title: Molecular characterization of preneoplastic lesions provides insight on the development of renal tumors.
abstract: Kidneys are the second most frequent site for chemically induced cancers in rats. However, there is still limited information on direct effects of carcinogens on pathways involved in the development of kidney tumors. Since transformed tumor cells have different characteristics than their cell of origin, it was hypothesized that healthy tissue and progressing stages of preneoplastic lesions are differentially influenced by chemical carcinogens. To elucidate this question, TSC2(-/-) Eker rats were gavaged with genotoxic aristolochic acid or nongenotoxic ochratoxin A for 3 and 6 months, respectively. Histopathology and cell proliferation analysis demonstrated a compound- and sex-specific onset of preneoplastic lesions. In contrast, comparable gene expression profiles of laser-microdissected preneoplastic lesions from carcinogen-treated and control rats, including reduced expression of genes involved in carcinogen uptake and metabolism, point to a compound-independent lesion progression. Gene expression profiles and additional immunostaining suggested that clonal expansion of renal lesions appears primarily driven by disturbed mammalian target of rapamycin complex 1 and mammalian target of rapamycin complex 2 pathway regulation. Finally, prolonged carcinogen exposure resulted in only marginal gene expression changes in tubules with normal morphology, indicating that some tubules may have adapted to the treatment. Taken together, these findings indicate that the final outcome of in vivo carcinogenicity studies is primarily determined by time-restricted initial events, while lesion progression may be a compound-independent process, involving deregulated mTOR signaling in the Eker rat model.
authors.affiliation: Department of Human and Environmental Toxicology, University of Konstanz, Konstanz 78457, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Ahr
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D034341:Aristolochic Acids / Q000633:toxicity; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009793:Ochratoxins / Q000633:toxicity; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D051381:Rats; D013194:Staining and Labeling; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; C545700:CRTC2 protein, rat; C519510:Crtc1 protein, rat; D009793:Ochratoxins; D015534:Trans-Activators; D014157:Transcription Factors; C025589:ochratoxin A; C000228:aristolochic acid I; D001973:Bromodeoxyuridine