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Interaction mechanisms between tumours and blood vessels

In recognition of the growing importance of angiogenesis research in the field of oncology, the German Research Foundation has established two new research consortia as part of its “Angiogenesis” research priority programme: one project focuses on the mechanisms of vascular differentiation and the second on the interaction between tumour cells and cells of the vascular wall, which are prerequisites for tumour growth and metastasis.

Number of papers published in expert journals on the topic of angiogenesis in Germany (right scale) and worldwide (left scale). © Final SPP 1069 report, DFG
The number of angiogenesis research projects has increased dramatically over the last decades. In eight years alone (1999 – 2006) at the time when the German Research Foundation founded the “Angiogenesis” (SPP 1069) priority programme, the number of publications in this research area increased more than three-fold per year. PubMed, a service attached to the US National Library of Medicine, currently cites more than 40,000 articles in international journals for the keyword “angiogenesis”. Particularly intensive research in angiogenesis is devoted to the development of tumours, as it has become clear that the growth of blood vessels is one of the most important, if not the most important, interaction between the tumour and the host organism. Last not least, research is also stimulated by the fact that the first anti-angiogenetic tumour drugs have been approved for clinical application in the last few years (see article: Cancer therapy targets angiogenesis). Many issues still need to be solved. These particularly include the molecular and functional interactions between tumour cells and endothelial cells, which play a huge role in tumour progression and metastasis and are not yet understood in detail.

One vascular research programme becomes two

For all these reasons, the Senate of the German Research Foundation resolved to create two new research programmes with more specific focal areas after the SPP 1069 had come to an end in 2006. These programmes are:

  1. the Germany-wide priority programme "The Tumour - Vessel Interface" (SPP 1190), which focuses on the numerous bi-directional interactions between tumour and endothelial cells that make the growth of tumours and metastasis possible;
  2. the TransRegio cooperative research centre (SFB 23) dealing with "Vascular Differentiation and Remodelling", in which the universities of Frankfurt, Freiburg and Heidelberg are working jointly on the basic research-oriented deciphering of the differentiation and remodelling mechanisms of blood and lymph vessels.
“Angiolab” illustration, the joint research division vascular biology of the Medical Faculty Mannheim (CBTM), University of Heidelberg, and the German Cancer Research Centre (DKFZ-ZMBH alliance)
“Angiolab” illustration, the joint research division vascular biology of the Medical Faculty Mannheim (CBTM), University of Heidelberg, and the German Cancer Research Centre (DKFZ-ZMBH alliance) © CBTM

The major focus of the “The Tumour – Vessel Interface” programme is the investigation of the molecular and functional interactions between tumour cells and cells of the vascular wall with regard to tumour progression and metastasis. Going beyond traditional research approaches that focused largely on tumour cells, the processes are now understood to be the result of complex molecular and cellular interactions between tumour cells and the endothelial cells surrounding the tumour. Around 20 groups of researchers from all over Germany are dealing with this superordinate aspect, focusing on topics such as tumour angiogensis, lymphatic angiogenesis, intratumoral vascular cell differentiation, hypoxia, cell adhesion, migration and invasion, inflammation, coagulation, new animal models, imaging as well as translational vascular and oncological research.

A picturesque meeting place for researchers

Seeon Abbey – a culture and education centre in Upper Bavaria © Bezirk Oberbayern

The SPP 1069 had already organised bi-annual symposia in the Seeon Abbey situated in a picturesque environment at the "Chiemsee" lake. These meetings were excellent platforms for scientific exchange and had become one of the most important meeting points for international angiogenesis researchers. These meetings have been continued with the two new research priorities. The Second International Seeon Abbey Meeting entitled "The Tumour - Vessel Interface" will be held from 19th to 22nd September 2009.

Professor Dr. Hellmut Augustin is the spokesperson of the SPP 1190. Augustin moved to the German Cancer Research Centre in Heidelberg from the Freiburg Tumour Biology Centre where he had coordinated the “angiogenesis” priority programme. He is now head of the Department of Vascular Biology and Metastasis and was also appointed chair of Vascular Biology and Angiogenesis Research of the Aventis Foundation established at the Centre for Biomedicine and Medical Technology Mannheim (CBTM) at the University of Heidelberg.

As part of the SPP 1190, Augustin leads a research project on the molecular analysis of the interactions between tumours and blood vessels that control the spread of tumour cells and their organ-specific metastasis. He writes: "Metastatic tumour cells induce angiogenesis, they intrude into blood vessels and migrate with the bloodstream to distant organs, attach to endothelial cells in secondary organs in order to intrude into the organ through the vascular wall and form metastases. Besides the induction of angiogenesis, the mechanisms of the numerous interactions between tumour and endothelial cells are barely understood on the molecular level."

Paradigm change in angiogenesis research

In previous investigations, Augustin and his group of researchers were able to show that EphB4 receptors and the corresponding EphrinB2 ligands control the attachment of tumour cells to endothelial cells as well as the interaction between the cells. Eph receptors are members of the tyrosine kinase receptor protein family; along with their Ephrin ligands, they are components of the signalling cascades that play a key role in cell-cell interactions of many differentiation processes – for example embryo genesis, the development of the nervous and vascular system as well as the development of cancer. Systematic experiments both on the cellular level and in vivo gave the scientists insights into the EphB/EphrinB interactions of tumour cells and endothelial cells upon contact with each other, as well as other adhesion mechanisms that might be involved in the metastatic spread of tumour cells. The scientists’ objective is to gain a mechanistic understanding of tumour cell and endothelial cell adhesions and eventually of the entire signalling cascade that leads to metastasis.

Paradigm change in angiogenesis research
Paradigm change in angiogenesis research © Angiolab

The idea that the sprouting of new capillaries and their intrusion into the tumour tissue follows a uniform mechanism turned out to be far too simple. There is growing evidence that angiogenesis is a highly complex three-dimensional process that is controlled by a cascade of hierarchically structured signalling systems. The investigation of angiogenesis, one of the fastest growing biomedical disciplines, is experiencing a paradigm change that will no doubt give rise to surprising discoveries and insights.

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