Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

• Published in: Acta pharmaceutica Sinica. B Vol. 11; no. 3; pp. 609 - 620
• Main Authors: Zhang, Jinghui, Fan, Jiajun, Zeng, Xian, Nie, Mingming, Luan, Jingyun, Wang, Yichen, Ju, Dianwen, Yin, Kai
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2021; Elsevier
• Subjects: Cancer stem cells; Carcinogenesis; Drug resistance; Gastrointestinal cancer; Hedgehog; Review; Tumor microenvironment; and leucovorin; BMI-1; DHH; IHH; G protein coupled receptor kinase 2; Drug resistance; PTCH; Carcinogenesis; BCL-2; SHH; CAFs; TAMs; SUFU; IL-10/6; PD-L1; TGF-β; FOLFOX; glioma-associated oncogene homologue; WNT; 5-Fu; ch5E1; CSCs; hypoxia-inducible factor 1α; BCC; SMAD3; Tumor microenvironment; Gastrointestinal cancer; EGF; VEGF; PKA; STAT3; ALK5; SNF5; TME; MDSCs; βArr2; Hedgehog; ITCH; SMO; ROS; NOX4; Cancer stem cells; ATO; NK; PD-1; FOLFOX, oxaliplatin; DHH, Desert Hedgehog; ALK5, TGF-β receptor I kinase; ITCH, itchy E3 ubiquitin ligase; TAMs, tumor-related macrophages; EGF, epidermal growth factor; BCL-2, B cell lymphoma 2; BMI-1, B cell-specific moloney murine leukemia virus insertion region-1; G protein coupled receptor kinase 2, HH; βArr2, β-arrestin2; TGF-β, transforming growth factor β; MDSCs, myeloid-derived suppressor cells; glioma-associated oncogene homologue, GRK2; hypoxia-inducible factor 1α, IFN-γ: interferon-γ; NOX4, NADPH Oxidase 4; TME, tumor microenvironment; PD-1, programmed cell death-1; SMO, Smoothened; IL-10/6, interleukin 10/6; SUFU, Suppressor of Fused; Hedgehog, HIF-1α; IHH, Indian Hedgehog; ROS, reactive oxygen species; and leucovorin, GLI; ATO, arsenic trioxide; SMAD3, mothers against decapentaplegic homolog 3; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor; CAFs, cancer-associated fibroblasts; 5-Fu, 5-fluorouracil; NK, natural killer; SHH, Sonic Hedgehog; BCC, basal cell carcinoma; PD-L1, programmed cell death ligand-1; WNT, Wingless/Integrated; PTCH, Patched; PKA, protein kinase A; SNF5, sucrose non-fermenting 5; CSCs, cancer stem cells; ch5E1, chimeric monoclonal antibody 5E1
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2020.10.022

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. Hedgehog pathway (HH) is one of the most important modulators of gastrointestinal cancer. This review concludes the role of HH pathway in gastrointestinal carcinogenesis as well as the development of tumor microenvironment, which indicates the mechanisms of immune tolerance and drug resistance in gastrointestinal cancers and highlights the potential therapeutics. [Display omitted]