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Group head "CEACAM1 and angiogenesis":
Andrea Kristina Horst, Ph.D.
M.Sc. Biochemistry/Molecular Biology
Contact information:
Andrea Kristina Horst,
University Medical Center Hamburg-Eppendorf (UKE)
Diagnostic Center, Institute of Clinical Chemistry
CAMPUS Research Building, N27
52, Martinistraße
D-20246 Hamburg
Phone: int. acc. code +49(0)40-7410-51905
Fax:: int. acc. code +49(0)40-7410-54971
E-mail: ahorst@uke.uni-hamburg.de
Awards and Fellowships:
Memberships
Since 2000: German Society of Clinical Chemistry and Laboratory Medicine (DGKL)
Curriculum vitae:
| 1992-1996 | M.Sc. Biochemistry/Molecular Biology, University of Hamburg |
| 1997 | graduation, M.Sc., University of Hamburg |
| 1997-2000 | Ph.D. thesis and diploma with Professor Christoph Wagener, Director of the Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Diagnostic Center |
| 2000-2002 | Postpoctoral trainee, McGill University, McGill Cancer Center, Montreal, Canada |
| Since 2003 | Assistant professor, University Medical Center Hamburg-Eppendorf, Diagnostic Center, Institute of Clinical Chemistry with Professor Christoph Wagener, Director of the Institute |
Christa Frenz, research assistance
Krimhild Scheike, research assistance
Sabine Harenkamp, research assistance
Thomas Bickert, Ph.D., M.Sc. Biology
Heike Pospisil, Ph.D., M.Sc. Biochemistry/Molecular Biology
Daniela Gerstel, M.Sc. Life Sciences
Mike Jahn, M.Sc. Biology
Peter Ludewig, cand. M.D., undergraduate
Open positions in BMBF-funded project: see end of section
The presentation of our projects here will give you an idea what our group is about. An outline of the project funded by the BMBF is given below.
Keywords: cell adhesion, transgenic models, angiogenesis, inflammation
Main expertise:
In the 1990s, we discovered that CEACAM1 is expressed on newly formed blood vessels in the placenta5. A few years later, we described CEACAM1 expression on tumoural blood vessels and on vessels in wounding tissues 6. This discovery prompted new projects, especially the development of different mouse models, to understand how and when CEACAM1 expression is relevant in the context of physiological and pathological vessel neo-formation (angiogenesis and vasculogenesis). A molecule homepage can be found at: http://www.carcinoembryonic-antigen.de/ or http://www.signaling-gateway.org/molecule/query?afcsid=A003597.
The process of vessel formation in different physiological and pathological contexts has been elaborated recently in the following Review series: Nature insight and Nature Reviews Cancer etc.:
In these series, you will also find clues and references to online databases that focus on clinical trials targeting molecules involved in pathological vessel formation. To provide but a few, you can use the following links to get more detailed information on angiogenesis and implications for anti-angiogenic therapies:
. http://www.nature.com/nature/supplements/insights/angiogenesis/index.html
. http://www.nature.com/nrm/journal/v10/n3/abs/nrm2639.html
. http://www.nature.com/nrc/journal/v8/n8/index.html
In our lab, we developed in vitro and in vivo (mouse) models to study CEACAM1 function in angiogenesis. A few examples are given below. Our interest is set on translational research, i.e. translating human disease into mouse systems and evaluating manipulative potentials for therapeutic intervention.
To start with, CEACAM1 is expressed on a variety of blood vessels in mouse tissues, and its vascular expression pattern is conserved in humans and rodents.
CEACAM1 expression in murine vasculature. CEACAM1 expression is shown in red or blue, respectively (photographs: A. Horst, © A. Horst).
For the analysis of CEACAM1 expression, we developed transgenic mouse lines that carry Tie2-promoter driven over-expression of CEACAM1 (CEACAM1endo+ mice) 7. The Ceacam1-/- mouse line (CEACAM1-knockout) was obtained from Professor Nicole Beauchemin, McGill University, Montreal, Canada.
To study the impact of vascular endothelial CEACAM1 expression, we use different ex vivo systems, for example the aortic ring assay. As shown in the figures below, lack of CEACAM1-expression in the Ceacam1-/- aortic ring (right panel) reduces endothelial cell sprouting, whereas endothelial over-expression can enhance endothelial branch formation 7.
Effects of endothelial CEACAM1-expression evaluated in aortic ring assays (photographs: A. Horst, © A. Horst). Lower panel, © JCI, 2006 7.
Links: http://www.tumorvessel.de
In this project, we analyze the angiogenic and metastatic behaviour of endogenously induced mammary adenocarcinoma in transgenic mice. Our focus is set on how CEACAM1-expression affects tumour metastases and angiogenesis.
