Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE

Ye, Cuifang; Li, Huan; Li, Yachao; Zhang, Yang; Liu, Guohao; Mi, Hailong; Li, Honglian; Xiao, Qungen; Niu, Li; Yu, Xingjiang

doi:10.1016/j.isci.2022.104872

Cited by 20 publications

(11 citation statements)

References 91 publications

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“…This finding suggests that GBMs induce the formation of a hypoxic pro-tumorigenic environment in organoids. The hypoxic microenvironment has been associated with aggressive and therapy-resistant tumors (Ye et al 2022) and with the abnormal specification of human cortical neurons (Bhaduri, Andrews, et al 2020). In addition, we observed increased enriched molecular pathways "positive regulation of vasculature development" and "angiogenesis" in neurons, and upregulation of pro-angiogenesis gene VEGFA in NPs (Fig.…”

Section: Datasetmentioning

confidence: 75%

Transcriptional changes consistent with impaired neuronal differentiation, angiogenesis, and tumor plasticity induced in human subpallial telencephalic organoid-glioblastoma chimeras

Chiola

Yang

Ullah

et al. 2023

Preprint

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Glioblastoma multiforme (GBM) is one of the most aggressive and therapy-resistant brain tumors prevalent in both adults and children. Despite extensive research to understand GBM pathology, it remains unclear how neural cells in the human brain interact with GBM cells to support their brain propagation and therapy resistance and whether GBM cells exert any influence on the properties of human neural cells. In this study, we co-culture human stem cell-derived subpallial telencephalic organoids with patient-derived proneural or mesenchymal GBM spheroids to investigate their reciprocal interactions. We show that both proneural and mesenchymal GBM spheroids readily fuse and propagate with human organoids, forming organoid-GBM chimeras, without the need for exogenous growth factors. GBM cells within the chimeras adapt by modulating gene expression profiles consistent with diminished proliferation, heightened hypoxia, increased angiogenesis, and proneural-to-mesenchymal transition in proneural GBM. Both proneural or mesenchymal GBMs also exert an impact on the properties of neural cells in the chimeras, leading to the suppression of neuronal genes and an upregulation expression of genes associated with hypoxia and angiogenesis. Collectively, this study identifies specific genes and molecular pathways that can be altered in GBM and neural cells by reciprocal interactions in a human developing brain-like environment for an increased understanding of GBM pathology and future therapy development.

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Section: Datasetmentioning

confidence: 75%

Transcriptional changes consistent with impaired neuronal differentiation, angiogenesis, and tumor plasticity induced in human subpallial telencephalic organoid-glioblastoma chimeras

Chiola

Yang

Ullah

et al. 2023

Preprint

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“…Using a proteomic approach, we identi ed HMGB1 as an Hsp70-binding protein. Recently, extracellular HMGB1 was established to bind with RAGE, stimulate the development of drug resistance after chemotherapy and regulate autophagy and apoptosis in neighboring tumor cells [51,52]; the protein has also been proposed as a non-invasive marker for the detection of bladder carcinoma. Very recently HMGB1 released from dead tumor cells was proved to be a trigger of repopulation of the residual hepatocellular carcinoma cells after radiotherapy [53].…”

Section: Discussionmentioning

confidence: 99%

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Sverchinsky,

Alhasan,

Mikeladze

et al. 2023

Preprint

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Background. Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods. Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results. It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions. These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.

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“…HMGB1 promotes CSC self-renewal. By interacting with specific receptors and signaling pathways, such as LC3II/TLR4 associated transcriptional regulator (YAP1), HMGB1 stimulates the expression of genes involved in stem cell maintenance and proliferation ( 12 , 13 ). This leads to an increase in the number of CSCs within the tumor, thereby enhancing the tumorigenic potential of cancer cells.…”

Section: Role Of Hmgb1 In Cancer Stem Cell Regulationmentioning

confidence: 99%

Multiple functions of HMGB1 in cancer

Lv,

Yang,

Gai

et al. 2024

Front. Oncol.

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High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein with a dual role in cancer, acting as an oncogene and a tumor suppressor. This protein regulates nucleosomal structure, DNA damage repair, and genomic stability within the cell, while also playing a role in immune cell functions. This review comprehensively evaluates the biological and clinical significance of HMGB1 in cancer, including its involvement in cell death and survival, its potential as a therapeutic target and cancer biomarker, and as a prosurvival signal for the remaining cells after exposure to cytotoxic anticancer treatments. We highlight the need for a better understanding of the cellular markers and mechanisms involved in the involvement of HMGB1in cancer, and aim to provide a deeper understanding of its role in cancer progression.

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Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE

Cited by 20 publications

References 91 publications

Transcriptional changes consistent with impaired neuronal differentiation, angiogenesis, and tumor plasticity induced in human subpallial telencephalic organoid-glioblastoma chimeras

Transcriptional changes consistent with impaired neuronal differentiation, angiogenesis, and tumor plasticity induced in human subpallial telencephalic organoid-glioblastoma chimeras

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Multiple functions of HMGB1 in cancer

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