Community Research and Development Information Service - CORDIS



Project ID: 335605
Funded under: FP7-IDEAS-ERC
Country: Israel

Mid-Term Report Summary - LIPINTOECTION (Lipoproteins and angiogenesis: A new look at an old problem)

All cells require a sufficient amount of lipids for essential production of energy and synthesis of the plasma membrane. Multicellular organisms have developed a specialized transport system for distributing lipids throughout the body based on lipoprotein (LIP) particles, which travel through the vasculature, reaching all organs. LIP particles are composed of triacylglycerol lipids, phospholipids, cholesterol lipids, and apoproteins, which enable them to be solubilized in the plasma. Due to their travel through the blood stream, the endothelium interacts continuously with plasma LIPs. In spite of the fact that ECs are exposed to LIPs to a higher degree than any other cell type, they were long thought to function as an inert barrier, through which lipids are exchanged between plasma and surrounding tissues. In contrast to this classic view work from my laboratory has challenged this assumption, by uncovering a previously unexplored direct crosstalk between plasma LIPs and ECs (Avraham-Davidi, 2012; Avraham-Davidi, 2013).

During the first period of this proposal we have focused our efforts on the following objectives:

1. Unravelling LIP-dependent signaling pathways in ECs, during embryonic development. In order to identify downstream components underlying the effects of lipoproteins within ECs we took advantage of our well-established zebrafish models of hyper-, and hypo-lipidemia, to carry out the first mRNA expression profiling of ECs facing differential LIP levels (Gibbs-Bar, Arterioscler Thromb Vasc Biol, in press). Our results showed that different levels of ApoB-LIPs result in differential expression of the secreted enzyme Autotaxin (Atx), which in turn affects EC sprouting and angiogenesis. We further demonstrated that the effects of Atx in vivo are mediated by lysophosphatidic acid (LPA) - a well-known Atx activity product, and that LPA and LPA receptors participate as well in the induction of ectopic sprouting in response to LIP deficiency. Taken together, our results uncover a previously uncharacterized pathway mediating the effects of ApoB-LIPs on ECs, and open new avenues for research into endothelial dysfunction associated with hyperlipidemia.

2. The role of ApoB-LIPs in tumor-angiogenesis and metastasis. How the tumor vasculature responds to increased lipid load has been a matter of debate and controversy over the past three decades. Several reports describe the enhancement of tumor angiogenesis under hypercholesterolemia, whereas others have presented contradictory results suggesting that cholesterol levels are inversely correlated to tumor vessel growth. In this project we decided to look at the contribution of LIPs to tumor-related angiogenesis. To this end we analyzed tumor vascularization and metastasis formation in two different mouse models- Ldlr-/- and ApoE-/-, which share increased cholesterol levels in circulation, but markedly differ in their apoprotein contents (Sela, Cancer Res, under revision). As a whole our results demonstrate that tumor-angiogenesis and metastasis formation inversely correlate to the plasma levels of Apoprotein-E and Apoprotein-B100 but not to cholesterol and triglycerides.These results are strongly supported by in vitro experiments demonstrating the direct effects of these apoproteins on EC behavior. Cholesterol and free fatty acids on the other hand proved beneficial for EC proliferation as shown for other cell types. Finally, our results provide important clues as to the potential non-desired contribution of statins to tumor angiogenesis and malignancy, and suggest a molecular mechanism explaining the controversy surrounding this subject. On a broader sense our findings contribute important new insights into the role of apoproteins in tumor progression, their mode of action and their potential benefits for cancer treatment.

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