Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling

AbstractIt has been postulated that cancer stem cells (CSCs) are involved in all aspects of human cancer, although the mechanisms governing the regulation of CSC self-renewal in the cancer state remain poorly defined. In the literature, both the pro- and anti-oncogenic activities of autophagy have been demonstrated and are context-dependent. Mounting evidence has shown augmentation of CSC stemness by autophagy, yet mechanistic characterization and understanding are lacking. In the present study, by generating stable human lung CSC cell lines with the wild-type TP53 (A549), as well as cell lines in which TP53 was deleted (H1229), we show, for the first time, that autophagy augments the stemness of lung CSCs by degrading ubiquitinated p53. Furthermore, Zeb1 is required for TP53 regulation of CSC self-renewal. Moreover, TCGA data mining and analysis show that Atg5 and Zeb1 are poor prognostic markers of lung cancer. In summary, this study has elucidated a new CSC-based mechanism underlying the oncogenic activity of autophagy and the tumor suppressor activity of p53 in cancer, i.e., CSCs can exploit the autophagy-p53-Zeb1 axis for self-renewal, oncogenesis, and progression.

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Sulforaphane Inhibits Self-renewal of Lung Cancer Stem Cells Through the Modulation of Polyhomeotic Homolog 3 and Sonic Hedgehog Signaling Pathways

10.21203/rs.2.11459/v1 ◽

2019 ◽

Author(s):

FanPing Wang ◽

Jiateng Zhong ◽

Shanshan Wang ◽

Caijuan Qiao ◽

Xiangyang Li ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Western Blot ◽

Cancer Cells ◽

Signaling Pathways ◽

Sonic Hedgehog ◽

Self Renewal ◽

Shh Signaling ◽

Lung Cancer Stem Cells

Abstract Background: Sulforaphane (SFN), an active compound in cruciferous vegetables has been characterized for its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. Methods: Lung cancer stem cells (CD133-positive cells) were isolated by MACs and then measured by flow cytometry. The ability of cell proliferation was assessed by MTT assays and tumorsphere formation assays. The expressions of Sonic Hedgehog (Shh), Smoothened (Smo), Gli1 and Human Polyhomeotic Homolog 3 (PHC3) in cells were measured by quantitative reverse transcription polymerase chain reaction (qPCR) and western blot assays. The expression of transcription factor SOX2 in lung cancer stem cells was also determined by western blot assay. Shh was knocked down by siRNA to further study the role of SFN and Shh signaling pathways in lung cancer. Results: SFN inhibited the proliferation of lung cancer cells and lung cancer stem cells simultaneously. Meanwhile, we observed that Sonic Hedgehog (SHH) signaling pathway, SOX2 and Polyhomeotic Homolog 3 (PHC3) were highly activated in lung cancer stem cells. Knock-down of Shh led to reduced H460 and A549 cells proliferation. Furthermore, we observed that SFN inhibited the activity of PHC3 and SHH signaling pathways in the lung cancer stem cells. In addition, SFN combined with Knock-down of Shh gene showed a greater effect on the proliferation of lung cancer cells. Conclusion: SFN is an effective new drug which can inhibit proliferation of lung cancer stem cells through the modulation of PHC3 and SHH signaling pathways. It provides a novel target for improving therapeutic efficacy for lung cancer stem cells.

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Abstract 2156: Lung niche factors for progenitor cell self-renewal sustain lung cancer stem cells and contribute to drug resistance to kinase inhibitors in non-small cell lung cancer

10.1158/1538-7445.am2018-2156 ◽

2018 ◽

Author(s):

Akinori Mitsui ◽

Sachiko Yokokawa ◽

Osamu Nagano ◽

Hideyuki Saya

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Progenitor Cell ◽

Kinase Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Self Renewal ◽

Lung Cancer Stem Cells

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Evidence for circulating cancer stem-like cells and epithelial–mesenchymal transition phenotype in the pleurospheres derived from lung adenocarcinoma using liquid biopsy

Tumor Biology ◽

10.1177/1010428317695915 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769591 ◽

Cited By ~ 6

Author(s):

