Helicobacter pylori generates cells with cancer stem cell properties via epithelial–mesenchymal transition-like changes

Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial–mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+/Oct4high/Sox-2high/c-Mychigh/Klf4low phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial–myofibroblast transition (EMyoT) of RGM1 cells favoring LGR−/Oct4high/Sox2low/c-Myclow/Klf4high phenotype (l.t.EMT−RGM1 cells). TGFβ1 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMT−RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm.

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TAZ Controls Helicobacter pylori-Induced Epithelial–Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties

Cells ◽

10.3390/cells9061462 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1462 ◽

Cited By ~ 1

Author(s):

Camille Tiffon ◽

Julie Giraud ◽

Silvia Elena Molina-Castro ◽

Sara Peru ◽

Lornella Seeneevassen ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Stem Cell ◽

Cancer Stem Cell ◽

Epithelial Mesenchymal Transition ◽

Gastric Carcinogenesis ◽

Gastric Epithelium ◽

Binding Motif ◽

Mesenchymal Transition ◽

H Pylori

Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiation and progression in many cancers including GC. Here, we investigated the role of TAZ in the early steps of H. pylori-mediated gastric carcinogenesis. TAZ implication in EMT, invasion, and CSC-related tumorigenic properties were evaluated in three gastric epithelial cell lines infected by H. pylori. We showed that H. pylori infection increased TAZ nuclear expression and transcriptional enhancer TEA domain (TEAD) transcription factors transcriptional activity. Nuclear TAZ and zinc finger E-box-binding homeobox 1 (ZEB1) were co-overexpressed in cells harboring a mesenchymal phenotype in vitro, and in areas of regenerative hyperplasia in gastric mucosa of H. pylori-infected patients and experimentally infected mice, as well as at the invasive front of gastric carcinoma. TAZ silencing reduced ZEB1 expression and EMT phenotype, and strongly inhibited invasion and tumorsphere formation induced by H. pylori. In conclusion, TAZ activation in response to H. pylori infection contributes to H. pylori-induced EMT, invasion, and CSC-like tumorigenic properties. TAZ overexpression in H. pylori-induced pre-neoplastic lesions and in GC could therefore constitute a biomarker of early transformation in gastric carcinogenesis.

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Partial acquisition of stemness properties in tumorspheres obtained from interleukin-8-treated MCF-7 cells

Tumor Biology ◽

10.1177/1010428320979438 ◽

2020 ◽

Vol 42 (12) ◽

pp. 101042832097943

Author(s):

Natalia Ospina-Muñoz ◽

Jean-Paul Vernot

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

First Generation ◽

Epithelial Mesenchymal Transition ◽

Cancer Cell Line ◽

Interleukin 8 ◽

Self Renewal ◽

Mesenchymal Transition ◽

Sphere Formation ◽

Mcf 7

The interleukin-8 is an important regulator of the tumor microenvironment, promoting the epithelial–mesenchymal transition and the acquisition of stem-like cell properties in cancer cells. The tumorsphere-formation assay has been used for the identification of cancer stem cell. Interleukin-8 induces the formation of larger tumorspheres in Michigan Cancer Foundation-7 (MCF-7) cells, suggesting cancer stem cell enrichment. In this work, we aimed to study the phenotypic and functional characteristics of the cells present within the tumorspheres of MCF-7 cells previously treated with interleukin-8. MCF-7 cells treated for 5 days or not with this cytokine were further cultivated in ultralow attachment plates for another 5 days to allow tumorspheres formation. We showed that the enhanced sphere formation by MCF-7 cells was not a consequence of higher cell proliferation by interleukin-8 stimulation. Despite maintaining an epithelial–mesenchymal transition phenotype with the presence of epithelial and mesenchymal markers, basic stemness properties were impaired in tumorspheres and in those treated with interleukin-8, while others were increased. Self-renewal capacity was increased in interleukin-8-treated cells only in the first generation of tumorspheres but was not sustained in consecutive assays. Accordingly, self-renewal and reprogramming gene expression, differentiation capacity to adipocytes, and clonogenicity were also impaired. We showed also that tumorspheres were enriched in differentiated luminal cells (EpCAM+/CD49f−). Nevertheless, cells were more quiescent and maintain a partial epithelial–mesenchymal transition, consistent with their increased resistance to Paclitaxel and Doxorubicin. They also presented higher migration and interleukin-8-directed invasion. Therefore, the breast cancer cell line MCF-7, having a low stemness index, might partially acquire some stem-like cell attributes after interleukin-8 stimulation, increasing its aggressiveness.

