Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

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.

Keywords: 5-Fu, 5-fluorouracil; ALK5, TGF-β receptor I kinase; ATO, arsenic trioxide; BCC, basal cell carcinoma; BCL-2, B cell lymphoma 2; BMI-1, B cell-specific moloney murine leukemia virus insertion region-1; CAFs, cancer-associated fibroblasts; CSCs, cancer stem cells; Cancer stem cells; Carcinogenesis; DHH, Desert Hedgehog; Drug resistance; EGF, epidermal growth factor; FOLFOX, oxaliplatin; G protein coupled receptor kinase 2, HH; Gastrointestinal cancer; Hedgehog; Hedgehog, HIF-1α; IHH, Indian Hedgehog; IL-10/6, interleukin 10/6; ITCH, itchy E3 ubiquitin ligase; MDSCs, myeloid-derived suppressor cells; NK, natural killer; NOX4, NADPH Oxidase 4; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; PKA, protein kinase A; PTCH, Patched; ROS, reactive oxygen species; SHH, Sonic Hedgehog; SMAD3, mothers against decapentaplegic homolog 3; SMO, Smoothened; SNF5, sucrose non-fermenting 5; STAT3, signal transducer and activator of transcription 3; SUFU, Suppressor of Fused; TAMs, tumor-related macrophages; TGF-β, transforming growth factor β; TME, tumor microenvironment; Tumor microenvironment; VEGF, vascular endothelial growth factor; WNT, Wingless/Integrated; and leucovorin, GLI; ch5E1, chimeric monoclonal antibody 5E1; glioma-associated oncogene homologue, GRK2; hypoxia-inducible factor 1α, IFN-γ: interferon-γ; βArr2, β-arrestin2.