Development of human epithelial cell transformation models for carcinogen screening, employing defined phenotypic endpoints mechanistically representative of rate-limiting events in human carcinogenesis

The use of laboratory animals to screen chemicals for carcinogenic activity is set to decline because of new EC regulations and continuing public pressure. This has revived interest in cell culture models for this purpose. Such cell transformation assays (CTAs) should: (i) include those based on metabolically competent normal human cells of epithelial origin (the source of most human cancers), (ii) employ objective transformation criteria that reflect key molecular events driving human cancer development, and (iii) be responsive to non-genotoxic and genotoxic carcinogens.

This project has been formulated to develop human CTAs meeting all these requirements. New models will be based on human mammary epithelial cells and squamous epithelial cells. Assays will employ transformation endpoints directly linked to two key events responsible for the immortality of human cancer cells (senescence-bypass). The applicants have already demonstrated the feasibility of developing exploitable CTAs using these approaches. Novel human CTAs will be exhaustively validated against panels of genotoxic and non-genotoxic carcinogens.

New assays will be available for further evaluation by industry and regulatory bodies by the end of the project. Human CTAs emerging from the project will have a major impact on reducing animal usage in carcinogenicity assessment, and therefore on the 3Rs.

Pickles JC et al. (2016). A mechanistic evaluation of the Syrian hamster embryo cell transformation assay (pH 6.7) and molecular events leading to senescence bypass in SHE cells. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 802:50-8. doi: 10.1016/j.mrgentox.2016.04.002

Carnero A et al. (2015). Disruptive chemicals, senescence and immortality. Carcinogenesis 36(1):S19-37. doi: 10.1093/carcin/bgv029

Yasaei H et al. (2013). Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells. Oncogene 32(2):171-9. doi: 10.1038/onc.2012.45

Creton S et al. (2012). Cell transformation assays for prediction of carcinogenic potential: state of the science and future research needs. Mutagenesis 27(1):93-101. doi: 10.1093/mutage/ger053

Back to top
Strategic grant

Status

Closed

Principal investigator

Professor Robert Newbold

Institution

Brunel University

Co-Investigator

Professor Martha Stampfer
Professor E Kenneth Parkinson
Professor Michael R O'Donovan

Grant reference number

NC/K500045/1

Award date

Mar 2012 - Mar 2015

Grant amount

£503,020