The overall objective of this project is to develop assay systems to detect genotoxic and non-genotoxic carcinogens based on an improved molecular and cellular understanding of human cell transformation mechanisms.
The specific aims are to (i) compare the molecular mechanisms of cell immortalization, a rate-limiting step in cell transformation, of human and rodent cells, (ii) examine whether induction of genomic instability is an important step in human cell transformation, (iii) develop biological markers useful for identifying transformed epithelial cells of various stages of transformation, and (iv) examine the usefulness of established human epithelial cell lines to detect carcinogens involved at different stages of carcinogenesis.
The project is aimed at establishing reliable cell transformation systems which detect human carcinogens acting by different mechanisms. We plan :
a) To investigate the differences between human and rodent cells in resistance to transformation with emphasis on :
(i) Induction of immortalization.
(ii) Induction of genomic instability.
b) To identify those transformation phenotypes of human epithelial cells which can be induced by carcinogens and to identify biological markers for these responses, which can be used as markers for different stages of transformation of human epithelial cells.
c) To develop epithelial cell transformation systems based on the results from 1 and 2. The intrinsic resistance of human cells to transformation means that it is unlikely to be possible to generate a system in which the full transformation of normal human epithelial cells can be reproducibly achieved and quantified. Therefore, we plan to establish separate systems for studying each of the individual steps in the process which respond to non-genotoxic carcinogens (i.e. manipulated human epithelial cell systems requiring only single events to progress to a further transformation stage).
d) To conduct a validation of assay systems with selected carcinogens, genotoxic and non-genotoxic.
Funding SchemeCSC - Cost-sharing contracts
UB8 3PH Uxbridge
2300 RA Leiden