Sheefa Mirza ◽

Nayan Jain ◽

Rakesh Rawal

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Tumor Stem Cells ◽

Mesenchymal Transition ◽

Lung Cancer Stem Cells

Lung cancer stem cells are supposed to be the main drivers of tumor initiation, maintenance, drug resistance, and relapse of the disease. Hence, identification of the cellular and molecular aspects of these cells is a prerequisite for targeted therapy of lung cancer. Currently, analysis of circulating tumor cells has the potential to become the main diagnostic technique to monitor disease progression or therapeutic response as it is non-invasive. However, accurate detection of circulating tumor cells has remained a challenge, as epithelial cell markers used so far are not always trustworthy for detecting circulating tumor cells, especially during epithelial–mesenchymal transition. As cancer stem cells are the only culprit to initiate metastatic tumors, our aim was to isolate and characterize circulating tumor stem cells rather than circulating tumor cells from the peripheral blood of NSCLC adenocarcinoma as limited data are available addressing the gene expression profiling of lung cancer stem cells. Here, we reveal that CD44(+)/CD24(−) population in circulation not only exhibit stem cell–related genes but also possess epithelial–mesenchymal transition characteristics. In conclusion, the use of one or more cancer stem cell markers along with epithelial, mesenchymal and epithelial mesenchymal transition markers will prospectively provide the most precise assessment of the threat for recurrence and metastatic disease and has a great potential for forthcoming applications in harvesting circulating tumor stem cells and their downstream applications. Our results will aid in developing diagnostic and prognostic modalities and personalized treatment regimens like dendritic cell–based immunotherapy that can be utilized for targeting and eliminating circulating tumor stem cells, to significantly reduce the possibility of relapse and improve clinical outcomes.

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Sulforaphane inhibits self-renewal of lung cancer stem cells through the modulation of sonic Hedgehog signaling pathway and polyhomeotic homolog 3

AMB Express ◽

10.1186/s13568-021-01281-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Fanping Wang ◽

Yanwei Sun ◽

Xiaoyu Huang ◽

Caijuan Qiao ◽

Wenrui Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Lung Cancer Cells ◽

Sonic Hedgehog Signaling ◽

Self Renewal ◽

Lung Cancer Stem Cells

AbstractSulforaphane (SFN), an active compound in cruciferous vegetables, has been characterized by its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. CD133+ cells were isolated with MACs from lung cancer A549 and H460 cells. In this study, we found that SFN inhibited the proliferation of lung cancer cells and self-renewal of lung cancer stem cells simultaneously. Meanwhile, the mRNA and protein expressions of Shh, Smo, Gli1 and PHC3 were highly activated in CD133+ lung cancer cells. Compared with siRNA-control group, Knock-down of Shh inhibited proliferation of CD133+ lung cancer cells, and decreased the protein expression of PHC3 in CD133+ lung cancer cells. Knock-down of PHC3 also affected the proliferation and decreased the Shh expression level in CD133+ lung cancer cells. In addition, SFN inhibited the activities of Shh, Smo, Gli1 and PHC3 in CD133+ lung cancer cells. Furthermore, the inhibitory effect of SFN on the proliferation of siRNA-Shh and siRNA-PHC3 cells was weaker than that on the proliferation of siRNA-control cells. Sonic Hedgehog signaling pathway might undergo a cross-talk with PHC3 in self-renewal of lung cancer stem cells. SFN might be an effective new drug which could inhibit self-renewal of lung cancer stem cells through the modulation of Sonic Hedgehog signaling pathways and PHC3. This study could provide a novel way to improve therapeutic efficacy for lung cancer stem cells.

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Autophagy Augments the Self-Renewal of Lung Cancer Stem Cells by Degradation of Ubiquitinated TP53

SSRN Electronic Journal ◽

10.2139/ssrn.3421598 ◽

2019 ◽

Author(s):

Jianyu Wang ◽

Doudou Liu ◽

Zhiwei Sun ◽

Ting Ye ◽

Jingyuan Li ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

The Self ◽

Self Renewal ◽

Lung Cancer Stem Cells

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Short hairpin RNA targeting AKT1 and PI3K/p85 suppresses the proliferation and self-renewal of lung cancer stem cells

Molecular Medicine Reports ◽

10.3892/mmr.2015.3393 ◽

2012 ◽

Vol 12 (1) ◽

pp. 363-370 ◽

Cited By ~ 5

Author(s):

