Project

angiogenesis; pericytes; vascular endothelium; extracellular matrix; tumor biology

Lead
Therapien gegen Krebserkrankungen zielen entweder direkt auf die Krebszellen oder sie verhindern die Bildung des Blutgefässsystems das den Tumor mit Nahrungsstoffen versorgt. Letzteres ist vielversprechend da es im Prinzip für viele Tumorarten anwendbar ist, führt aber mit den aktuell verwendeten Methoden zu unerwünschten Nebenwirkungen. Wir haben ein neues Molekül entdeckt Olfactomedin-like 3 (Olfml3), das in der unmittelbaren Umgebung von Tumorgefässen für deren Wachstum und Entwicklung notwendig ist. Hemmung dieses Moleküls könnte Krebstherapien verbessern.
Lay summary
Neue Blutgefässe entstehen durch Aussprossung von Endothelzellen aus bestehenden Gefässen, wenn diese Wachstumsfaktoren ausgesetzt werden. Dabei bilden Endothelzellen neue, schlauchähnliche Gefässe, die dann von sogenannten Perizyten stabilisiert werden. Unser Olfml3 bindet den vaskulären Wachstumsfaktor BMP4 und präsentiert  diesen den Blutgefässen in Tumoren. Wir werden versuchen, diese Präsentation mittels sogenannten monoklonalen Antikörpern zu verhindern, solche wurden von unserem Labor bereits produziert. Dies  versuchen wir mit in vitro Zellsystemen und im Tierexperiment zu zeigen. Dabei werden verschiedene Tumorarten eingesetzt. Ferner werden wir eine Maus untersuchen, die defekt für das Olfml3 Gen ist. Und schliesslich möchten wir die Signale untersuchen, die von dem Komplex Olfml3/BMP4 in Endothelzellen ausgelöst werden. Ferner untersuchen wir die Rolle von Olfml3 in der Interaktion von Perizyten mit dem Endothel.  Für das Funktionieren eines Blutgefässes scheint dies von imminenter Bedeutung zu sein.

Direct link to Lay Summary

Last update: 27.03.2014

Number	Title	Start	Funding scheme

Most cancer therapies are directed against tumor cells, however a growing number of cancer therapeutics target cells of the tumor microenvironment. Antiangiogenic drugs have been used as anticancer agents to target tumor endothelial cells or pericytes. Because of the limited efficacy of current monotherapies, there is a strong demand for the dual targeting of endothelial cells and pericytes. We have recently identified Olfactomedin-like 3 (Olfml3) as a novel matricellular cue within the tumor microenvironment, which exhibits proangiogenic properties. Similarly to other matricellular proteins, Olfml3 is highly expressed during development, whilst its expression in the adult is limited largely to tissues undergoing normal or pathological remodeling. In addition,Olfml3-/- mice are viable and exhibit no overt vascular morphogenetic defects, suggesting that Olfml3 isdispensable for normal embryogenesis like most matricellular proteins. Finally, our recent study has demonstrated the ability of Olfml3 to regulate adult vascular remodeling under normal or pathological conditions e.g. tumor angiogenesis. We have shown that tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes, and deposited in the perivascular compartment. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. In vitro, Olfml3 targeting is sufficient to inhibit endothelial cell migration and sprouting. Moreover, Olfml3 has been previously described as an extracellular modulator of bone morphogenetic protein (BMP) signaling. We have demonstrated that both mouse and human homologues of Olfml3 interact with BMP4, which has been characterized as a potent pro-angiogenic factor. Olfml3 alone or through binding to BMP4 enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis.As an integral part of the experiments proposed in this grant application, we aim to dissect the role of Olfml3 in the alternative mechanisms that regulate the formation of blood vessels within solid tumors. A prerequisite for these studies will be elucidating the role of Olfml3 in cell-matrix and cell-cell communications and how these are influenced by e.g. microRNAs and/or growth factors like BMP4. Experiments orientated towards understanding the signal transduction cascade mediated by Olfml3 and how this can influence gene expression and cell behavior are also considered high priority. Further studies are needed to determine if blocking Olfml3 will be a more effective strategy in controlling tumor growth by targeting two distinct cell types within the tumor microenvironment using a single molecule. If pericytes are also identified as a target for tumor therapy, it becomes important to map the molecular mechanism involved in pericyte recruitment to the tumor vessel wall. For this reason, one of the objectives of this grant proposal is to clarify the regulatory role of Olfml3 in endothelial-pericyte crosstalk. We also plan to explore the potential role of Olfml3 in atherosclerosis. Consistent with this approach, our broader focus will remain at translating the rapidly expanding knowledge base of the matricellular protein family into a clinical setting. This will be done by identifying promising drug targets and defining new therapeutic strategies to treat vascular and malignant disorders.