cGAMP inhibits tumor growth in colorectal cancer metastasis through the STING/STAT3 axis in a zebrafish xenograft model

Publication date: Available online 2 October 2019Source: Fish &Shellfish ImmunologyAuthor(s): Xiaofeng Jiang, Guangping Liu, Zhiyi Hu, Guiqian Chen, Jianqing Chen, Zhengbing LvAbstractThe leading cause of mortality due to colorectal cancer (CRC) is highly associated with the development of liver metastases. Recently, we described cGAMP that is closely related to the metastatic state wherein the progress of metastatic tumors is associated with favorable outcomes in a zebrafish xenograft model. cGAMP was administered and the expression levels of type-I interferons were induced amongst tumor tissues to illuminate the overall measure of the induced STING/STAT3 axis in colorectal liver metastases. Furthermore, cGAMP–STING dependent STAT3 activation resulted in the inhibition of tumor cell proliferation, viability, and invasion in vitro. The subtotal reduction in tumor growth attributed to a large number of infiltrating inflammatory cells in vivo. We showed that cGAMP inhibited migration through angiogenesis by up-regulating IL-2, TNF-α, and IFN-γ, whereas STAT3 down-regulation inhibited CXCL8, BCL-2, and VEGFA expression. The importance of cGAMP in inhibiting the invasion front of CRC confirmed that the cGAMP dependent activation of STING/STAT3 axis played a key role in the inhibition of tumor progression.
Source: Fish and Shellfish Immunology - Category: Biology Source Type: research

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The stimulator of IFN genes (STING) signaling pathway is a critical link between innate and adaptive immunity and induces antitumor immune responses. STING is expressed in vasculatures, but its role in tumor angiogenesis has not been elucidated. Here, we investigated STING-induced tumor vascular remodeling and the potential of STING-based combination immunotherapy. Endothelial STING expression was correlated with enhanced T cell infiltration and prolonged survival in human colon and breast cancer. Intratumoral STING activation with STING agonists (cGAMP or RR-CDA) normalized tumor vasculatures in implanted and spontaneous ...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
The cGAS-STING pathway can be activated by radiation induced DNA damage and because of its important role in anti-cancer immunity activation, methods to increase its activation in cancer cells could provide significant therapeutic benefits for patients. We explored the impact of hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy on cell death, DNA damage, and activation of the cGAS-STING pathway. We demonstrate that NBTXR3 activated by radiotherapy enhances cell destruction, DNA double strand breaks, micronuclei formation and cGAS-STING pathway activation in a human colorectal cancer model, compared to radiotherapy alone.
Source: Radiotherapy and Oncology - Category: Radiology Authors: Tags: Short Communication Source Type: research
Abstract The cGAS-STING pathway can be activated by radiation induced DNA damage and because of its important role in anti-cancer immunity activation, methods to increase its activation in cancer cells could provide significant therapeutic benefits for patients. We explored the impact of hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy on cell death, DNA damage, and activation of the cGAS-STING pathway. We demonstrate that NBTXR3 activated by radiotherapy enhances cell destruction, DNA double strand breaks, micronuclei formation and cGAS-STING pathway activation in a human colorectal cancer model, co...
Source: Radiotherapy and Oncology : journal of the European Society for Therapeutic Radiology and Oncology - Category: Radiology Authors: Tags: Radiother Oncol Source Type: research
Marjolein Schluck1,2, Roel Hammink1,2, Carl G. Figdor1,2,3, Martijn Verdoes1,3*† and Jorieke Weiden1,2,3*† 1Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands 2Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, Netherlands 3Institute for Chemical Immunology, Nijmegen, Netherlands Traditional tumor vaccination approaches mostly focus on activating dendritic cells (DCs) by providing them with a source of tumor antigens and/or adjuvants, which in turn activate tumor-reactive T c...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conclusion As a critical regulator of inflammation and cell survival, the NFκB pathway is a promising target for diagnosing and treating kidney diseases. For modulation of the NFκB pathway in the clinic, a number of molecules can effectively inhibit NFκB signaling by targeting the receptors, associated adaptors, IKKs, IκBs and transcriptional regulators (144). There is further clinical evidence on small-molecule inhibitors of IKKα and NIK from recent trials on anti-cancer therapies (145). These clinical trials showed that the cancer-selective pharmacodynamic response of DTP3, the co-inhibitor...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
In this study, several biopsies from a patient-derived primary renal-cell carcinoma were analyzed by whole-exome sequencing and aligned to healthy tissue. Next to several shared mutations between different subclones, ca. 23% of the mutations were only found in specific regions of the tumor. Strikingly, a single biopsy of that same tumor only covered around 55% of the total mutational diversity, underlining the need for multi-region sampling. Tracing the order of mutations in different subclones revealed that they develop in a branching fashion from the primary tumor clone, harboring the driver mutation, rather than in a li...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Design of amidobenzimidazole STING receptor agonists with systemic activity, Published online: 07 November 2018; doi:10.1038/s41586-018-0705-yA small-molecule agonist for the cGAS–STING pathway has systemic activity in a mouse model of colon cancer.
Source: Nature AOP - Category: Research Authors: Source Type: research
Preclinical models indicate that DNA damage induces type I interferon (IFN), which is crucial for the induction of an anti-tumor immune response. In human cancers, however, the association between DNA damage and an immunogenic cell death (ICD), including the release and sensing of danger signals, the subsequent ER stress response and a functional IFN system, is less clear.Methods: Neoadjuvant-treated colorectal liver metastases (CLM) patients, undergoing liver resection in with a curative intent, were retrospectively enrolled in this study (n=33). DNA damage (γH2AX), RNA and DNA sensors (RIG-I, DDX41, cGAS, STING), E...
Source: Theranostics - Category: Molecular Biology Authors: Tags: Research Paper Source Type: research
To  investigate the induction of type III interferons (IFNs) in human cancer cells by gamma-rays.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Tags: Biology Contribution Source Type: research
Ionizing radiation augments anti-tumor immune responses with interferons (IFN) acting as mediators. Of the three types of IFNs, type I and II IFNs are induced in irradiated tumors with induction of type III IFNs (IFNLs) currently not reported. Here, we investigated the induction of type III IFNs in human cancer cells by gamma-rays and its mechanisms.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Tags: Biology Contribution Source Type: research
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