Predictive value of hypoxia in advanced head and neck cancer after treatment with hyperfractionated radio-chemotherapy and hypoxia modification

Clavo, Bernardino; Robaina, Francisco; Fiuza, Dolores; Ruíz, A.; Lloret, M.; Rey-Baltar, D.; Llontop, Pedro; Riveros, A; Rivero, José Casas; Castañeda, Francisco; Quintero, Santiago; Santana‐Rodríguez, Norberto

doi:10.1007/s12094-016-1541-x

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…The tumor microenvironment is essential for tumor genesis and tumor development ( 4 , 5 ), with hypoxia a strong research topic in recent years. Hypoxia can induce vascular formation in tumors, and is also widely involved in tumor formation, development, metastasis and recurrence ( 6 – 8 ). Hypoxia accelerates epithelial-mesenchymal transition, invasion, and metastasis in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Combined inhibition of JAK1,2/Stat3‑PD‑L1 signaling pathway suppresses the immune escape of castration‑resistant prostate cancer to NK cells in hypoxia

Zhu

et al. 2018

Mol Med Report

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Castration-resistant prostate cancer (CRPC) is difficult to treat in current clinical practice. Hypoxia is an important feature of the CRPC microenvironment and is closely associated with the progress of CRPC invasion. However, no research has been performed on the immune escape of CRPC from NK cells. The present study focused on this subject. Firstly, when the CRPC cell lines C4-2 and CWR22Rv1 were induced by hypoxia, the expression of the UL16 binding protein (ULBP) ligand family of natural killer (NK) group 2D (NKG2D; ULBP-1, ULBP-2 and ULBP-3) and MHC class I chain-related proteins A and B (MICA/MICB) decreased. NKG2D is the main activating receptor of NK cells. Tumor cells were then co-cultured with NK cells to conduct NK cell-mediated cytotoxicity experiments, which revealed the decreased immune cytolytic activity of NK cells on hypoxia-induced CRPC cells. In exploring the mechanism behind this observation, an increase in programmed death-ligand 1 (PD-L1) expression in CRPC cells induced by hypoxia was observed, while the addition of PD-L1 antibody effectively reversed the expression of NKG2D ligand and enhanced the cytotoxic effect of NK cells on CRPC cells. In the process of exploring the upstream regulatory factors of PD-L1, inhibition of the Janus kinase (JAK)1,2/signal transducer and activator of transcription 3 (Stat3) signaling pathway decreased the expression of PD-L1 in CRPC cells. Finally, it was observed that combined inhibition of JAK1,2/PD-L1 or Stat3/PD-L1 was more effective than inhibition of a single pathway in enhancing the immune cytolytic activity of NK cells. Taking these results together, it is thought that combined inhibition of the JAK1,2/PD-L1 and Stat3/PD-L1 signaling pathways may enhance the immune cytolytic activity of NK cells toward hypoxia-induced CRPC cells, which is expected to provide novel ideas and targets for the immunotherapy of CRPC.

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Section: Introductionmentioning

confidence: 99%

Combined inhibition of JAK1,2/Stat3‑PD‑L1 signaling pathway suppresses the immune escape of castration‑resistant prostate cancer to NK cells in hypoxia

Zhu

et al. 2018

Mol Med Report

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“…65 Evaluating hypoxia could also be indicative for the selection of patients who would most benefit of chemo-radiotherapy. 66 The in vivo effect of hypoxia on the concentration of circulating NcfDNA and McfDNA was evaluated in the plasma of mice engrafted with an autologous lung epithelial tumour model (TC1) cell line. As would be expected from our in vitro results, plasmatic NcfDNA concentration is highly correlated to tumour weight and size, both of which are increased in mice bred in a hypoxic atmosphere, as has been observed in the previous study.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia differently modulates the release of mitochondrial and nuclear DNA

