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  • 1.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    VEGF-mediated vascular functions in health and disease2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Angiogenesis is essential for physiological processes including embryonic development, tissue regeneration, and reproduction. Under various pathological conditions the same angiogenic process contribute to the onset, development, and progression of many human diseases including cancer, diabetic complications, ocular disease, chronic inflammation and cardiovascular disease. Vascular endothelial growth factor (VEGF) is a key angiogenic factor for physiological and pathological angiogenesis. In addition to its strong angiogenic activity, VEGF also potently induces vascular permeability, often causing tissue edema in various pathological tissues. VEGF transduces its vascular signal through two tyrosine kinase receptors-VEGFR1 and VEGFR2, the latter being a functional receptor that mediates both angiogenic and vascular permeability effects. To study physiological and pathological functions of VEGF, we developed novel zebrafish disease models that permit us to study hypoxia-induced retinopathy and cancer metastasis processes. We have also administered anti-VEGF and anti-VEGFR specific antibodies to healthy mice to study the homeostatic role of VEGF in the maintenance of vascular integrity and its functions in various tissues and organs.

    Finally, using a zebrafish model, we evaluated if VEGF expression is regulated by circadian clock genes. In paper I, we developed protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1:EGFP zebrafish were placed in hypoxic water for 3-10 days with retinal neovascularization being analyzed using confocal microscopy. This model provides a unique opportunity to kinetically study the development of retinopathy in adult animals using non-invasive protocols and to assess the therapeutic efficacy of orally administered anti-angiogenic drugs. In paper II, we developed a zebrafish metastasis model to dissect the complex events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells were implanted into the perivitelline cavity of 48-hour-old zebrafish embryos, which were subsequently placed in hypoxic water for 3 days. Tumor cell invasion, metastasis and pathological angiogenesis were analyzed using fluorescent microscopy in the living fish. The average experimental time for this model is 7 days. Our protocol offers an opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis. In paper III, we show that systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody cause global vascular regression in mice. Among all examined tissues, the vasculature in endocrine glands, intestinal villi, and the uterus are most affected in response to VEGF or VEGFR-2 blockades. Pro-longed anti-VEGF treatment resulted in a significant decrease in the circulating levels of the predominant thyroid hormone, free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid function. These findings provide structural and functional bases of anti-VEGF-specific druginduced side effects in relation to vascular changes in healthy tissues. In paper IV, we show that disruption of the circadian clock by constant exposure to light coupled with genetic manipulation of key genes in the 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. These results offer mechanistic insights into 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. Overall, the results in this thesis provide further insight to angiogenic mechanistic properties in tissues and suggest possible novel therapeutic targets for the treatment of various angiogenesis-dependent diseases.

    List of papers
    1. Hypoxia-induced retinopathy model in adult zebrafish
    Open this publication in new window or tab >>Hypoxia-induced retinopathy model in adult zebrafish
    Show others...
    2010 (English)In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1903-1910Article in journal (Refereed) Published
    Abstract [en]

    Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available. In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-63381 (URN)10.1038/nprot.2010.149 (DOI)000284884100003 ()
    Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2017-12-11Bibliographically approved
    2. Hypoxia-induced metastasis model in embryonic zebrafish
    Open this publication in new window or tab >>Hypoxia-induced metastasis model in embryonic zebrafish
    Show others...
    2010 (English)In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1911-1918Article in journal (Refereed) Published
    Abstract [en]

    Hypoxia facilitates tumor invasion and metastasis by promoting neovascularization and co-option of tumor cells in the peritumoral vasculature, leading to dissemination of tumor cells into the circulation. However, until recently, animal models and imaging technology did not enable monitoring of the early events of tumor cell invasion and dissemination in living animals. We recently developed a zebrafish metastasis model to dissect the detailed events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells are implanted into the perivitelline cavity of 48-h-old zebrafish embryos, which are subsequently placed in hypoxic water for 3 d. Tumor cell invasion, metastasis and pathological angiogenesis are detected under fluorescent microscopy in the living fish. The average experimental time for this model is 7 d. Our protocol offers a remarkable opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-63382 (URN)10.1038/nprot.2010.150 (DOI)000284884100004 ()
    Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2017-12-11Bibliographically approved
    3. Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues
    Open this publication in new window or tab >>Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues
    Show others...
    2013 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 29, p. 12018-12023Article in journal (Refereed) Published
    Abstract [en]

    Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.

