Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related deaths and has a 5-year survival rate of less than 10%, far below the ~70% national average for all cancers. This poor prognosis is driven by an extreme resistance to nearly all known cancer treatments, which has long been attributed to hypoxia driven interactions between tumor cells and the supporting stromal microenvironment. The cellular response to hypoxia is driven by the transcription factors known as the hypoxia inducible factors (HIFs), which have been hypothesized to play a role in the pathobiology of PDAC as well as a potential therapeutic target based on years of cell culture data. Attempts to validate the oncogenic role of HIF in PDAC through rigorous spontaneous tumor models have paradoxically shown that the HIFs may act as a tumor suppressor in epithelial cells. Here, we seek to resolve this paradox by discussing the roles of HIFs both in cancer cells and the supporting microenvironment and place them into context of current model systems that could be used to interrogate these interactions. We suggest that HIF may exert its oncogenic influences by modulating the form and function of the stroma rather than direct effects on cancer cells.

胰腺导管腺癌 (PDAC) 目前是癌症相关死亡的第三大原因，5 年生存率不到 10%，远低于全国所有癌症平均水平的 70%。这种不良预后是由对几乎所有已知癌症治疗方法的极端耐药性造成的，长期以来，这种耐药性一直归因于肿瘤细胞与支持性基质微环境之间的缺氧驱动相互作用。细胞对缺氧的反应是由称为缺氧诱导因子 (HIF) 的转录因子驱动的，根据多年的细胞培养数据，HIF 已被假设在 PDAC 的病理生物学以及潜在的治疗靶点中发挥作用。通过严格的自发性肿瘤模型验证 HIF 在 PDAC 中的致癌作用的尝试自相矛盾地表明 HIF 可能在上皮细胞中充当肿瘤抑制因子。在这里，我们试图通过讨论 HIFs 在癌细胞和支持微环境中的作用来解决这个悖论，并将它们置于可用于询问这些相互作用的当前模型系统的背景中。我们认为 HIF 可能通过调节基质的形式和功能而不是直接作用于癌细胞来发挥其致癌影响。