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Keywords | Tumour-host interactions | tumour targeting |<br />
Anti-tumour targeting<br />
Modulation of the Recruitment of<br />
the Vessels and Immune Cells by<br />
Malignant Tumours: Targeting of Tumour<br />
Vessels and Triggering of Anti-Tumour<br />
Defence Mechanisms<br />
Summary<br />
All malignant tumours acquire the capacity for efficient<br />
recruitment of blood vessels, which are absolutely necessary<br />
for tumour growth beyond a certain size. They also<br />
frequently stimulate lymphangiogenesis supporting dissemination<br />
of tumour cells, not only via the blood vasculature<br />
but also via the lymphatic system, leading to metastasis.<br />
Vessel growth is promoted by sprouting angiogenesis and<br />
the homing of bone marrow progenitor cells into the<br />
tumours and tumour vessels. The extensive vascularisation<br />
facilitates the invasion of cells of the innate and adaptive<br />
immune system, which stay largely functionally suppressed<br />
by the tumour environment, and even contribute to angiogenesis<br />
and tumour growth by cytokine and growth factor<br />
secretion.<br />
We propose in this application to:<br />
• further investigate key regulatory pathways by which<br />
tumour-secreted molecules promote vascularisation<br />
and inhibit immune cell function;<br />
• develop methods to inhibit tumour growth and metastasis<br />
by blocking vessel and tumour cell growth;<br />
• achieve tumour clearance by additionally promoting<br />
activation and homing of functional immune cells to the<br />
tumours.<br />
The project will comprise the collaboration of laboratories<br />
with complementary expertise. It will include experts in blood<br />
vessel and lymph vessel angiogenesis, metastasis formation,<br />
progenitor cell incorporation into tumours and tumour<br />
vessels, anti-tumour defence mechanisms of the immune<br />
system and viral transduction techniques. The final goal will<br />
be the preclinical evaluation of strategies in murine models<br />
of three of the most prevalent forms of human cancer,<br />
i.e. carcinomas of the breast, colon and prostate.<br />
The strategies to target the tumour will be based on gene, cell<br />
and immune therapy methods. They will include the use of:<br />
• adenoviruses for the expression of angiogenesis inhibitors<br />
following targeted delivery of the viruses to the tumour<br />
vasculature;<br />
• the genetic modification of murine embryonic and human<br />
umbilical cord/bone marrow progenitor cells and their<br />
directed homing into the tumour;<br />
• the use of genetically-engineered immune cell products or<br />
the transduction of immune cells to activate targeting of<br />
the tumours by innate and adaptive anti-tumour defence<br />
mechanisms. We expect that this project will contribute to<br />
innovation on three levels. Firstly, we will gain basic additional<br />
novel knowledge on important pathways and<br />
regulatory molecules for the recruitment of host cells to<br />
the tumours and their functional interaction with the<br />
tumour. Secondly, we will use this knowledge to test novel<br />
ways of targeting viruses and (transduced) cells to the<br />
tumours. Finally, we will evaluate whether, by a combination<br />
of anti-angiogenesis therapy with directed anti-tumour<br />
immunotherapy, it would be possible not only to inhibit<br />
tumour growth, but also to eradicate residual disease.<br />
Problem<br />
Despite significant improvements in diagnosis, surgical techniques,<br />
general patient care, and local and systemic adjuvant<br />
therapies, many solid tumours remain a major cause of death.<br />
Among the most prevalent and fatal forms are carcinomas of<br />
the breast, colon and prostate. Most deaths from cancer are<br />
due to metastases, seeded from the primary tumour via the<br />
blood and lymph vasculature, which are resistant to conventional<br />
therapies. The main barrier to the non-surgical treatment<br />
of the primary neoplasm and its metastases is the genetic<br />
instability and biological heterogeneity of cancer cells leading<br />
to the rapid development and growth of resistant cells. Since<br />
the expansion of solid tumours and their metastases beyond<br />
a minimal size is absolutely dependent on the formation of<br />
new blood vessels, anti-angiogenesis therapies constitute<br />
a promising alternative. In this case the genetically normal<br />
endothelial cells of the tumour vessels are targeted, avoiding<br />
the problem of resistance development. Furthermore, immune<br />
therapies are based on the ability of the immune system,<br />
evolved over evolutionary times, to cope with an almost unlimited<br />
number of antigens, thus opening the possibility to find<br />
a mechanism to target any tumour variant as long as the<br />
inhibitory milieu of the tumour environment can be overcome.<br />
Therefore angiogenesis and immune therapies remain among<br />
the most promising fields of cancer therapy.<br />
BIOLOGY 15