Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

Zhou, Chengke; Fan, Ningbo; Liu, Fanyu; Fang, Nan; Plum, Patrick Sven; Thieme, René; Gockel, Ines; Gromnitza, Sascha; Hillmer, Axel M.; Schlößer, Hans; Bruns, Christiane; Zhao, Yue

doi:10.3390/cells9061481

Cited by 24 publications

(20 citation statements)

References 213 publications

(241 reference statements)

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“…For example, a Wnt/β-catenin activator WNT10A is highly expressed in OSCC tissue. Consistently cells with the expression of WNT10A showed enrichment for CD44+/CD24−, and these cells showed increased self-renewal, invasive and metastatic potential ( 40 , 41 ). Notch signaling is another prominent driver of cancer stemness in OAC.…”

Section: Targeting Signaling Pathways In Esophageal Cancer Stem Cellsmentioning

confidence: 74%

“…The signaling pathways which trigger embryogenesis also play a significant role in oncogenesis ( 40 ). The pathways highly associated with the maintenance of esophageal CSCs include Wnt/β-catenin, Notch, Hh, and Hippo pathways ( 39 ).…”

Section: Targeting Signaling Pathways In Esophageal Cancer Stem Cellsmentioning

confidence: 99%

“…However, aberrant activation of this pathway is associated with many cancers including esophageal cancer. For instance, over-activation of the Wnt/β-catenin pathway can be an underlying factor of progression, metastasis, and invasion in OSCC by inducing a CSC phenotype ( 40 ). Therefore, targeting the Wnt/β-catenin pathway has potential for the inhibition of CSC growth.…”

Section: Targeting the Wnt/β-catenin Pathway In Esophageal Cancer Stementioning

confidence: 99%

“…Notch signaling is highly activated in less differentiated tumors and drives CSC phenotypes and carcinogenesis in both OSCC and OAC ( 39 , 42 ). This signaling helps to maintain a robust population of CSCs, thereby resulting in therapy resistance and cancer recurrence ( 38 , 40 ). Notch inhibition depletes CSC populations in tumors and sensitizes cancer cells to chemotherapeutic agents, which leads to promising response toward neoadjuvant chemotherapy (NAC) in patients with both OSCC and OAC ( Figure 1 , Table 1 ).…”

Section: Targeting Notch Signaling In Esophageal Cancer Stem Cellsmentioning

confidence: 99%

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Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas

et al. 2021

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Cancer stem cells (CSCs) in esophageal cancer have a key role in tumor initiation, progression and therapy resistance. Novel therapeutic strategies to target CSCs are being tested, however, more in-depth research is necessary. Eradication of CSCs can result in successful therapeutic approaches against esophageal cancer. Recent evidence suggests that targeting signaling pathways, miRNA expression profiles and other properties of CSCs are important strategies for cancer therapy. Wnt/β-catenin, Notch, Hedgehog, Hippo and other pathways play crucial roles in proliferation, differentiation, and self-renewal of stem cells as well as of CSCs. All of these pathways have been implicated in the regulation of esophageal CSCs and are potential therapeutic targets. Interference with these pathways or their components using small molecules could have therapeutic benefits. Similarly, miRNAs are able to regulate gene expression in esophageal CSCs, so targeting self-renewal pathways with miRNA could be utilized to as a potential therapeutic option. Moreover, hypoxia plays critical roles in esophageal cancer metabolism, stem cell proliferation, maintaining aggressiveness and in regulating the metastatic potential of cancer cells, therefore, targeting hypoxia factors could also provide effective therapeutic modalities against esophageal CSCs. To conclude, additional study of CSCs in esophageal carcinoma could open promising therapeutic options in esophageal carcinomas by targeting hyper-activated signaling pathways, manipulating miRNA expression and hypoxia mechanisms in esophageal CSCs.

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Section: Targeting Signaling Pathways In Esophageal Cancer Stem Cellsmentioning

confidence: 74%

Section: Targeting Signaling Pathways In Esophageal Cancer Stem Cellsmentioning

confidence: 99%

Section: Targeting the Wnt/β-catenin Pathway In Esophageal Cancer Stementioning

confidence: 99%

Section: Targeting Notch Signaling In Esophageal Cancer Stem Cellsmentioning

confidence: 99%

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Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas

et al. 2021

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“…A leading contributing factor to metastasis and treatment resistance is the heterogeneity and plasticity of the cells within tumors 6 . As a small pool of tumor cells, cancer stem cells (CSCs), which contribute to tumor heterogeneity, are characterized by self-renewal and therapy resistance, and promote initiation or tumorigenesis 7 – 9 . Increasing evidence has shown that many cancers, including breast cancer exist CSCs.…”

Section: Introductionmentioning

confidence: 99%

A novel Lnc408 maintains breast cancer stem cell stemness by recruiting SP3 to suppress CBY1 transcription and increasing nuclear β-catenin levels

et al. 2021

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Tumor initiation, development, and relapse may be closely associated with cancer stem cells (CSCs). The complicated mechanisms underlying the maintenance of CSCs are keeping in illustration. Long noncoding RNAs (lncRNAs), due to their multifunction in various biological processes, have been indicated to play a crucial role in CSC renewal and stemness maintenance. Using lncRNA array, we identified a novel lncRNA (named lnc408) in epithelial–mesenchymal transition-related breast CSCs (BCSCs). The lnc408 is high expressed in BCSCs in vitro and in vivo. The enhanced lnc408 is critical to BCSC characteristics and tumorigenesis. Lnc408 can recruit transcript factor SP3 to CBY1 promoter to serve as an inhibitor in CBY1 transcription in BCSCs. The high expressed CBY1 in non-BCSC interacts with 14-3-3 and β-catenin to form a ternary complex, which leads a translocation of the ternary complex into cytoplasm from nucleus and degradation of β-catenin in phosphorylation-dependent pattern. The lnc408-mediated decrease of CBY1 in BCSCs impairs the formation of 14-3-3/β-catenin/CBY1 complex, and keeps β-catenin in nucleus to promote CSC-associated CD44, SOX2, Nanog, Klf4, and c-Myc expressions and contributes to mammosphere formation; however, restoration of CBY1 expression in tumor cells reduces BCSC and its enrichment, thus lnc408 plays an essential role in maintenance of BCSC stemness. In shortly, these findings highlight that the novel lnc408 functions as an oncogenic factor by recruiting SP3 to inhibit CBY1 expression and β-catenin accumulation in nucleus to maintain stemness properties of BCSCs. Lnc408–CBY1–β-catenin signaling axis might serve as a new diagnostic and therapeutic target for breast cancer.

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Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer

Narusaka

Ohara

Noma

et al. 2021

Intl Journal of Cancer

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Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin (CDDP) and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. Our study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although CDDP did result in high induction.Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Overall, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.

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Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

Cited by 24 publications

References 213 publications

Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas

Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas

A novel Lnc408 maintains breast cancer stem cell stemness by recruiting SP3 to suppress CBY1 transcription and increasing nuclear β-catenin levels

Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer

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