Bansod Sapana, Dodhiawala Paarth B, Lim Kian-Huat
Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Medical Scientist Training Program, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Cancers (Basel). 2021 Oct 31;13(21):5481. doi: 10.3390/cancers13215481.
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.
胰腺导管腺癌（PDAC）对治疗仍具有高度难治性。虽然致癌基因几乎存在于所有PDAC病例中，并导致了PDAC的许多恶性特征，但在患者中靶向KRAS或其典型的直接效应子级联反应仍未成功。PDAC的顽固性质也在很大程度上受到其高度纤维化炎症性肿瘤微环境（TME）的影响，该微环境由无细胞的细胞外基质和各种类型的非肿瘤细胞组成，包括成纤维细胞、免疫细胞和脂肪细胞，这突出表明迫切需要阐明PDAC细胞与TME之间的双向信号相互作用，以便开发新的治疗策略。几篇综述已经很好地阐述了肿瘤细胞KRAS信号传导对TME中各种细胞类型的影响。在本文中，我们批判性地回顾了包括我们小组的研究在内的证据，即TME中的反馈炎症信号如何影响PDAC细胞中的致癌KRAS信号并与其协同作用，最终增强其恶性行为。我们讨论了过去和正在进行的针对PDAC关键炎症途径的临床试验，并强调了从试验结果中吸取的教训。最后，我们通过理解KRAS和炎症信号网络的广度和复杂性，对未来开发PDAC治疗策略的前景发表了看法。
