title: Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts.
abstract: Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect the earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts before adenoma formation, also found in irradiated crypts. However, the underlying driving mechanism for this is not known. Wnt signaling is a key regulator of proliferation, and elevated Wnt signaling is implicated in cancer. Nonetheless, how cells differentiate Wnt signals of varying strengths is not understood. We use computational modeling to compare alternative hypotheses about how Wnt signaling and contact inhibition affect proliferation. Direct comparison of simulations with published experimental data revealed that the model that best reproduces proliferation patterns in normal crypts stipulates that proliferative fate and cell cycle duration are set by the Wnt stimulus experienced at birth. The model also showed that the broadened proliferation zone induced by tumorigenic radiation can be attributed to cells responding to lower Wnt concentrations and dividing at smaller volumes. Application of the model to data from irradiated crypts after an extended recovery period permitted deductions about the extent of the initial insult. Application of computational modeling to experimental data revealed how mechanisms that control cell dynamics are altered at the earliest stages of carcinogenesis.
authors.affiliation: Microsoft Research, Cambridge CB1 3LS, United Kingdom.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Dunn
authors.affiliation: School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia jmosborne@unimelb.edu.au i.s.nathke@dundee.ac.uk.
authors.forename: J M
authors.initials: JM
authors.lastname: Osborne
authors.affiliation: Division of Cell and Developmental Biology, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: P L
authors.initials: PL
authors.lastname: Appleton
authors.affiliation: Division of Cell and Developmental Biology, University of Dundee, Dundee DD1 5EH, United Kingdom jmosborne@unimelb.edu.au i.s.nathke@dundee.ac.uk.
authors.forename: I
authors.initials: I
authors.lastname: Näthke
mesh_terms: D000818:Animals; D002455:Cell Division / Q000528:radiation effects; D049109:Cell Proliferation / Q000502:physiology / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D003198:Computer Simulation; D003260:Contact Inhibition / Q000528:radiation effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000528:radiation effects*
chemical_list: D051153:Wnt Proteins