. The TNF-alpha-TNFR1 signalling pathway directly stimulates lymphatic endothelial cell activity through a VEGFR3-independent mechanism. However, VEGFR3-induced lymphatic endothelial cell tips are a prerequisite for lymphatic vessel growth in vivo, and a VEGFR3 blockade completely ablates TNF-alpha-induced lymphangiogenesis. Moreover, TNF-alpha-TNFR1-activated inflammatory macrophages produce high levels of VEGF-C to coordinately activate VEGFR3. Genetic deletion of TNFR1 (Tnfr1(-/-)) in mice or depletion of tumour-associated macrophages (TAMs) virtually eliminates TNF-alpha-induced lymphangiogenesis and lymphatic metastasis. Gain-of-function experiments show that reconstitution of Tnfr1(+/+) macrophages in Tnfr1(+/+) mice largely restores tumour lymphangiogenesis and lymphatic metastasis. These findings shed mechanistic light on the intimate interplay between inflammation and lymphangiogenesis in cancer metastasis, and propose therapeutic intervention of lymphatic metastasis by targeting the TNF-alpha-TNFR1 pathway.
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| 6. |
- Lim, Sharon, et al.
(författare)
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Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis
- 2016
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 7:25, s. 38282-38291
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Tidskriftsartikel (refereegranskat)abstract
- Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.
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| 7. |
- Wang, Jian, et al.
(författare)
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Novel Mechanism of Macrophage-Mediated Metastasis Revealed in a Zebrafish Model of Tumor Development
- 2015
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 75:2, s. 306-315
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Tidskriftsartikel (refereegranskat)abstract
- Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. Although imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved that are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL6 and TNF alpha promoted the ability of macrophages to mediate this step. M2 macro-phages were particularly potent when induced by IL4, IL10, and TGF beta. In contrast, IFN gamma-lipopolysaccharide-induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal, and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications.
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| 8. |
- Yang, Yunlong, et al.
(författare)
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The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11385
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Tidskriftsartikel (refereegranskat)abstract
- Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.
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