Project B6 (completed)

Vascular endothelial cells play a pivotal role for angiogenesis during organogenesis, bone fracture healing as well as during pathological  processes such as osteoporosis and malignant tumorigenesis. Tumor-induced angiogenesis does not only have a vital impact on the growth of solid tumors and their metastatic potential but also for lymphomas as e.g. multiple myeloma (MM). An essential feature of the malignant MM is its settlement in bone marrow which entails tumor induced angiogenesis and osteolysis. The development of a microvascular network within the tumor tissue is dependent on a balance between angiogenic activators and inhibitors (“angiogenic switch”). A precondition for the successful application of material which is intended as a scaffold for osteoinductive processes is the migration of mesenchymal cells into the material. Ideally vascular endothelial cells should migrate and sprout into the material and finally by vascularisation support the bone regeneration.

In subproject B6 we study the endothelial behaviour with regard to migration, adhesion and proliferation of endothelial cells alone or during crosstalk with other normal or malignant cell populations (as for instance osteoblasts/osteoclasts and myeloma cells) on various biomaterials. By additional modification and coating of the scaffold material using components of the extracellular matrix (ECM), cyto- or chemokines and/or defined oligo-/polysaccharides employing a proangiogenic effect we intend to improve the homing of endothelial cells into the material and by that angiogenesis. Glycosylated macromolecules have been shown to have an essential influence on angiogenesis by i) enhancing the affinity of cellular receptors for defined growth factors, ii) regulating cell-cell and cell- ECM interactions, iii) exerting a direct impact on cellular growth by contact to receptors (lectins). For the design and development of bone reconstitution materials the targeted application of defined poly- or oligosaccharides may positively influence the above mentioned functions during endothelial vessel formation.

We intend to test various bone reconstitution materials developed within the SFB-TRR 79 and their modifications with regard to their angiogenic potential.  We shall further analyse the context between cellular interactions with bone substitution material in the pathological situation of osteoporosis and malignant multiple myeloma.

The migration and settlement of osteoprogenitor and endothelial cells into scaffolds of osteoinductive material is the pivotal step for the formation of new bone tissue in lesions caused by malignant tumour  cells or during osteoporosis. Endothelial cells are initiating the vascularization of the bone. In order to support blood vessel formation (angiogenesis) within the bone substitution material it is important to mimic a natural microenvironment suitable for the settlement of vascular endothelial cells. Polysaccharides, such as heparan sulphates, as components of the extracellular matrix, have several functions during angiogenesis and may thus be suitable as supportive material. On the other side, malignant tumours like multiple myeloma produce pro-angiogenic factors which further the tumour specific vessel formation. Therefore, our goal is to test various structurally modified polysaccharides which may support normal angiogenesis of the healthy tissue without increasing tumour angiogenesis.

The capacity of endothelial cells to form vessels can be tested in vitro by the so-called tubing assay. Co-cultures of fibroblasts and endothelial cells form tubes in the presence of the pro-angiogenic factor VEGF. The tube formation can be visualized by immuno-staining with a monoclonal antibody (anti-CD31) specific for endothelial cells. Modified heparins and various cellulose sulphates inhibit the tube formation at different extent. Instead of forming tubes, endothelial cells grow in patches.

Principle Investigators (PI)

• PD Dr. rer. nat. Reinhard Schwartz-Albiez

Deutsches Krebsforschungszentrum
Nationales Centrum für Tumorerkrankungen
Translationale Immunologie D015
Contact:
Im Neuenheimer Feld 580
69120 Heidelberg
Telefon: +49 (0)6221 / 42 3713
Fax: +49 (0)6221 / 42 3737
E-Mail: r.s-albiez@dkfz-heidelberg.de 

• PD Dr. med. Thomas Möhler

Deutsches Krebsforschungszentrum
Nationales Centrum für Tumorerkrankungen
Translationale Immunologie D015
Contact:
Im Neuenheimer Feld 580
69120 Heidelberg
Telefon: +49 (0)6221 / 42 3713
Fax: +49 (0)6221 / 42 3737
E-Mail: thomas_moehler@med.uni-heidelberg.de