PI: Christine Brostjan, Ph.D.
Associate Professor for Vascular Biology
Lab Location: Anna Spiegel Center of Translational Research, Level 5
Associated Clinical Department: General Surgery
Email: christine.brostjan@meduniwien.ac.at
Phone: +43-1-40400-73514, -73524
Research Focus:
Tumor growth and metastasis are supported by the formation of new blood vessels, a process which is called angiogenesis. In the past decades, essential mediators and mechanisms of tumor angiogenesis have been unraveled. Correspondingly, therapeutic agents have been developed to control cancer expansion by inhibiting blood vessel growth. In this context, our research team focuses on
a) basic aspects of endothelial cell activation by cancer signals to characterize regulatory mechanisms and identify novel therapeutic targets of tumor angiogenesis,
b) clinical parameters of tumor angiogenesis which reflect the prognosis of cancer patients and their response to anti-angiogenic and conventional cancer therapy.
Current Projects:
1. Ras protein transfer during transendothelial passage
The oncogene ras is frequently mutated in cancer cells and drives cell proliferation, migration and survival. We currently investigate whether active Ras protein can be transferred from tumor cells onto endothelial cells, when they traverse the blood vessel in the metastatic process. Furthermore, we aim to unravel whether transferred Ras protein activates endothelial cells to adopt an angiogenic phenotype.
2. Prognostic and predictive markers in anti-VEGF cancer therapy
Cancer patients receiving anti-VEGF antibodies (bevacizumab) in addition to standard chemotherapy experience marked changes in their blood levels of angiogenesis factors. We are closely monitoring colorectal and pancreatic cancer patients under therapy with respect to
- pro- and anti-angiogenic factors like VEGF, PD-ECGF, Ang-2, and TSP-1 in patient plasma,
- cell populations associated with angiogenesis such as platelets, circulating endothelial cells, endothelial progenitor cells, and Tie2-expressing monocytes in patient blood.
Among the parameters investigated, circulating endothelial cell populations generally show the highest correlation with treatment response and patient survival. Furthermore, our analyses indicate that the choice of chemotherapy may crucially determine the efficacy of anti-VEGF treatment. Highly thrombocytopenic agents like gemcitabine affect platelet-stored angiogenesis factors and may therefore prove unfavorable in combination with anti-angiogenic cancer therapy.
Of interest, the target molecule VEGF is systemically increased in a feedback-response to inactivation by the antibody bevacizumab. We are investigating the regulatory mechanisms leading to the VEGF rise in patient blood and the extent of VEGF inactivation by the remaining antibody. We are further interested in the impact of preoperative anti-angiogenic therapy on physiological angiogenesis during surgery-associated wound healing.
3. Regulation of the angiogenesis inhibitor thrombospondin-1 (TSP-1)
TSP-1 is a multidomain protein primarily released by platelets and endothelial cells and exerts diverse effects in angiogenesis, coagulation and cell-matrix interactions. It is subject to proteolytic processing which yields molecule fragments of distinct functions. Based on blood samples of patients we investigate the proteolytic isoforms generated during disease. Furthermore, we aim to characterize the mechanism of isoform processing by in vitro cell culture models.