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Jinghui Zhang, Jiajun Fan, Xian Zeng, Mingming Nie, Jingyun Luan, Yichen Wang, Dianwen Ju, Kai Yin. Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 609-620

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment
Jinghui Zhanga,b, Jiajun Fanb,c, Xian Zengb,c, Mingming Niea, Jingyun Luanb,c, Yichen Wangb,c, Dianwen Jub,c, Kai Yina
a Department of Gastrointestinal Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China;
b Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China;
c Shanghai Engineering Research Center of Immunotherapeutics, Shanghai 201203, China
Abstract:
The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.
Key words:    Hedgehog    Carcinogenesis    Tumor microenvironment    Gastrointestinal cancer    Cancer stem cells    Drug resistance   
Received: 2020-06-01     Revised: 2020-07-29
DOI: 10.1016/j.apsb.2020.10.022
Funds: This work was supported by Scientific Research Project of Shanghai Health and Family Planning Committee (Grant No. 201640017, China), National Science and Technology Major Project (Grant No. 2017ZX09304030, China), and Shanghai Science and Technology Funds (Grant No. 19ZR1456100, China).
Corresponding author: Dianwen Ju, Kai Yin     Email:dianwenju@fudan.edu.cn;kyin67@smmu.edu.cn
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Jinghui Zhang
Jiajun Fan
Xian Zeng
Mingming Nie
Jingyun Luan
Yichen Wang
Dianwen Ju
Kai Yin

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