Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Cancer Cell. 2012 Jun 12;21(6):836-47. doi: 10.1016/j.ccr.2012.04.024.
Stromal responses elicited by early stage neoplastic lesions can promote tumor growth. However, the molecular mechanisms that underlie the early recruitment of stromal cells to sites of neoplasia remain poorly understood. Here, we demonstrate an oncogenic Kras(G12D)-dependent upregulation of GM-CSF in mouse pancreatic ductal epithelial cells (PDECs). An enhanced GM-CSF production is also observed in human PanIN lesions. Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells. The suppression of GM-CSF production inhibits the in vivo growth of Kras(G12D)-PDECs, and, consistent with the role of GM-CSF in Gr1(+)CD11b(+) mobilization, this effect is mediated by CD8(+) T cells. These results identify a pathway that links oncogenic activation to the evasion of antitumor immunity.
早期肿瘤病变引起的基质反应可促进肿瘤生长。然而，肿瘤发生部位基质细胞早期募集的分子机制仍知之甚少。在这里，我们证明了致癌性 Kras(G12D)在小鼠胰腺导管上皮细胞（PDECs）中上调 GM-CSF。在人类 PanIN 病变中也观察到 GM-CSF 产生增强。体内 Kras(G12D)依赖性 GM-CSF 产生对于 Gr1(+)CD11b(+)髓样细胞的募集是必需的。GM-CSF 产生的抑制抑制了 Kras(G12D)-PDECs 的体内生长，并且与 GM-CSF 在 Gr1(+)CD11b(+)动员中的作用一致，这种效应是由 CD8(+)T 细胞介导的。这些结果确定了一条将致癌激活与逃避抗肿瘤免疫联系起来的途径。
