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Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer

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
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Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2675; https://doi.org/10.3390/cancers12092675
Received: 1 September 2020 / Revised: 16 September 2020 / Accepted: 17 September 2020 / Published: 19 September 2020
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
Chronic inflammation is a major mechanism that underlies the aggressive nature and treatment resistance of pancreatic cancer. In many ways, the molecular mechanisms that drive chronic inflammation in pancreatic cancer are very similar to our body’s normal innate immune response to injury or invading microorganisms. Therefore, during cancer development, pancreatic cancer cells hijack the innate immune pathway to foster a chronically inflamed tumor environment that helps shield them from immune attack and therapeutics. While blocking the innate immune pathway is theoretically reasonable, untoward side effects must also be addressed. In this review, we comprehensively summarize the literature that describe the role of innate immune signaling in pancreatic cancer, emphasizing the specific role of this pathway in different cell types. We review the interaction of the innate immune pathway and cancer-driving signaling in pancreatic cancer and provide an updated overview of novel therapeutic opportunities against this mechanism.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies. View Full-Text
Keywords: NF-κB; pancreatic cancer; inflammation; IRAK4; TPL2; TAK1 NF-κB; pancreatic cancer; inflammation; IRAK4; TPL2; TAK1
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MDPI and ACS Style

Khurana, N.; Dodhiawala, P.B.; Bulle, A.; Lim, K.-H. Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer. Cancers 2020, 12, 2675. https://doi.org/10.3390/cancers12092675

AMA Style

Khurana N, Dodhiawala PB, Bulle A, Lim K-H. Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer. Cancers. 2020; 12(9):2675. https://doi.org/10.3390/cancers12092675

Chicago/Turabian Style

Khurana, Namrata; Dodhiawala, Paarth B.; Bulle, Ashenafi; Lim, Kian-Huat. 2020. "Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer" Cancers 12, no. 9: 2675. https://doi.org/10.3390/cancers12092675

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Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

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