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Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

Journal of Oncology ◽

10.1155/2011/591427 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 30

Author(s):

Tetsu Hayashida ◽

Hiromitsu Jinno ◽

Yuko Kitagawa ◽

Masaki Kitajima

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Breast Cancer Metastasis ◽

Cell Junctions ◽

Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

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The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition

Journal of Molecular Signaling ◽

10.1186/1750-2187-5-14 ◽

2010 ◽

Vol 5 ◽

pp. 14 ◽

Cited By ~ 118

Author(s):

Su-Ni Tang ◽

Chandan Singh ◽

Dara Nall ◽

Daniel Meeker ◽

Sharmila Shankar ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition

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Re-expression of miR-21 contributes to migration and invasion by inducing epithelial-mesenchymal transition consistent with cancer stem cell characteristics in MCF-7 cells

Molecular and Cellular Biochemistry ◽

10.1007/s11010-011-1195-5 ◽

2011 ◽

Vol 363 (1-2) ◽

pp. 427-436 ◽

Cited By ~ 75

Author(s):

Mingli Han ◽

Manran Liu ◽

Yimeng Wang ◽

Zhiqiang Mo ◽

Xiaokai Bi ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Mcf 7

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HERV-K HML-2 transcription in diverse cancers is related with cancer stem cell and epithelial-mesenchymal transition markers

10.1101/451997 ◽

2018 ◽

Cited By ~ 1

Author(s):

Audrey T. Lin ◽

Cindy G. Santander ◽

Fabricia F. Nascimento ◽

Emanuele Marchi ◽

Timokratis Karamitros ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cell ◽

Human Genome ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Embryonic Stem ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Mesenchymal Transition

AbstractEndogenous retroviruses (ERVs) are remnants of ancient retroviral infections that make up 8% of the human genome. Although these elements are mostly fragmented and inactive, many proviruses belonging to the HERV-K (HML-2) family, the youngest lineage in the human genome, have intact open reading frames, some encoding for accessory genes called np9 and rec that interact with oncogenic pathways. Many studies have established that ERVs are transiently expressed in both stem cells and cancer, resulting in aberrant self-renewal and uncontrolled proliferation. np9 and rec expression are significantly correlated with a range of cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) biomarkers, including cellular receptors, transcription factors, and histone modifiers. Surprisingly, these ERV genes are negatively correlated with genes known to promote pluripotency in embryonic stem cell lines, such as Oct4. These results indicate that HERV-K (HML-2) is part of the transcriptional landscape responsible for cancer cells undergoing the phenotypic switch that characterises EMT. The discovery of np9 and rec’s correlation with CSC and EMT biomarkers suggest a yet undescribed role affecting the transitional CSC-like state in EMT and the shift towards cancer malignancy.ImportanceIn this study, we find that human endogenous retrovirus HERV-K (HML-2)-encoded genes np9 and rec are correlated with the expression of many biomarkers associated with cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT). There has been a significant effort to develop novel treatments targeting CSC and EMT-specific signalling pathways and cell surface markers. This research describes HERV-K (HML-2) as interacting or being part of the regulatory network that make up reversible cell state switching in EMT. Our findings suggest these specific HERVs may be good candidate biomarkers in identifying the transitional CSC-like states that are present during the progression of EMT and cancer metastasis.

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Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition

Oncotarget ◽

10.18632/oncotarget.3556 ◽

2015 ◽

Vol 6 (11) ◽

pp. 8807-8821 ◽

Cited By ~ 29

Author(s):

Si-Rui Ma ◽

Wei-Ming Wang ◽

Cong-Fa Huang ◽

Wen-Feng Zhang ◽

Zhi-Jun Sun

Keyword(s):

Squamous Cell Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Epithelial Mesenchymal Transition ◽

Neck Squamous Cell Carcinoma ◽

High Grade ◽

Mesenchymal Transition

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RUNX1 suppresses breast cancer stemness and tumor growth

10.1101/315093 ◽

2018 ◽

Author(s):

Deli Hong ◽

Andrew J. Fritz ◽

Kristiaan H. Finstad ◽

Mark P. Fitzgerald ◽

Adam L. Viens ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Tumor Suppressor ◽

Cancer Stem Cell ◽

Tumor Growth ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Cell Activity ◽

Mesenchymal Transition

SummaryRecent studies have revealed that mutations in the transcription factor Runx1 are prevalent in breast tumors. Yet, how loss of Runx1 contributes to breast cancer (BCa) remains unresolved. We demonstrate for the first time that Runx1 represses the breast cancer stem cell (BCSC) phenotype and consequently, functions as a tumor suppressor in breast cancer. Runx1 ectopic expression in MCF10AT1 and MCF10CA1a BCa cells reduces (60%) migration, invasion and in vivo tumor growth in mouse mammary fat pad (P<0.05). Runx1 is decreased in BCSCs, and overexpression of Runx1 suppresses tumorsphere formation and reduces the BCSC population. Furthermore, Runx1 inhibits Zeb1 expression, while Runx1 depletion activates Zeb1 and the epithelial-mesenchymal transition. Mechanistically Runx1 functions as a tumor suppressor in breast cancer through repression of cancer stem cell activity. This key regulation of BCSCs by Runx1 may be shared in other epithelial carcinomas, highlighting the importance of Runx1 in solid tumors.

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