Figure 3. Inhibition of tumor and stromal Tgfβr2 results in reduced primary pancreatic tumor growth and metastasis in murine models.

A, Orthotopic Pan02 tumors were established and mice randomized and treated for 4 weeks with vehicle (control), gemcitabine (Gem, 25 mg/kg/week), 2G8 (60 mg/kg/week) or 2G8+Gem. 2G8 alone and in combination with gemcitabine reduced primary tumor growth (n=7–10/group). B, LSL-Kras^G12D; Cdkn2a^lox/lox; p48^Cre (KIC) mice (n = 8–12/group) were randomized when 4 weeks old and treated for 4 weeks as above with Gem (12.5 mg/kg 3×/week), 2G8 (120 mg/kg/week) or the combination. At sacrifice, mice treated with 2G8 and 2G8+Gem had reduced tumor growth. C and D, Pan02 tumors were harvested and sections were evaluated by immunohistochemistry for proliferation (phospho-histone H3 (ph3+), C) and apoptosis (cleaved caspase-3, D). 2G8 reduced the number of ph3+ cells and increased the number of cells positive for cleaved caspase 3 compared to control. E and F, Total gross metastases in Pan02 bearing animals were determined by evaluation of liver, diaphragm, GI lymph nodes, and lung at the time of sacrifice. Metastatic burden in the KIC model was determined by histologic evaluation of H&E stained liver tissue. 2–3 sections of the anterior lobe of the liver (n=at least 5/group) were scored for lesions. 2G8 alone suppressed metastasis in each tumor model. Results are expressed as mean+/−SEM. *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001 vs. control; ^, p<0.05; ^^, p<0.01; ^^^, p<0.0001 vs. Gem.