Cancer Research - Europa

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