Department of Surgery, University of Michigan, Ann Arbor, United States.
Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Elife. 2017 Oct 5;6:e27388. doi: 10.7554/eLife.27388.
Dedifferentiation of acini to duct-like cells occurs during the physiologic damage response in the pancreas, but this process can be co-opted by oncogenic Kras to drive carcinogenesis. Myeloid cells infiltrate the pancreas during the onset of pancreatic cancer, and promote carcinogenesis. Here, we show that the function of infiltrating myeloid cells is regulated by oncogenic Kras expressed in epithelial cells. In the presence of oncogenic Kras, myeloid cells promote acinar dedifferentiation and carcinogenesis. Upon inactivation of oncogenic Kras, myeloid cells promote re-differentiation of acinar cells, remodeling of the fibrotic stroma and tissue repair. Intriguingly, both aspects of myeloid cell activity depend, at least in part, on activation of EGFR/MAPK signaling, with different subsets of ligands and receptors in different target cells promoting carcinogenesis or repair, respectively. Thus, the cross-talk between epithelial cells and infiltrating myeloid cells determines the balance between tissue repair and carcinogenesis in the pancreas.
在胰腺的生理损伤反应过程中，腺泡细胞向导管样细胞分化，但这一过程可被致癌 Kras 劫持，从而驱动癌变。髓系细胞在胰腺癌发生时浸润胰腺，并促进癌变。在这里，我们表明，浸润的髓系细胞的功能受上皮细胞中表达的致癌 Kras 调控。在存在致癌 Kras 的情况下，髓系细胞促进腺泡细胞去分化和癌变。当致癌 Kras 失活时，髓系细胞促进腺泡细胞的再分化、纤维性基质的重塑和组织修复。有趣的是，髓系细胞活性的这两个方面至少部分依赖于 EGFR/MAPK 信号的激活，不同的配体和受体亚群在不同的靶细胞中分别促进癌变或修复。因此，上皮细胞和浸润的髓系细胞之间的串扰决定了胰腺中组织修复和癌变之间的平衡。