    Place, publisher, year, edition, pages
    National Academy of Sciences, 2013
    Keywords
    angiogenesis, antiangiogenic therapy, off-tumor targets, vascular homeostasis, vessel regression
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102114 (URN)10.1073/pnas.1301331110 (DOI)000322086100078 ()23818623 (PubMedID)
    Available from: 2013-12-01 Created: 2013-12-01 Last updated: 2017-12-06Bibliographically approved
    4. Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish
    Open this publication in new window or tab >>Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish
    Show others...
    2012 (English)In: Cell Reports, ISSN 2211-1247, Vol. 2, no 2, p. 231-241Article in journal (Refereed) Published
    Abstract [en]

    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.

    Place, publisher, year, edition, pages
    Elsevier (Cell Press), 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85304 (URN)10.1016/j.celrep.2012.07.005 (DOI)000309715100004 ()
    Note

    Funding Agencies|Swedish Research Council||Swedish Cancer Foundation||Karolinska Institute Foundation||Karolinska Institute||Tianjin Natural Science Foundation (CMM-Tianjin)|09ZCZDSF04400|Torsten Soderbergs Foundation||European Union|222741|European Research Council (ERC)|250021|

    Available from: 2012-11-16 Created: 2012-11-15 Last updated: 2017-03-27Bibliographically approved
  • 2.
    Cao, Ziquan
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Jensen, Lasse
    Karolinska Institute, Sweden.
    Rouhi, Pegah
    Karolinska Institute.
    Hosaka, Kayoko
    Karolinska Institute.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Steffensen, John F
    University of Copenhagen.
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Cao, Yihai
    Karolinska Institute.
    Hypoxia-induced retinopathy model in adult zebrafish2010In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1903-1910Article in journal (Refereed)
    Abstract [en]

    Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available. In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs.

  • 3.
    Chen, Xiaoyun
    et al.
    Sun Yat Sen University, Peoples R China; Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Yang, Huasheng
    Sun Yat Sen University, Peoples R China.
    Sun, Yuping
    Shandong University, Peoples R China.
    Zhuang, Rujie
    Chinese Medical University, Peoples R China.
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 10351Article in journal (Refereed)
    Abstract [en]

    Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses.

  • 4.
    Dahl Jensen, Lasse
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Nakamura, Masaki
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Brautigam, Lars
    Karolinska Institute, Sweden .
    Andersson, Patrik
    Karolinska Institute, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Hosaka, Kayoko
    Karolinska Institute, Sweden .
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish2012In: Cell Reports, ISSN 2211-1247, Vol. 2, no 2, p. 231-241Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Dong, Mei
    et al.
    Shandong University, Peoples R China .
    Yang, Xiaoyan
    Shandong University, Peoples R China .
    Lim, Sharon
    Karolinska Institute, Sweden .
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Honek, Jennifer
    Karolinska Institute, Sweden .
    Lu, Huixia
    Shandong University, Peoples R China .
    Zhang, Cheng
    Shandong University, Peoples R China .
    Seki, Takahiro
    Karolinska Institute, Sweden .
    Hosaka, Kayoko
    Karolinska Institute, Sweden .
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Yang, Jianmin
    Shandong University, Peoples R China .
    Zhang, Lei
    Shandong University, Peoples R China .
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Sun, Baocun
    Tianjin Medical University, Peoples R China .
    Li, Xuri
    Sun Yat Sen University, Peoples R China .
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China .
    Zhang, Yun
    Shandong University, Peoples R China .
    Cao, Yihai
    Karolinska Institute, Sweden .
    Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-Dependent Lipolysis2013In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 18, no 1, p. 118-129Article in journal (Refereed)
    Abstract [en]

    Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E-/- [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.

  • 6.
    Lim, Sharon
    et al.
    Karolinska Institute.
    Honek, Jennifer
    Karolinska Institute.
    Xue, Yuan
    Karolinska Institute.
    Seki, Takahiro
    Karolinska Institute.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Patrik
    Karolinska Institute.
    Yang, Xiaojuan
    Karolinska Institute.
    Hosaka, Kayoko
    Karolinska Institute.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice2012In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 7, no 3, p. 606-615Article in journal (Refereed)
    Abstract [en]

