Overview: Cellular plasticity, cancer stem cells and metastasis

ElShamy, Wael M.; Duhé, Roy J.

doi:10.1016/j.canlet.2013.06.020

Cited by 61 publications

(61 citation statements)

References 79 publications

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“…To shed light on the engagement of CD44/CD44v6 in CIC activities, we will first introduce the CD44 molecule, CIC and exosomes (Exo) and then outline the state of knowledge on the linkage between CD44/CD44v6 and CIC with emphasis on the requirement of a niche (Prasetyanti et al, 2013), apoptosis resistance (Ramdass et al, 2013; Colak and Medema, 2014; Vlashi and Pajonk, 2015), epithelial mesenchymal transition (EMT) (Dontu and Wicha, 2005; Wells et al, 2011) and tumor progression (Elshamy and Duhé, 2013). Finally, the contribution of CD44/CD44v6 to metastatic settlement being promoted by tumor exosomes (TEX), which are suggested to transfer CIC-features to Non-CIC, to promote angiogenesis, to prepare a premetastatic niche and to modulate hematopoiesis toward an immunosuppressive phenotype (Hannafon and Ding, 2015; Minciacchi et al, 2015), will be discussed.…”

Section: Introductionmentioning

confidence: 99%

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CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

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Section: Introductionmentioning

confidence: 99%

“…CIC are a minor subpopulation within the primary tumor mass, yet are suggested to account for tumor initiation, propagation, recurrence, metastasis, and drug- and radiation resistance (Elshamy and Duhé, 2013; Kozovska et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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“…Accumulating experimental and clinical evidence suggests that EMT can generate cells with stem/progenitor-like properties and enables plasticity between cancer stem cells (CSC) and non-CSC [4], [7]–[9], thus providing a link between EMT and CSCs [10], [11].…”

Section: Introductionmentioning

confidence: 99%

“…During the process of carcinogenesis, which is often enabled by EMT, disseminated cancer cells seem to acquire self-renewal capability, similar to that displayed by stem cells [10] [11]. This raises the possibility that the EMT process may also impart a self-renewal capability to disseminated cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting of Alpha-V Integrins Reduces Malignancy of Bladder Carcinoma

et al. 2014

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Low survival rates of metastatic cancers emphasize the need for a drug that can prevent and/or treat metastatic cancer. αv integrins are involved in essential processes for tumor growth and metastasis and targeting of αv integrins has been shown to decrease angiogenesis, tumor growth and metastasis. In this study, the role of αv integrin and its potential as a drug target in bladder cancer was investigated. Treatment with an αv integrin antagonist as well as knockdown of αv integrin in the bladder carcinoma cell lines, resulted in reduced malignancy in vitro, as illustrated by decreased proliferative, migratory and clonogenic capacity. The CDH1/CDH2 ratio increased, indicating a shift towards a more epithelial phenotype. This shift appeared to be associated with downregulation of EMT-inducing transcription factors including SNAI2. The expression levels of the self-renewal genes NANOG and BMI1 decreased as well as the number of cells with high Aldehyde Dehydrogenase activity. In addition, self-renewal ability decreased as measured with the urosphere assay. In line with these observations, knockdown or treatment of αv integrins resulted in decreased metastatic growth in preclinical in vivo models as assessed by bioluminescence imaging. In conclusion, we show that αv integrins are involved in migration, EMT and maintenance of Aldehyde Dehydrogenase activity in bladder cancer cells. Targeting of αv integrins might be a promising approach for treatment and/or prevention of metastatic bladder cancer.

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“…Despite advances in diagnosis and treatment of OSCC, the 5-year survival rate after curative surgery is only 20–30%, mainly due to tumour metastasis, tumour recurrence and chemoresistance1. Recently, increasing evidence suggests that cancer stem cells (CSCs) represent an important subset of tumour cells that are responsible for tumour metastasis, tumour recurrence and chemoresistance3456. CSCs are a subset of cancer cells that are biologically distinct from the others and have stem cell-like features7.…”

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confidence: 99%

Integrin α7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma

et al. 2016

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Non-CG methylation has been associated with stemness regulation in embryonic stem cells. By comparing differentially expressed genes affected by non-CG methylation between tumour and corresponding non-tumour tissues in oesophageal squamous cell carcinoma (OSCC), we find that Integrin α7 (ITGA7) is characterized as a potential cancer stem cell (CSC) marker. Clinical data show that a high frequency of ITGA7+ cells in OSCC tissues is significantly associated with poor differentiation, lymph node metastasis and worse prognosis. Functional studies demonstrate that both sorted ITGA7+ cells and ITGA7 overexpressing cells display enhanced stemness features, including elevated expression of stemness-associated genes and epithelial–mesenchymal transition features, as well as increased abilities to self-renew, differentiate and resist chemotherapy. Mechanistic studies find that ITGA7 regulates CSC properties through the activation of the FAK-mediated signalling pathways. As knockdown of ITGA7 can effectively reduce the stemness of OSCC cells, ITGA7 could be a potential therapeutic target in OSCC treatment.

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Overview: Cellular plasticity, cancer stem cells and metastasis

Cited by 61 publications

References 79 publications

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Targeting of Alpha-V Integrins Reduces Malignancy of Bladder Carcinoma

Integrin α7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma

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