Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov, Alexander E.; Yakimova, A. O.; Matchuk, Olga N.

doi:10.3390/cells9040892

Cited by 62 publications

(65 citation statements)

References 269 publications

(757 reference statements)

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“…Packaged nanoparticles with miR-34a can downregulate the level of CD44 marker of CSCs in a mouse model of prostate cancer (Wang et al, 2016). Although the success of targeting CSCs has been limited, this may soon be a viable option for intervention strategies, disease identification, metastasis prevention, and identification of selective drug targets (Kabakov et al, 2020). Recently, many CSCs have demonstrated phenotypic plasticity and altered their transcriptomes under therapeutic challenges to escape destruction, cooperating with intratumoral heterogeneity and the immune microenvironment (Miranda et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Reveals an Association Between Cancer Cell Stemness, Gene Mutations, and the Immune Microenvironment in Stomach Adenocarcinoma

Zheng

Zeng

et al. 2020

Front. Genet.

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Cancer stem cells (CSCs), characterized by infinite proliferation and self-renewal, greatly challenge tumor therapy. Research into their plasticity, dynamic instability, and immune microenvironment interactions may help overcome this obstacle. Data on the stemness indices (mRNAsi), gene mutations, copy number variations (CNV), tumor mutation burden (TMB), and corresponding clinical characteristics were obtained from The Cancer Genome Atlas (TCGA) and UCSC Xena Browser. Tumor purity and infiltrating immune cells in stomach adenocarcinoma (STAD) tissues were predicted using the ESTIMATE R package and CIBERSORT method, respectively. Differentially expressed genes (DEGs) between the high and low mRNAsi groups were used to construct prognostic models with weighted gene co-expression network analysis (WGCNA) and Lasso regression. The association between cancer stemness, gene mutations, and immune responses was evaluated in STAD. A total of 6,739 DEGs were identified between the high and low mRNAsi groups. DEGs in the brown (containing 19 genes) and blue (containing 209 genes) co-expression modules were used to perform survival analysis based on Cox regression. A nine-gene signature prognostic model (ARHGEF38-IT1, CCDC15, CPZ, DNASE1L2, NUDT10, PASK, PLCL1, PRR5-ARHGAP8, and SYCE2) was constructed from 178 survival-related DEGs that were significantly related to overall survival, clinical characteristics, tumor microenvironment immune cells, TMB, and cancer-related pathways in STAD. Gene correlation was significant across the prognostic model, CNVs, and drug sensitivity. Our findings provide a prognostic model and highlight potential mechanisms and associated factors (immune microenvironment and mutation status) useful for targeting CSCs.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Reveals an Association Between Cancer Cell Stemness, Gene Mutations, and the Immune Microenvironment in Stomach Adenocarcinoma

Zheng

Zeng

et al. 2020

Front. Genet.

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“…Several molecular chaperones are determinants of cancer cell stemness and potential targets for therapeutic approaches directed against CSCs [ 28 , 29 ]. They are involved in the maintenance of the CSC phenotype and are components of the cytoprotective machinery, allowing CSCs to survive to unfavorable environments.…”

Section: Discussionmentioning

confidence: 99%

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

Lettini

Condelli

Pietrafesa

et al. 2020

IJMS

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Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.

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“…In addition, hypoxic niches are enriched of cancer stem cells (CSCs) that are usually chemoresistant [ 176 ], because they have higher expression of ABC transporters [ 177 , 178 ] and HIF-1α-mediated up-regulation of MMP9, C-X-C chemokine receptor type 4 (CXCR4), osteopontin, IL-8 and VEGF [ 179 ] that promote invasion and chemoresistance. In addition, CSCs may show a differential UPR response than differentiated cells [ 180 ].…”

Section: Hypoxia and Altered Upr: Two Partners In Crime Of Chemoresismentioning

confidence: 99%

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Akman

Belisario

Salaroglio

et al. 2021

J Exp Clin Cancer Res

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Solid tumors often grow in a micro-environment characterized by < 2% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Cited by 62 publications

References 269 publications

Bioinformatics Analysis Reveals an Association Between Cancer Cell Stemness, Gene Mutations, and the Immune Microenvironment in Stomach Adenocarcinoma

Bioinformatics Analysis Reveals an Association Between Cancer Cell Stemness, Gene Mutations, and the Immune Microenvironment in Stomach Adenocarcinoma

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

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