    Exposure of humans and rodents to cold activates thermogenic activity in brown adipose tissue (BAT). This protocol describes a mouse model to study the activation of BAT and angiogenesis in adipose tissues by cold acclimation. After a 1-week exposure to 4 degrees C, adult C57BL/6 mice show an obvious transition from subcutaneous white adipose tissue (WAT) into brown-like adipose tissue (BRITE). The BRITE phenotype persists after continuous cold exposure, and by the end of week 5 BRITE contains a high number of uncoupling protein-1-positive mitochondria, a characteristic feature of BAT. During the transition from WAT into BRITE, the vascular density is markedly increased owing to the activation of angiogenesis. In BAT, cold exposure stimulates thermogenesis by increasing the mitochondrial content and metabolic rate. BAT and the increased metabolic rate result in a lean phenotype. This protocol provides an outstanding opportunity to study the molecular mechanisms that control adipose mass.

  • 7.
    Rouhi, Pegah
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Jensen, Lasse D
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Hosaka, Kayoko
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Fleng Steffensen, John
    Marine Biological Laboratory, Biological Institute, University of Copenhagen, Helsingor, Denmark.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Hypoxia-induced metastasis model in embryonic zebrafish2010In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1911-1918Article in journal (Refereed)
    Abstract [en]

    Hypoxia facilitates tumor invasion and metastasis by promoting neovascularization and co-option of tumor cells in the peritumoral vasculature, leading to dissemination of tumor cells into the circulation. However, until recently, animal models and imaging technology did not enable monitoring of the early events of tumor cell invasion and dissemination in living animals. We recently developed a zebrafish metastasis model to dissect the detailed events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells are implanted into the perivitelline cavity of 48-h-old zebrafish embryos, which are subsequently placed in hypoxic water for 3 d. Tumor cell invasion, metastasis and pathological angiogenesis are detected under fluorescent microscopy in the living fish. The average experimental time for this model is 7 d. Our protocol offers a remarkable opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis.

  • 8.
    Wang, Jian
    et al.
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Zhang, Xing-Mei
    Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Sun, Meili
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Hartman, Johan
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Harris, Robert A.
    Karolinska Institute, Sweden.
    Sun, Yuping
    Shandong University, Peoples R China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Novel Mechanism of Macrophage-Mediated Metastasis Revealed in a Zebrafish Model of Tumor Development2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 2, p. 306-315Article in journal (Refereed)
    Abstract [en]

    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.

  • 9.
    Yang, Xiaojuan
    et al.
    Karolinska Institute, Sweden; Tongji University, Peoples R China.
    Zhang, Yin
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Andersson, Patrik
    Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden.
    Tholander, Fredrik
    Karolinska Institute, Sweden.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Morikawa, Hiromasa
    Karolinska Institute, Sweden.
    Tegner, Jesper
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Sweden.
    Lim, Sharon
    Karolinska Institute, Sweden.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 22, p. E2900-E2909Article in journal (Refereed)
    Abstract [en]

    The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

  • 10.
    Yang, Xiaojuan
    et al.
    Karolinska Institute, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Lim, Sharon
    Karolinska Institute, Sweden .
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Rak, Janusz
    McGill University, Canada .
    Cao, Yihai
    Karolinska Institute, Sweden .
    Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 34, p. 13932-13937Article in journal (Refereed)
    Abstract [en]

    Placental growth factor (PIGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PIGF and VEGF in modulation of tumor angiogenesis and vascular remodeling is less understood. Here we report that PlGF positively and negatively modulate tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism. In two independent tumor models, we show that PlGF inhibited tumor growth and angiogenesis and displayed a marked vascular remodeling effect, leading to normalized microvessels with infrequent vascular branches and increased perivascular cell coverage. Surprisingly, elimination of VEGF gene (i.e., VEGF-null) in PIGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PIGF-induced vascular normalization. Thus, PIGF positively and negatively modulates tumor growth, angiogenesis, and vascular remodeling through VEGF-dependent spatiotemporal mechanisms. Our data uncover molecular mechanisms underlying the complex interplay between PIGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy.

  • 11.
    Yang, Yunlong
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Zhang, Yin
    Karolinska Institute, Stockholm, Sweden.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Ji, Hong
    Karolinska Institute, Stockholm, Sweden.
    Yang, Xiaojuan
    Karolinska Institute, Stockholm, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Stockholm, Sweden.
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Sun, Baocun
    Tianjin Medical University, China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Stockholm, Sweden.
    Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 29, p. 12018-12023Article in journal (Refereed)
    Abstract [en]

    Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.

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