AI-GUI JIANG ◽

HUI-YU LU ◽

DE-GENG ZHANG ◽

LI-XIN ZHANG ◽

XIAO-YAN GAO

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Short Hairpin Rna ◽

Hairpin Rna ◽

Self Renewal ◽

Rna Targeting ◽

Lung Cancer Stem Cells ◽

Short Hairpin

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Harnessing the BMP signaling pathway to control the formation of cancer stem cells by effects on epithelial-to-mesenchymal transition

Biochemical Society Transactions ◽

10.1042/bst20160177 ◽

2017 ◽

Vol 45 (1) ◽

pp. 223-228 ◽

Cited By ~ 7

Author(s):

Ashish Bosukonda ◽

William D. Carlson

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Cells ◽

Primary Tumor ◽

Epithelial To Mesenchymal Transition ◽

Bmp Signaling ◽

Human Breast ◽

Self Renewal ◽

Breast Cscs ◽

Mesenchymal Transition

Cancer stem cells (CSCs) persist in tumors as a distinct population and may be causative in metastasis and relapse. CSC-rich tumors are associated with higher rates of metastasis and poor patient prognosis. Targeting CSCs therapeutically is challenging, since they seem to be resistant to standard chemotherapy. We have shown that a novel peptide agonist of bone morphogenetic protein (BMP) signaling, P123, is capable of inhibiting the growth of primary tumor cells by interacting with type I receptors selectively [activin receptor-like kinase 2 (ALK2) and ALK3, but not ALK6] and type II BMP receptors, activating SMAD 1/5/8 signaling and controlling the cell cycle pathway. Furthermore, the compound is capable of blocking transforming growth factor-β induced epithelial-to-mesenchymal transition (EMT) in primary tumor cells, a critical step for tumor progression and metastasis. In addition, we have investigated the effects of P123 on self-renewal, growth, differentiation (reversal of EMT) and apoptosis of isolated human breast CSCs. We have shown that P123 and BMP-7 reverse the EMT process in human breast CSCs, and inhibit self-renewal and growth. Moreover, compared with single treatment with paclitaxel, co-treatment with paclitaxel and P123 showed an increase in cell apoptosis. Together, these findings suggest that P123 has the therapeutic potential to suppress both bulk tumor cells and CSCs. We believe that P123 represents a new class of drugs that have the potential to eliminate the primary tumor, prevent reoccurrence and metastasis, and enhance the treatment of breast cancer.

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Asymmetric Division Gene Neurl2 Mediates Twist2 Regulation of Self-Renewal of Mouse Lewis Lung Cancer Stem Cells

Journal of Cancer ◽

10.7150/jca.31553 ◽

2019 ◽

Vol 10 (15) ◽

pp. 3381-3388 ◽

Cited By ~ 1

Author(s):

Doudou Liu ◽

H. Rosie Xing ◽

Yongli Liu ◽

Zhiwei Sun ◽

Ting Ye ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Asymmetric Division ◽

Lewis Lung ◽

Lewis Lung Cancer ◽

Self Renewal ◽

Lung Cancer Stem Cells

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Signaling pathways governing breast cancer stem cells behavior

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02321-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kai Song ◽

Maryam Farzaneh

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Signaling Pathways ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

The Body ◽

Breast Cancer Stem Cells ◽

Self Renewal ◽

Mesenchymal Transition

AbstractBreast cancer is the second common cancer and the leading cause of malignancy among females overall. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that play a critical role in the metastasis of breast cancer to other organs in the body. BCSCs have both self-renewal and differentiation capacities, which are thought to contribute to the aggressiveness of metastatic lesions. Therefore, targeting BCSCs can be a suitable approach for the treatment and metastasis of breast cancer. Growing evidence has indicated that the Wnt, NFκB, Notch, BMP2, STAT3, and hedgehog (Hh) signaling pathways govern epithelial-to-mesenchymal transition (EMT) activation, growth, and tumorigenesis of BCSCs in the primary regions. miRNAs as the central regulatory molecules also play critical roles in BCSC self-renewal, metastasis, and drug resistance. Hence, targeting these pathways might be a novel therapeutic approach for breast cancer diagnosis and therapy. This review discusses known signaling mechanisms involved in the stimulation or prevention of BCSC self-renewal, metastasis, and tumorigenesis.

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