Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

Zhang, Jinghui; Fan, Jiajun; Zeng, Xian; Nie, Mingming; Luan, Jingyun; Wang, Yichen; Ju, Dianwen; Yin, Kai

doi:10.1016/j.apsb.2020.10.022

Cited by 61 publications

(41 citation statements)

References 159 publications

(153 reference statements)

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“…Aberrant activation of Notch signaling has been shown to promote self-renewal in breast CSCs [ 22 , 23 ]. The conserved Sonic Hedgehog signaling pathway modulates a critical stage in the development of an organism, which includes embryonic development, tissue repair, and cell differentiation (this specifically pertaining to gastrointestinal cell lineages) [ 24 , 25 ]. Gene expression analysis of bladder CSCs revealed that upregulation of the Sonic Hedgehog pathway was crucial for self-renewal and population expansion [ 26 ].…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

Wang

Golino

Xie

2022

Cancers

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Cancer stem cells (CSCs) are a subset of the tumor population that play critical roles in tumorigenicity, metastasis, and relapse. A key feature of CSCs is their resistance to numerous therapeutic strategies which include chemotherapy, radiation, and immune checkpoint inhibitors. In recent years, there is a growing body of literature that suggests a link between CSC maintenance and autophagy, a mechanism to recycle intracellular components during moments of environmental stress, especially since CSCs thrive in a tumor microenvironment that is plagued with hypoxia, acidosis, and lack of nutrients. Autophagy activation has been shown to aid in the upkeep of a stemness state along with bolstering resistance to cancer treatment. However, recent studies have also suggested that autophagy is a double-edged sword with anti-tumorigenic properties under certain circumstances. This review summarizes and integrates what has been published in the literature in terms of what role autophagy plays in stemness maintenance of CSCs and suggests that there is a more complex interplay between autophagy and apoptosis which involves multiple pathways of regulation. Future cancer therapy strategies are needed to eradicate this resistant subset of the cell population through autophagy regulation.

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Section: Cancer Stem Cellsmentioning

confidence: 99%

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

Wang

Golino

Xie

2022

Cancers

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“…Tumor-associated macrophages (TAMs) expressing M2 (alternatively activated)-like phenotype imitate type II T-helper cells that express interleukin (IL)-4, IL-5, IL-6, IL-13, and IL-10 to suppress anti-tumor immune response [120,121]. CAF can produce tumor-promoting cytokines such as CXCL12, IL-6, HIF1a, and TGF-b2 [123], and monocytic MDSCs can promote tumor epithelial to mesenchymal transition (EMT) [80].…”

Section: Hedgehog Signaling Suppresses Anti-tumor Immune Responsementioning

confidence: 99%

Hedgehog Pathway Inhibitors against Tumor Microenvironment

Gampala

Yang

2021

Cells

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Targeting the hedgehog (HH) pathway to treat aggressive cancers of the brain, breast, pancreas, and prostate has been ongoing for decades. Gli gene amplifications have been long discovered within malignant glioma patients, and since then, inhibitors against HH pathway-associated molecules have successfully reached the clinical stage where several of them have been approved by the FDA. Albeit this success rate implies suitable progress, clinically used HH pathway inhibitors fail to treat patients with metastatic or recurrent disease. This is mainly due to heterogeneous tumor cells that have acquired resistance to the inhibitors along with the obstacle of effectively targeting the tumor microenvironment (TME). Severe side effects such as hyponatremia, diarrhea, fatigue, amenorrhea, nausea, hair loss, abnormal taste, and weight loss have also been reported. Furthermore, HH signaling is known to be involved in the regulation of immune cell maturation, angiogenesis, inflammation, and polarization of macrophages and myeloid-derived suppressor cells. It is critical to determine key mechanisms that can be targeted at different levels of tumor development and progression to address various clinical issues. Hence current research focus encompasses understanding how HH controls TME to develop TME altering and combinatorial targeting strategies. In this review, we aim to discuss the pros and cons of targeting HH signaling molecules, understand the mechanism involved in treatment resistance, reveal the role of the HH pathway in anti-tumor immune response, and explore the development of potential combination treatment of immune checkpoint inhibitors with HH pathway inhibitors to target HH-driven cancers.

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“…The targeted inhibition of Smo and Gli1 activity has provided information on the role of the Hh/Ptch pathway in the immune response against tumour cells. Thus, Hh signalling influences the activity of macrophages in the tumour microenvironment [ 11 , 12 , 13 ], as well as the activation of T lymphocytes [ 3 , 4 , 14 , 15 ] and the polarisation of T cells towards different T helper (Th) cell phenotypes (Th1, Th2 and Th17) [ 16 , 17 , 18 , 19 ] and modulates the development of different inflammatory pathologies, such as arthritis, pancreatitis, dermatitis, intestinal inflammations or experimental autoimmune encephalomyelitis (EAE) [ 18 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Hedgehog Signalling Modulates Immune Response and Protects against Experimental Autoimmune Encephalomyelitis

Ballester

Guijarro

Bravo

et al. 2022

IJMS

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The Hedgehog (Hh) pathway is essential for the embryonic development and homeostatic maintenance of many adult tissues and organs. It has also been associated with some functions of the innate and adaptive immune system. However, its involvement in the immune response has not been well determined. Here we study the role of Hh signalling in the modulation of the immune response by using the Ptch-1-LacZ+/− mouse model (hereinafter referred to as ptch+/−), in which the hemizygous inactivation of Patched-1, the Hh receptor gene, causes the constitutive activation of Hh response genes. The in vitro TCR stimulation of spleen and lymph node (LN) T cells showed increased levels of Th2 cytokines (IL-4 and IL-10) in ptch+/−cells compared to control cells from wild-type (wt) littermates, suggesting that the Th2 phenotype is favoured by Hh pathway activation. In addition, CD4+ cells secreted less IL-17, and the establishment of the Th1 phenotype was impaired in ptch+/− mice. Consistently, in response to an inflammatory challenge by the induction of experimental autoimmune encephalomyelitis (EAE), ptch+/− mice showed milder clinical scores and more minor spinal cord damage than wt mice. These results demonstrate a role for the Hh/ptch pathway in immune response modulation and highlight the usefulness of the ptch+/− mouse model for the study of T-cell-mediated diseases and for the search for new therapeutic strategies in inflammatory diseases.

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Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

Cited by 61 publications

References 159 publications

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

Hedgehog Pathway Inhibitors against Tumor Microenvironment

Hedgehog Signalling Modulates Immune Response and Protects against Experimental Autoimmune Encephalomyelitis

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