Combined changes in Wnt signalling response and contact inhibition induce altered proliferation in radiation treated intestinal crypts

摘要

Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts prior to adenoma formation, also found in irradiated crypts. However, the underlying mechanism 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 modelling to compare alternative hypotheses about how Wnt signaling and contact inhibition affect proliferation. Directly comparing 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 is set by the Wnt stimulus experienced at birth. The model also showed that the broadened proliferation zone induced by tumourigenic radiation can be attributed to cells responding to lower Wnt concentrations and divide at smaller volumes. Applying the model to data from irradiated crypts after an extended recovery period permitted deductions about the extent of the initial insult. Applying computational modelling to experimental data revealed how mechanisms that control cell dynamics are altered at the earliest stages of carcinogenesis.