Fig. 2.

Loss of Hh response promotes PDA development. (A and B) KC and KCS mice were euthanized at age 55 wk. (A) Representative histology of pancreata. (B) Quantification of percentage of PanIN and PDA (Left), number of high-grade PanIN2/3 (Center), and percentage of PDA (Right) in aged KC (n = 13) and KCS (n = 11) mice. The line indicates the mean value. **P < 0.001. (C–E) KPC and KPCS mice were euthanized upon signs of illness (Materials and Methods). (C) Kaplan–Meier analysis showing time to euthanization. All animals had verified PDA. (D) Immunohistochemistry for Meca32; chart (Lower) shows quantification of staining from 10 hpf from five pancreata per group; *P < 0.035. Error bars indicate SEM. (E) Immunohistochemistry for PCNA reveals increased proliferation in KPCS pancreata compared with KPC control mice; *P < 0.03. Error bars indicate SEM. (F) Kaplan–Meier analysis demonstrates that vismodegib treatment (red) starting on day 35 decreases survival in KICG mice compared with vehicle (black). (G) Transverse B-mode ultrasound image of a representative 2.5-mm pancreatic cancer focus in the body/tail region of the pancreas. The yellow arrows denote outline of the tumor surface. (Scale bar: 1 mm.) (H) Vismodegib treatment starting on day 35 accelerates growth of tumors as measured by ultrasound imaging. Total volumes of tumors detected per mouse in each treatment group are shown. A significant difference in median tumor size was measured on day 44 (*P = 0.029; n = 16 per group) and was further increased by day 49 (**P = 0.027; n = 12). There was no significant difference on day 37 (P = 0.296; n = 16 per group). Error bars indicate SEM.