Principal Investigator, Ph.D.
Translational Cancer Biology Research Program Biomedicum Helsinki
Wihuri Research Institute
P.O. Box 63 (Haartmaninkatu 8) FI-00014 University of Helsinki Finland
Tel. +358 2 941 25521 Fax +358 2 941 25510
Figure 1. Endothelial cell-to-cell junctions visualized using transmission electron microscopy and immunofluorescence staining.
Our research focuses on understanding endothelial cell signaling in tumors. We aim to identify novel mechanisms regulating tumor blood vessel growth and metastasis with therapeutic potential for targeting the tumor vasculature.
Our special interest is on the mechanisms by which the angiopoietin growth factors and the Tie receptor tyrosine kinases regulate tumor growth, angiogenesis and metastasis. We develop and utilize cellular, ex vivo and in vivo models to discover novel regulators of the angiopoietin-Tie pathway to understand its function during vascular homeostasis and in pathological angiogenesis.
In collaboration with clinical researchers, we aim to identify potential biomarkers for anti-angiogenic therapies and to understand more about the angiopoietin-Tie pathway in human cancer.
Figure 2. The angiopoietin-Tie system.
Tumor angiogenesis is a rate-limiting step in solid tumor growth, and tumors lacking angiogenesis exhibit a dormant phenotype. During the first steps of the angiogenic switch of tumors the pre-existing host blood vessels are engaged by the growing tumor, leading to endothelial cell activation. The activated endothelial cells express the angiopoietin-2 (Ang2, Angpt2) growth factor, which may destabilize the co-opted vessels resulting in hypoxia, hypoxia-induced expression of Ang2 and VEGF and tumor angiogenesis driven by VEGF and Ang2. We, and others have shown that blocking Ang2 significantly inhibits tumor growth and angiogenesis. We further showed that blocking Ang2 inhibits tumor metastasis, in part by improving the integrity of endothelial cell-cell junctions (Holopainen, Saharinen et al., JNCI, 2012).
The angiopoietin-Tie pathway is unique, because it is activated in endothelial cell-cell junctions via Tie receptor complexes that form in trans from one cell to another (Saharinen et al., Nat cell Biol 2008). This way, angiopoietin-1 may stabilize the vasculature. Angiopoieitins can also bind to cell matrix, thereby coupling Tie receptor activation to extracellular matrix changes. Angiopoietin-2 is an endothelial cell derived growth factor, whose expression is increased in tumors and diseases characterized with endothelial dysfunction, such as sepsis and acute lung injury. The orphan Tie1 receptor interacts with Tie2 and promotes tumor growth and vascularization (Damico et al., J Clin Invest, 2014).