et al. 2020

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BACKGROUND:We investigated the influence of hypoxia on the concentration of mitochondrial and nuclear cell-free DNA (McfDNA and NcfDNA, respectively). METHOD: By an ultra-sensitive quantitative PCR-based assay, McfDNA and NcfDNA were measured in the supernatants of different colorectal cell lines, and in the plasma of C57/Bl6 mice engrafted with TC1 tumour cells, in normoxic or hypoxic conditions. RESULTS: Our data when setting cell culture conditions highlighted the higher stability of McfDNA as compared to NcfDNA and revealed that cancer cells released amounts of nuclear DNA equivalent to the mass of a chromosome over a 6-h duration of incubation. In cell model, hypoxia induced a great increase in NcfDNA and McfDNA concentrations within the first 24 h. After this period, cfDNA total concentrations remained stable in hypoxia consecutive to a decrease of nuclear DNA release, and noteworthy, to a complete inhibition of daily mitochondrial DNA release. In TC1-engrafted mice submitted to intermittent hypoxia, plasma NcfDNA levels are much higher than in mice bred in normoxia, unlike plasma McfDNA concentration that is not impacted by hypoxia. CONCLUSION: This study suggests that hypoxia negatively modulates nuclear and, particularly, mitochondrial DNA releases in long-term hypoxia, and revealed that the underlying mechanisms are differently regulated.

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“…Hypoxia is a common characteristic of rapidly growing malignant tumors and is known to promote cancer progression. Studies have shown that hypoxia has a negative impact on the efficacy of both radiotherapy and chemotherapy in various cancer types, including mammary carcinoma (Gilkes and Semenza, 2013), head and neck carcinoma (Clavo et al, 2017), and uterine cervix carcinoma (Durand and Aquino-Parsons, 2006). Therefore, hypoxia is considered to be a potential therapeutic target for various solid tumors to help alleviate tumor resistance to these common forms of therapy.…”

Section: Discussionmentioning

confidence: 99%

Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia

Zhang¹,

Jiang

et al. 2019

Front. Pharmacol.

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Chemosensitivity is one of the key factors affecting the therapeutic effect on cancer, but the clinical application of corresponding drugs is rare. Hypoxia, a common feature of many solid tumors, including hepatocellular carcinoma (HCC), has been associated with resistance to chemotherapy in part through the activation of the Sonic Hedgehog (SHh) pathway. Hypoxia has also been associated with the increased SUMOylation of multiple proteins, including GLI family proteins, which are key mediators of SHh signaling, and has become a promising target to develop drug-resistant drugs for cancer treatment. However, there are few target drugs to abrogate chemotherapy resistance. Saikosaponin-d (Ssd), one of the main bioactive components of Radix bupleuri, has been reported to exert multiple biological effects, including anticancer activity. Here, we first found that Ssd inhibits the malignant phenotype of HCC cells while increasing their sensitivity to the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) drug system under hypoxia in vitro and in vivo. Furthermore, we had explored that GLI family activation and extensive protein SUMOylation were characteristics of HCC cells, and hypoxia could activate the SHh pathway and promote epithelial-mesenchymal transition (EMT), invasion, and chemosensitivity in HCC cells. SUMOylation is required for hypoxia-dependent activation of GLI proteins. Finally, we found that Ssd could reverse the effects promoted by hypoxia, specifically active sentrin/small ubiquitin-like modifier (SUMO)-specific protease 5 (SENP5), a SUMO-specific protease, in a time- and dose-dependent manner while inhibiting the expression of SUMO1 and GLI proteins. Together, these findings confirm the important role of Ssd in the chemoresistance of liver cancer, provide some data support for further understanding the molecular mechanisms of Ssd inhibition of malignant transformation of HCC cells, and provide a new perspective for the application of traditional Chinese medicine in the chemical resistance of liver cancer.

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Predictive value of hypoxia in advanced head and neck cancer after treatment with hyperfractionated radio-chemotherapy and hypoxia modification

Cited by 17 publications

References 30 publications

Combined inhibition of JAK1,2/Stat3‑PD‑L1 signaling pathway suppresses the immune escape of castration‑resistant prostate cancer to NK cells in hypoxia

Combined inhibition of JAK1,2/Stat3‑PD‑L1 signaling pathway suppresses the immune escape of castration‑resistant prostate cancer to NK cells in hypoxia

Hypoxia differently modulates the release of mitochondrial and nuclear DNA

Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia

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