See article, p. 276

Autophagy is increased in pancreatic ductal adenocarcinoma (PDAC) and supports tumor growth. However, the mechanisms by which autophagy promotes tumorigenesis have not been fully elucidated, and mouse models to investigate these mechanisms are lacking. Further, it is not clear if therapeutic inhibition of autophagy will be feasible. To determine the effects of targeting autophagy on PDACs, Yang and colleagues developed a mouse model that allowed reversible inhibition of autophagy in mouse models of autochthonous PDAC by inducible expression of a dominant negative mutant of ATG4B, a cysteine protease required to form the autophagosome membrane. Using this system, inhibiting autophagy reduced the growth of established PDAC tumors, and even intermittent autophagy inhibition was sufficient to suppress tumor growth and extend survival. Autophagy inhibition directly affected PDAC tumor cell growth, increasing apoptosis and reducing cell proliferation, but also increased intratumoral macrophages for an indirect effect on tumor growth. Accordingly, macrophage depletion reduced the antitumor effects of autophagy inhibition. Further, autophagy inhibition in the tumor stroma suppressed tumor seeding. In addition to delineating tumor cell intrinsic and extrinsic roles for autophagy in supporting PDAC maintenance, these results suggest that autophagy inhibitors warrant further investigation for the potential treatment of patients with PDAC.

参见第233页。276

自噬在胰腺导管腺癌（PDAC）中增加并支持肿瘤生长。但是，自噬促进肿瘤发生的机制尚未完全阐明，并且缺乏研究这些机制的小鼠模型。此外，尚不清楚治疗性自噬抑制是否可行。为了确定靶向自噬对PDAC的影响，Yang及其同事开发了一种小鼠模型，该模型可通过诱导性表达ATG4B显性负突变体（形成自噬体膜所需的半胱氨酸蛋白酶）来逆转抑制自体PDAC小鼠模型中的自噬。使用该系统，抑制自噬会降低已建立的PDAC肿瘤的生长，甚至间歇性自噬抑制也足以抑制肿瘤的生长并延长生存期。自噬抑制作用直接影响PDAC肿瘤细胞的生长，增加细胞凋亡并减少细胞增殖，但也增加了肿瘤内巨噬细胞，从而间接影响了肿瘤的生长。因此，巨噬细胞耗竭减少了自噬抑制的抗肿瘤作用。此外，肿瘤基质中的自噬抑制抑制了肿瘤播种。除了描述肿瘤细胞在自噬中支持PDAC维持的内在和外在作用外，这些结果还表明，自噬抑制剂值得进一步研究以研究PDAC的潜在治疗方法。巨噬细胞耗竭减少了自噬抑制的抗肿瘤作用。此外，肿瘤基质中的自噬抑制抑制了肿瘤播种。除了描述肿瘤细胞在自噬中支持PDAC维持的内在和外在作用外，这些结果还表明，自噬抑制剂值得进一步研究以研究PDAC的潜在治疗方法。巨噬细胞耗竭减少了自噬抑制的抗肿瘤作用。此外，肿瘤基质中的自噬抑制抑制了肿瘤播种。除了描述肿瘤细胞在自噬支持PDAC维持中的内在和外在作用外，这些结果还表明自噬抑制剂需要进一步研究以治疗PDAC患者。