Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Cancer Res. 2009 Dec 15;69(24):9169-74. doi: 10.1158/0008-5472.CAN-09-1705.
To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-Kras(G12D) (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1(+/-) mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1(+/-) mice developed preinvasive lesions compared with 100% of EL-Kras (wild-type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1(+/-) mice were considerably larger than those in EL-Kras mice. Yet, the mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1(+/-) mice. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer.
为了剖析组成性改变的 TGFBR1 信号在胰腺癌发展中的作用，我们将 Elastase-Kras(G12D) (EL-Kras) 小鼠与 TGFBR1 杂合不足小鼠杂交，生成 EL-Kras/Tgfbr1(+/-) 小鼠。在 6 至 9 个月时处死小鼠，比较胰腺中癌前病变的发生率、频率和大小。与 100% 的 EL-Kras（野生型 TGFBR1）小鼠相比，只有 50% 的所有 EL-Kras/Tgfbr1(+/-) 小鼠发生了侵袭前病变。在杂合不足小鼠中，癌前病变的频率比对照小鼠低 4 倍。矛盾的是，EL-Kras/Tgfbr1(+/-) 小鼠的癌前病变明显大于 EL-Kras 小鼠。然而，癌前细胞的有丝分裂指数以及可观察到的纤维化、脂肪萎缩和淋巴细胞浸润水平在 EL-Kras/Tgfbr1(+/-) 小鼠中降低。我们得出结论，TGFBR1 信号促进了小鼠癌前病变的发展。这些发现表明，具有组成性降低 TGFBR1 表达的个体可能患胰腺癌的风险降低。
