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. 2020 Aug 15;11(1):161–179. doi: 10.1016/j.jcmgh.2020.08.004

Figure 3.

Figure 3

ProAgio depletes CAPaSC by targeting integrin αVβ3and resorbs tumor collagen. (A) Endogenous alleles of KrasG12D and Trp53R172H are conditionally activated in the pancreata of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (triple mutant) mice. (B) Specific polymerase chain reaction analysis of genomic DNA of generated GEM-KPC mice. (C and D) Kaplan–Meier survival analysis of GEM-KPC (median survival: vehicle, 20 days; ProAgio, 51 days) (A), and OrKPC (B) mice treated with vehicle or 10 mg/kg ProAgio (median survival: vehicle, 31 days; ProAgio, 39 days) (10 daily doses + 10 alternate day doses). Treatment was started after 13 weeks of age in GEM-KPC mice in panel C, or 30 days after tumor inoculation in panel D. The numbers in parentheses indicate the group size. (E) Representative images of Sirius red (red) and Masson trichrome (blue) staining and IHC staining of α-SMA of tumor sections from GEM-KPC mice treated with vehicle or 10 mg/kg ProAgio at different time points (Rx 20, at end of 20 doses; End stage, end of survival experiments). (F and G) Quantitative analyses of Sirius red staining (presented as Sirius red+ area %) (F) and αSMA+ staining area % (G) in tumor sections of vehicle or ProAgio-treated (10 mg/kg) GEM-KPC mice. A higher staining of Sirius red was observed in vehicle-treated tumors on day 80 (Rx 20 doses) than ProAgio-treated tumors on day 110 (end stage) in GEM-KPC mice (P < .001; n = 7–9). (H) Representative images of Sirius red (Sirius red) and IHC staining of α-SMA in tumor sections of vehicle or ProAgio-treated (10 mg/kg) OrKPC mice at the end of 20 doses (Rx 20 doses). (I) mRNA levels of α-SMA (left panel) and FAP (right panel) in the tumor tissue lysates of GEM-KPC mice treated with vehicle or ProAgio (n = 4) were analyzed by quantitative reverse-transcription polymerase chain reaction. The mRNA levels in the tumor extracts were normalized to mRNA level of β-actin. (G) Error bars represent means ± SEM. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001, ∗∗∗∗P < .0001. n.s., denotes not significant; WT, wild-type.