Novel Mechanism of Macrophage-Mediated Metastasis Revealed in a Zebrafish Model of Tumor Development

Wang, Jian; Cao, Ziquan; Zhang, Xing-Mei; Nakamura, Masaki; Sun, Meili; Hartman, Johan; Harris, Robert A.; Sun, Yehuan; Cao, Yihai

doi:10.1158/0008-5472.can-14-2819

Cited by 119 publications

(120 citation statements)

References 32 publications

(32 reference statements)

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“…C or CD8 C T cells, amongst others; [251][252][253] (2) the circulating levels of multiple cytokines, such as interferon, gamma (IFNG; best known as IFN-g), 254 IL6, 255 and tumor necrosis factor (TNF); 256-258 (3) the amounts of TAA-specific T cells (via tetramer assays); 259,260 (4) the tumor mutational load and/or the abundance of predicted neo-antigens (via genome or whole-exome sequencing); 115,138,[261][262][263][264][265] and (5) the levels of circulating biomarkers of ICD (via proteomic or metabolomic assays).…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

et al. 2017

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The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

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Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

et al. 2017

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“…Consistent with this notion, we have correlated the cancer invasion in the zebrafish model and the metastatic disease in a limited number of cancer patients. Our preliminary findings show that highly metastatic cancer types can be accurately predicted in our zebrafish model 222 . It would be interesting to expand this type of studies in the future and hopefully this functional assay could be routinely used in the clinic in combination with observational clinical data when needed.…”

Section: Future Perspectivesmentioning

confidence: 64%

“…Future studies based using this zebrafish metastasis model should also be able to recapitulate the tumor microenvironment in which various host cells can be included in the metastatic assays. To this end, we have shown that the tumor-associated microphages, especially the M2 microphage subpopulation, are crucial for promoting cancer metastasis 222 . In line with this we plan to develop multi-color-coded system to label various cells including tumor cell, macrophage, stromal fibroblast, endothelial cell, and perivascular cells with different color to study their role in facilitating cancer metastasis.…”

Section: Future Perspectivesmentioning

confidence: 99%

VEGF-mediated vascular functions in health and disease

Cao¹

2015

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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 ...

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“…Zebra fish models present various features, including genetic traceability, rapid development, appropriateness for in vivo imaging and chemical screening, making it an attractive cancer model [97][98][99]. Generated tumours mimic human cancers at genomic, histological and metastasis levels [99][100][101]. The ability to perform in vivo imaging, high-throughput transgenesis and genetic and chemical screening presents an exceptional possibility to characterise the cancer genome efficiently.…”

Section: Page 10 Of 44mentioning

confidence: 99%