In vivo prediction and discrimination of carcinogenic compounds using Schmidtea mediterranea's stem cell proliferation patterns

Abstract

Accurate and reliable carcinogenicity assays are imperative, as cancer risks are directly associated with the type and potency of a compound. A challenge for the development of alternative test methods is the prediction of non-genotoxic carcinogens, which entail different assessments of human cancer risk. The variety of non-genotoxic cancer pathways complicates the search for sensitive and reliable parameters expressing their carcinogenicity. The presented assay enables a simple, rapid and inexpensive prediction and discrimination of both genotoxic and non-genotoxic carcinogens by means of flatworm stem cell dynamics. Our methodology entails an exposure to carcinogenic compounds during the animal's regeneration process, and the most striking differences between non-genotoxic and genotoxic carcinogen-induced proliferative responses were detected during the initial stages of the regeneration process, i.e. at the moment stem cells proliferate. We present a two-step-approach that combines in vivo adult stem cell proliferation patterns and phenotypic appearances. Based on the observed differences in stem cell dynamics we were able to discriminate between genotoxic and non-genotoxic carcinogens in a selected group of compounds (MMS, 4NQO, CsA, S-PB, MPH, CPZ). More specifically, genotoxic carcinogens were characterized by significantly fewer mitotic cells after 3 days exposure in comparison with a 1-day exposure set-up, while, on the contrary, non-genotoxic carcinogens were characterized by significantly more mitotic cells after 3 days exposure in comparison with a 1-day exposure set-up. The ability to discriminate between genotoxic and non-genotoxic compounds makes this approach unique and with significant added value to current research and drug development.