Project C3

Tumor-Specific Vascular Reprogramming in HCC: Mechnisms  and Therapeutic Targets

Principal Investigators: Prof. Dr. Sergij Goerdt, Prof. Dr. Hellmut Augustin



Short Summary

Hepatocellular carcinoma (HCC) is one of few tumor types for which anti-angiogenic tumor therapy has proven clinically effective as a monotherapy. However, the molecular mechanisms behind HCC-associated angiogenesis are less well-studied compared to other solid tumors. HCC is complicated by the contribution of two different vascular beds to tumor vascularization, i.e. sinusoid-derived vessels that form early and arterial-derived vessel that form late. Combining the specific expertise of both groups in hepatic sinusoidal endothelial cell biology and tumor angiogenesis, the project aims at molecularly and functionally studying the angiogenic and pre-angiogenic reprogramming of the hepatic vasculature during HCC tumorigenesis and developing improved anti-angiogenic therapies.


List of relevant publications

  1. Nasarre P, Thomas M, Kruse K, Helfrich I, Wolter V, Deppermann C, Schadendorf D, Thurston G, Fiedler U, Augustin HG (2009) Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res 69:1324-33.
  2. Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165-77.
  3. Kzhyshkowska J, Gratchev A, Schmuttermaier C, Brundiers H, Krusell L, Mamidi S, Zhang J, Workman G, Sage EH, Anderle C, Sedlmayr P, Goerdt S (2008) Alternatively activated macrophages regulate extracellular levels of the hormone placental lactogen via receptor-mediated uptake and transcytosis. J Immunol 180:3028-37.
  4. Klein D, Demory A, Peyre F, Kroll J, Augustin HG, Helfrich W, Kzhyshkowska J, Schledzewski K, Arnold B, Goerdt S (2008) Wnt2 acts as a cell type-specific, autocrine growth factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway. Hepatology  47:1018-31.
  5. Alajati A, Laib AM, Weber H, Boos AM, Bartol A, Ikenberg K, Korff T, Zentgraf H, Obodozie C, Graeser R, Christian S, Finkenzeller G, Stark GB, Heroult M, Augustin HG (2008) Spheroid-based engineering of a human vasculature in mice. Nat Methods 5:439-45.
  6. Falkowska-Hansen B, Falkowski M, Metharom P, Krunic D, Goerdt S (2007) Clathrin-coated vesicles form a unique net-like structure in liver sinusoidal endothelial cells by assembling along undisrupted microtubules. Exp Cell Res 313:1745-57.
  7. Kzhyshkowska J, Workman G, Cardo-Vila M, Arap W, Pasqualini R, Gratchev A, Krusell L, Goerdt S, Sage EH (2006) Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J Immunol 176:5825-32.
  8. Kzhyshkowska J, Mamidi S, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S (2006) Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 107:3221-28.
  9. Martens JH, Kzhyshkowska J, Falkowski-Hansen M, Schledzewski K, Gratchev A, Mansmann U, Schmutter­maier C, Dippel E, Koenen W, Riedel F, Sankala M, Tryggvason K, Kobzik L, Moldenhauer G, Arnold B, Goerdt S (2006) Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis. J Pathol 208:574-89.
  10. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG (2006) Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 12:235-39.
  11. Hansen B, Longati P, Elvevold K, Nedredal GI, Schledzewski K, Olsen R, Falkowski M, Kzhyshkowska J, Carlsson F, Johansson S, Smedsrod B, Goerdt S, Johansson S, McCourt P (2005) Stabilin-1 and stabilin-2 are both directed into the early endocytic pathway in hepatic sinusoidal endothelium via interactions with clathrin/AP-2, independent of ligand binding. Exp Cell Res 303:160-73.
  12. Scharpfenecker M, Fiedler U, Reiss Y, Augustin HG (2005) The Tie-2 ligand angiopoietin-2 destabilizes quie­scent endothelium through an internal autocrine loop mechanism. J Cell Sci 118:771-80.
  13. Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K (2005) Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol 169:239-43
  14. Hegen A, Koidl S, Weindel K, Marme D, Augustin HG, Fiedler U (2004) Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arteriosclerosis, thrombosis, and vascular biology 24:1803-09.
  15. Fiedler U, Scharpfenecker M, Koidl S, Hegen A, Grunow V, Schmidt JM, Kriz W, Thurston G, Augustin HG (2004) The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 103:4150-56.
  16. Kzhyshkowska J, Gratchev A, Martens JH, Pervushina O, Mamidi S, Johansson S, Schledzewski K, Hansen B, He X, Tang J, Nakayama K, Goerdt S (2004) Stabilin-1 localizes to endosomes and the trans-Golgi network in human macrophages and interacts with GGA adaptors. Journal of leukocyte biology 76:1151-61.
  17. Fiedler U, Krissl T, Koidl S, Weiss C, Koblizek T, Deutsch U, Martiny-Baron G, Marme D, Augustin HG (2003) Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J Biol Chem 278:1721-27.
  18. Politz O, Gratchev A, McCourt PA, Schledzewski K, Guillot P, Johansson S, Svineng G, Franke P, Kannicht C, Kzhyshkowska J, Longati P, Velten FW, Johansson S, Goerdt S (2002) Stabilin-1 and -2 constitute a novel family of fasciclin-like hyaluronan receptor homologues. Biochem J 362:155-64.
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