Communication Between Epithelial–Mesenchymal Plasticity and Cancer Stem Cells: New Insights Into Cancer Progression

Zheng, Xiangkuo; Dai, Fuzhen; Feng, Lei; Zou, Hong; Li, Feng; Xu, Mingqing

doi:10.3389/fonc.2021.617597

Cited by 32 publications

(30 citation statements)

References 93 publications

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“…Repressed production of ROS in high glucose treatment is in line with findings of previous investigation (4). ROS has a dual role to play in cancer biology; and its low level upkeeps the survival of cancer stem cells, which correlates with chemoresistance (44,45). Curcumin was able to augment the ROS production by doxorubicin even in the hyperglycemic condition.…”

Section: Discussionsupporting

confidence: 88%

Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells

et al. 2021

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Along with direct anticancer activity, curcumin hinders the onset of chemoresistance. Among many, high glucose condition is a key driving factor for chemoresistance. However, the ability of curcumin remains unexplored against high glucose-induced chemoresistance. Moreover, chemoresistance is major hindrance in effective clinical management of liver cancer. Using hepatic carcinoma HepG2 cells, the present investigation demonstrates that high glucose induces chemoresistance, which is averted by the simultaneous presence of curcumin. Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production. Modulated molecular regulators are suggested to play a crucial role as curcumin pretreatment also prevented the onset of chemoresistance by high glucose. High glucose instigated suppression in the intracellular accumulation of anticancer drug doxorubicin and drug-induced chromatin compactness along with declined expression of drug efflux pump MDR-1 and transcription factors and signal transducers governing the survival, aggressiveness, and apoptotic cell death (p53, HIF-1α, mTOR, MYC, STAT3). Curcumin alleviated the suppression of drug retention and nuclear condensation along with hindering the high glucose-induced alterations in transcription factors and signal transducers. High glucose-driven resistance in cancer cells was associated with elevated expression of metabolic enzymes HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, transporters, and receptors in cancer cells. Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition. Taken together, the findings of the present investigation first time demonstrate the ability of curcumin against high glucose-induced chemoresistance, along with its molecular mechanism. This will have implication in therapeutic management of malignancies in diabetic conditions.

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Section: Discussionsupporting

confidence: 88%

Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells

et al. 2021

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“…The fact that CSCs can change phenotypes via different programs, such as dynamic epithelial/mesenchymal status, has led to the speculation that non-CSCs can transform back to CSCs ( 47 – 49 ). Therefore, CSC plasticity can be presumed as the cell state capable of being shaped by EMT, wherein this process can allow interconversion of CSCs and non-CSCs ( 50 – 53 ).…”

Section: Plasticity Of Cscs Contributes To Tumor Heterogeneitymentioning

confidence: 99%

Linking Tumor Microenvironment to Plasticity of Cancer Stem Cells: Mechanisms and Application in Cancer Therapy

Zheng

2021

Front. Oncol.

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Cancer stem cells (CSCs) are a minority subset of cancer cells that can drive tumor initiation, promote tumor progression, and induce drug resistance. CSCs are difficult to eliminate by conventional therapies and eventually mediate tumor relapse and metastasis. Moreover, recent studies have shown that CSCs display plasticity that renders them to alter their phenotype and function. Consequently, the varied phenotypes result in varied tumorigenesis, dissemination, and drug-resistance potential, thereby adding to the complexity of tumor heterogeneity and further challenging clinical management of cancers. In recent years, tumor microenvironment (TME) has become a hotspot in cancer research owing to its successful application in clinical tumor immunotherapy. Notably, emerging evidence shows that the TME is involved in regulating CSC plasticity. TME can activate stemness pathways and promote immune escape through cytokines and exosomes secreted by immune cells or stromal cells, thereby inducing non-CSCs to acquire CSC properties and increasing CSC plasticity. However, the relationship between TME and plasticity of CSCs remains poorly understood. In this review, we discuss the emerging investigations on TME and CSC plasticity to illustrate the underlying mechanisms and potential implications in suppressing cancer progression and drug resistance. We consider that this review can help develop novel therapeutic strategies by taking into account the interlink between TME and CSC plasticity.

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“…As a result, the less organized tumour structures create a local microenvironment conducive for increased cell mobility, which is thought to promote invasion and metastases [ 259 ]. Thus, EMT not only plays a key role in the generation, selection, and survival of tumour cells, it is simultaneously the product of enhanced mesenchymal or stromal-cell-like properties, and phenotypic heterogeneity [ 260 , 261 ].…”

Section: Notch Signalling and Tumour Cell Plasticitymentioning

confidence: 99%

“…Additional, very detailed studies were performed to further investigate the role of NOTCH4 in this context [ 315 ], also in other cancer entities. We strongly recommend two recent reviews, which cover the topic of epithelial–mesenchymal plasticity, TME and their contribution to developing CSC [ 260 , 316 ]. The alternatives for targeting the Notch signalling pathway in CSCs are summarized in a review by Venkatash et al [ 324 ].…”

Section: Notch Signalling and Tumour Cell Plasticitymentioning

confidence: 99%

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

Kałafut

Czerwonka

Anameriç

et al. 2021

Cancers

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Head and Neck Squamous Cell Carcinoma (HNSCC) is often aggressive, with poor response to current therapies in approximately 40–50% of the patients. Current therapies are restricted to operation and irradiation, often combined with a small number of standard-of-care chemotherapeutic drugs, preferentially for advanced tumour patients. Only very recently, newer targeted therapies have entered the clinics, including Cetuximab, which targets the EGF receptor (EGFR), and several immune checkpoint inhibitors targeting the immune receptor PD-1 and its ligand PD-L1. HNSCC tumour tissues are characterized by a high degree of intra-tumour heterogeneity (ITH), and non-genetic alterations that may affect both non-transformed cells, such as cancer-associated fibroblasts (CAFs), and transformed carcinoma cells. This very high degree of heterogeneity likely contributes to acquired drug resistance, tumour dormancy, relapse, and distant or lymph node metastasis. ITH, in turn, is likely promoted by pronounced tumour cell plasticity, which manifests in highly dynamic and reversible phenomena such as of partial or hybrid forms of epithelial-to-mesenchymal transition (EMT), and enhanced tumour stemness. Stemness and tumour cell plasticity are strongly promoted by Notch signalling, which remains poorly understood especially in HNSCC. Here, we aim to elucidate how Notch signal may act both as a tumour suppressor and proto-oncogenic, probably during different stages of tumour cell initiation and progression. Notch signalling also interacts with numerous other signalling pathways, that may also have a decisive impact on tumour cell plasticity, acquired radio/chemoresistance, and metastatic progression of HNSCC. We outline the current stage of research related to Notch signalling, and how this pathway may be intricately interconnected with other, druggable targets and signalling mechanisms in HNSCC.

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Communication Between Epithelial–Mesenchymal Plasticity and Cancer Stem Cells: New Insights Into Cancer Progression

Cited by 32 publications

References 93 publications

Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells

Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells

Linking Tumor Microenvironment to Plasticity of Cancer Stem Cells: Mechanisms and Application in Cancer Therapy

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

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