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Keywords | Tumour | host | signalling | stem cell | angiogenesis | lentivirus |<br />
Tumour-Host Genomics<br />
Genome-wide Analysis of Signalling<br />
Pathways in Regulation of the<br />
Interactions between Tumour and Host<br />
Cells: Applications of <strong>Cancer</strong> Therapy<br />
Summary<br />
In addition to oncogenic mutations that act cellautonomously,<br />
tumour cell growth depends on interactions with its<br />
microenvironment. The tumour microenvironment consists<br />
of cells of haematopoietic and mesenchymal origin, including<br />
infl ammatory cells, stem and progenitor cells, fi broblasts,<br />
endothelial cells and vascular mural cells. Tumour cell<br />
growth is known to depend on the interaction of tumour<br />
cells with such stromal cells. For example, a growing tumour<br />
needs to recruit normal endothelial and vascular mural cells<br />
to form its blood vessels. In addition, tumour cells induce<br />
stromal cells to secrete factors that contribute to tumour<br />
cell growth and invasion. Stromal cell-dependent interactions<br />
represent an attractive target for cancer therapy,<br />
because normal cells are genetically stable, and would not<br />
be expected to develop resistance to therapeutic agents.<br />
The development of such therapies is hampered by the fact<br />
that the molecular mechanisms behind tumour-stroma<br />
interactions are often poorly understood.<br />
In summary, the work plan entails development of novel<br />
advanced functional genomic instruments, technologies<br />
and methods to study tumour-host interactions in cancer,<br />
and to apply these techniques to the identifi cation of molecules<br />
and processes in normal cells, which could be targeted<br />
by novel anti-cancer therapeutic agents. In addition, we will<br />
develop targeted lentiviruses which would allow in vivo<br />
delivery of therapeutic agents into tumours. Functional validation<br />
of the discovered targets and developed delivery<br />
systems will be performed in in vivo models of murine<br />
tumour growth and dissemination. For purely technical reasons,<br />
melanoma and prostate cancer models are planned to<br />
be utilised fi rst. However, tumour-host interactions are<br />
universally.<br />
Essential for the growth and dissemination of any malignant<br />
disease, and the results of the experiments will be applicable<br />
for any kind of human cancer. The work has signifi cant<br />
exploitation potential and relevance for health in the understanding<br />
of the molecular mechanisms of tumourhost<br />
interactions, and in the treatment of cancer.<br />
BIOLOGY<br />
Problem<br />
Tumour cell growth depends on interactions with its microenvironment.<br />
The development of cancer therapies targeting<br />
these interactions is hampered by the fact that the molecular<br />
mechanisms behind tumourhost interactions are often poorly<br />
understood.<br />
Aim<br />
• To identify endothelial/BM cell-specifi c cis-regulatory<br />
elements for use in lentiviral in vivo targeting vectors.<br />
• To develop a targeted lentiviral library for the inhibition<br />
of selected major cell signalling pathways.<br />
• To identify tumour-derived factors that lead to increased<br />
angiogenesis and recruitment of stromal cells contributing<br />
to a microenvironment permissible for tumour growth.<br />
• To identify host-derived factors that induce tumour cell<br />
growth and tumour stem cell self-renewal.<br />
• To test in vivo the eff ect of targeted lentiviruses in inhibition<br />
of tumour growth and metastasis.<br />
Expected results<br />
The project aims to develop novel tools and methods to<br />
study tumourhos interactions in cancer, and to apply these<br />
techniques to the identifi cation of molecules and processes<br />
in normal cells, which could be targeted by novel anticancer<br />
therapeutic agents. In addition, we also propose to<br />
develop targeted lentiviruses that specifi cally express genes<br />
in bone marrow-derived cells and/or in endothelial cells,<br />
which would allow in vivo delivery of therapeutic agents into<br />
tumours.<br />
Potential applications<br />
Potential target genes for the treatment of cancer will allow<br />
the search, and preclinical and clinical validation of respective<br />
lead compounds.<br />
Tumour-host interactions are universally essential for the<br />
growth and dissemination of any malignant disease, and<br />
the results of this project could in principle ultimately be<br />
applicable for any kind of human cancer.<br />
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