4 research outputs found
Mechanisms of malignant and non-malignant angiogenesis using zebrafish models
Pathological angiogenesis significantly contribute to the onset,
development and progression of most common and severe human diseases
including cancer, metastatic disease, cardiovascular disease, age-related
macular degeneration, diabetic retinopathy and retinopathy of
prematurity. Under these pathological conditions, tissue hypoxia often
acts as a trigger to switch on angiogenesis. However, there has been
lacking non-invasive and clinically relevant animal models that allow us
to study mechanisms of human diseases. Zebrafish, as a complementary
animal model to mice, is a highly genetically and pharmacologically
tractable vertebrate which is easily visualized during development.
Zebrafish offers a unique opportunity to study angiogenesis under
hypoxia.
This thesis describes development and characterization of four novel
zebrafish models in relation to hypoxia-induced angiogenesis, vascular
and tumor pathology. Using these models, we demonstrate that hypoxia
plays a causal role in development of retinopathy and cancer cell
metastasis and thus provide important insights needed for the development
of therapeutic approaches aimed at interfering with these processes.
In paper I, we showed that hypoxia could induce neovascular retinopathy
in zebrafish and this model is highly relevant to clinical retinopathy
caused by diabetes. This zebrafish retinopathy model also allows us study
the therapeutic potential of various antiangiogenic agents. In paper II,
we demonstrate a novel principle that regulates blood perfusion in
lymphatics as an effective defense against tissue hypoxia in zebrafish
and kryptopterus bicirrhis. The arterial-lymphatic shunt is controlled by
nitric oxide and the implication of this work is that NO-induced
lymphatic perfusion might facilitate tumor cell spread from the blood
stream into the lymphatic system. In paper III, we take advantage of the
transparent nature of zebrafish embryos and availability of the
transgenic strain fli1:EGFP to develop a zebrafish metastasis model.
Using this model, we are the first to study the role of hypoxia in
relation to angiogenesis in facilitating tumor cell dissemination,
invasion and metastasis. To the best of our knowledge, this is the first
animal model that allows scientists to study the early events of
metastasis at a single cell level. In paper IV, We show that PI3 kinase
is a key signaling component that mediates angiogenesis in the developing
embryonic retina and in the regenerating adult fins.
In conclusion, development of these zebrafish disease models have paved
new avenues for studying mechanisms of pathological angiogenesis in
malignant and non malignant diseases and offers unique opportunities for
assessment of therapeutic potentials of known and novel drugs against
these most common and lethal diseases
Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-8
Fat is a major tissue component in human breast cancer (BC). Whether breast adipocytes (BAd) affect early stages of BC metastasis is yet unknown. BC progression is dependent on angiogenesis and inflammation, and interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) are key regulators of these events. Here, we show that BAd increased the dissemination of estrogen receptor positive BC cells (BCC) in vivo in the zebrafish model of metastasis, while dissemination of the more aggressive and metastatic BCC such as estrogen receptor negative was unaffected. While anti-VEGF and anti-IL-8 exhibited equal inhibition of angiogenesis at the primary tumor site, anti-IL-8 reduced BCC dissemination whereas anti-VEGF had minor effects on this early metastatic event. Mechanistically, overexpression of cell-adhesion molecules in BCC and neutrophils via IL-8 increased the dissemination of BCC. Importantly, the extracellular in vivo levels of IL-8 were 40-fold higher than those of VEGF in human BC. Our results suggest that IL-8 is a clinical relevant and promising therapeutic target for human BC
Hypoxia-Induced Retinal Angiogenesis in Zebrafish as a Model to Study Retinopathy
Mechanistic understanding and defining novel therapeutic targets of diabetic retinopathy and age-related macular degeneration (AMD) have been hampered by a lack of appropriate adult animal models. Here we describe a simple and highly reproducible adult fli-EGFP transgenic zebrafish model to study retinal angiogenesis. The retinal vasculature in the adult zebrafish is highly organized and hypoxia-induced neovascularization occurs in a predictable area of capillary plexuses. New retinal vessels and vascular sprouts can be accurately measured and quantified. Orally active anti-VEGF agents including sunitinib and ZM323881 effectively block hypoxia-induced retinal neovascularization. Intriguingly, blockage of the Notch signaling pathway by the inhibitor DAPT under hypoxia, results in a high density of arterial sprouting in all optical arteries. The Notch suppression-induced arterial sprouting is dependent on tissue hypoxia. However, in the presence of DAPT substantial endothelial tip cell formation was detected only in optic capillary plexuses under normoxia. These findings suggest that hypoxia shifts the vascular targets of Notch inhibitors. Our findings for the first time show a clinically relevant retinal angiogenesis model in adult zebrafish, which might serve as a platform for studying mechanisms of retinal angiogenesis, for defining novel therapeutic targets, and for screening of novel antiangiogenic drugs