As shown in the figure below, CEACAM1 expression is altered in a variety of human cancers. In our mammary adenocarcinoma mouse model, we try to validate CEACAM1-dependent tumour progression. Mammary tumour development and progression are characterized by an initial phase of enhanced angiogenesis in low grade tumours (G0 and G1 grade), followed by insufficient angiogenesis in moderately and poorly differentiated adenocarcinoma (G2 and G3 grade), thereby leading to tumour necrosis in the central mass of the tumour. However, angiogenesis increases again in undifferentiated and anaplastic tumours (G4 grade) ("angiogenic switch"). Currently, we are studying the influence of endothelial CEACAM1 on tumour vascularization and stroma formation at different stages of tumour development and progression, and reveal the cross-talk between CEACAM1 and other angiogenic factors.
CEACAM1 expression is dysregulated in a variety of human cancers. Copyright : Springer
From Horst & Wagener: CEACAM1 adhesion molecule in Encyclopedia of Cancer, 2nd edition 4,
© Springer Press
The stimulus for collateral growth (arteriogenesis) is the occlusion of femoral artery in our model of hindlimb ischemia. Arterial occlusion causes dramatic hemodynamic alterations and induces endothelial cell and smooth muscle cells proliferation, as well as outward remodeling of the vasculature. Within a week after fermoral artery occlusion, smooth muscle cells de-differentiate from the contractile to the synthetic phenotype, leading to neo-intima formation and re-differentiation, which in turn increases vascular tortuousity and lumen regression. After the occlusion, hypoxia is induced in the lower leg, which triggers the formation of new capillaries by angiogenesis. In our mouse models of hindlimb ischemia, we are currently studying CEACAM1-mediated effects in both arteriogenesis and angiogenesis. Examples for CEACAM1 implication and its assistance in re-establishing tissue perfusion in this model are outlined below.
Model of hindlimb ischemia in the mouse: the femoral artery is ligated surgically. After one week, collateral vessels grow into the poorly perfused areas of the muscle.
Angiogenesis in hypoxic calf muscles in CEACAM1-transgenic (CEACAM1endo+)and Ceacam1-/- mice. Vessels are shown in red (anti-CD31 labelling). © JCI,2006 7
The aim of this project is to define and manipulate glycan-mediated dissemination processes that aid dissemination of malignant melanomas to the draining lymph nodes. Melanomas belong to the most malignant tumours and they frequently metastasize to the lymph nodes. Lymph node metastasis is a prognostic parameter that determines clinical outcome and patient survival. The molecular basis for this dissemination is still poorly understood. The basis for our approach is the hypothesis that the presence of tumour cell glycans in the host causes re-programming of future metastatic sites, towards aiding reception of metastatic tumour cells by expression of corresponding glycan receptors. Therefore, we intend to characterize the glycan profile of the tumours in vivo as well as changes in the glycan receptor profile in the lymph nodes prior to and during metastasis in a mouse model 8. Further information can be found on the webpage of the Federal German Ministry for Education and Research: www.bmbf.de/pub/glykobiotechnologie.pdf.
Further links that yield information on glycostructures and glycobiology research are:
. http://www.functionalglycomics.org/static/index.shtml
. http://www.chemie.uni-hamburg.de/sfb470/
In our model for retinopathy, we use our different CEACAM1-transgenic mouse lines to evaluate retinal angiogenesis. The rationale of this model is that it translates into human diseases like age- or diabetes-related macular degeneration (AMD) or retinal angiogenesis observed in prematurely born children. The macula is the central retinal region specialized for high acuity vision. Regarding AMD, almost every 3rd person beyond their 7th life decade are affected. In both infant and age-related macula degeneration, newly formed or dysfunctional vessels may grow from the choroid into the retina and interfere with vision and may cause blindness. At http://www.nature.com/nrn/journal/v7/n11/full/nrn2007.html , you can find out more about AMD and therapeutic implications for anti-angiogenic strategies.
Cross section through a mouse retina. Blood vessels are labelled in green (©Peter Ludewig and Andrea Horst).
Within the UKE - Hamburg Medical Center Hamburg-Eppendorf:
Outside the UKE & international:
current as of March 2009
We would like to welcome new members in our group:
1 Research Assistant/Technician, E9, level 2 (V/MTA); BTA: E8, level 2
1 graduate student (E13/2, level 2)
For the project: Glycan- and glycan-receptor-mediated processes in the early dissemination of malignant melanoma (Mouse model), funded by the BMBF
Your profile:
We are looking for people who are dedicated to their profession, who are enthusiastic about research. In our project, we study tumour models in vitro and in vivo and we intend to develop phage-library derived antibodies, so we would welcome anyone with profound experience in histology, molecular biology and protein biochemistry.
In our laboratory, we can offer multiple techniques from in vitro to in vivo, and you are welcome to participate and make use our technical platforms in your project and develop your own perspectives. Our focus is set on molecular mechanisms of blood and lymphatic vessel growth in different pathological conditions. Our target molecules in the various studies are cell surface glycoproteins.
