Breast cancer stem cells: Multiple capacities in tumor metastasis

Geng, Shaoqing; Alexandrou, Aris T.; Li, Jian Jian

doi:10.1016/j.canlet.2014.03.036

Cited by 154 publications

(140 citation statements)

References 98 publications

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“…8 Consequently there is an urgent need, not only to further define the nature of heterogeneity in breast tumors, but also to develop new therapeutic protocols for targeting this sub-population of "hard core" cancer cells. HSP90 has been considered as an attractive molecular target for cancer therapy for more than a decade, because it can simultaneously affect numerous oncogenic proteins and pathways.…”

Section: Discussionmentioning

confidence: 99%

“…To avoid confusion with normal stem cells, it has been proposed that cancer stem cells be designated as "tumor initiating cells," or "cancer stem-like cells," thereby defining the subset of cancer cells that has the ability to drive the growth and spread of a tumor. 8 Breast cancer is a significant cause of mortality in women, and has a high incidence of recurrence and treatment failure. It is a heterogeneous disease reflected both at morphological and genetic levels.…”

Section: Introductionmentioning

confidence: 99%

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Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Stivarou

Stellas

Vartzi

et al. 2016

Cancer Biology & Therapy

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Breast cancer stem cells (BCSC) have been identified in breast carcinoma as CD44 C /CD24 ¡/low cells, which display tumorigenic activity and have the ability to self-renew, differentiate and metastasize. Previous studies showed that extracellular HSP90 (eHSP90) participates in the invasion and metastatic processes of various cancers including breast cancer. Here, we show for the first time that eHSP90 is over-expressed in mammosphere cultures that are derived from the MDA-MB-231, MDA-MB-453 and MCF-7 breast cancer cell lines. These mammospheres are highly enriched in cells of the CD44 C /CD24 ¡/low BCSC phenotype and additionally show high expression of the BCSC markers CD49f and Sox2. Thus our results indicate that eHSP90 represents a potential novel BCSC marker. Moreover, we present evidence that eHSP90 is functionally involved in BCSC activity in vitro and in vivo. Selective neutralization of eHSP90, using the monoclonal antibody mAb 4C5, has the capacity to inhibit stem cell activity in vitro because the formation of mammosphere-derived colonies is dramatically reduced in its presence. In vivo, the treatment of mice with mAb4C5 using a prophylactic protocol, significantly inhibited the primary growth of MDA-MB-231 and mammosphere-derived tumors. More importantly, administration of this antibody in a therapeutic protocol caused a statistically significant regression of established tumors derived from MDA-MB-231 originating mammospheres. Tumor regression was even greater when mAb 4C5 was administered in combination with paclitaxel. Overall, our findings implicate eHSP90 as a potential novel BCSC biomarker. Moreover they show that eHSP90 participates in BCSC-derived primary tumor growth. Finally, we provide additional support for the possible therapeutic value of mAb4C5 in the treatment of breast cancer.Abbreviations: ALDH1, aldehyde dehydrogenase 1; BCSC, breast cancer stem cells; eHSP90, extracellular heat shock protein 90; ER, estrogen receptor; EGF, epidermal growth factor; FGF, fibroblast growth factor; MMP-2, matrix metalloproteinase 2

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Stivarou

Stellas

Vartzi

et al. 2016

Cancer Biology & Therapy

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“…Cancer stem/progenitor cells (CSCs) are a subpopulation of cancer cells with the characteristics of tumor initiation (1), resistance to therapy (2) and metastasis (3). In breast cancer, breast CSCs (BCSCs) have been identified as cells with cluster of differentiation (CD) 24 -CD44 + surface markers (4) or with high intracellular aldehyde dehydrogenase activity (5).…”

Section: Introductionmentioning

confidence: 99%

Hinokitiol inhibits vasculogenic mimicry activity of breast cancer stem/progenitor cells through proteasome-mediated degradation of epidermal growth factor receptor

Lee

et al. 2016

Oncology Letters

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Abstract. Hinokitiol, alternatively known as β-thujaplicin, is a tropolone-associated natural compound with antimicrobial, anti-inflammatory and antitumor activity. Breast cancer stem/progenitor cells (BCSCs) are a subpopulation of breast cancer cells associated with tumor initiation, chemoresistance and metastatic behavior, and may be enriched by mammosphere cultivation. Previous studies have demonstrated that BCSCs exhibit vasculogenic mimicry (VM) activity via the epidermal growth factor receptor (EGFR) signaling pathway. The present study investigated the anti-VM activity of hinokitiol in BCSCs. At a concentration below the half maximal inhibitory concentration, hinokitiol inhibited VM formation of mammosphere cells derived from two human breast cancer cell lines. Hinokitiol was additionally indicated to downregulate EGFR protein expression in mammosphere-forming BCSCs without affecting the expression of messenger RNA. The protein stability of EGFR in BCSCs was also decreased by hinokitiol. The EGFR protein expression and VM formation capability of hinokitiol-treated BCSCs were restored by co-treatment with MG132, a proteasome inhibitor. In conclusion, the present study indicated that hinokitiol may inhibit the VM activity of BCSCs through stimulating proteasome-mediated EGFR degradation. Hinokitiol may act as an anti-VM agent, and may be useful for the development of novel breast cancer therapeutic agents. IntroductionCancer stem/progenitor cells (CSCs) are a subpopulation of cancer cells with the characteristics of tumor initiation (1), resistance to therapy (2) and metastasis (3). In breast cancer, breast CSCs (BCSCs) have been identified as cells with cluster of differentiation (CD)24 -CD44 + surface markers (4) or with high intracellular aldehyde dehydrogenase activity (5). BCSCs may additionally be enriched by cultivation in a serum-free, non-adherent environment, known as the mammosphere, which is a floating clump composed of breast cancer cells (6,7). In addition to tumor initiation and chemoresistant properties, BCSCs have also been indicated to exhibit vasculogenic mimicry (VM) activity (8), defined as the formation of perfusable, matrix-rich and vasculogenic-like networks by tumor cells, without involvement of endothelial cells (9). A previous study demonstrated that the VM activity of BCSCs is regulated by epidermal growth factor receptor (EGFR) signaling (8).Hinokitiol, alternatively known as β-thujaplicin, is a tropolone-associated natural compound isolated from heartwood cupressaceous plants (10), and has been widely used as an antimicrobial agent in toothpastes, cosmetics and food (11). In addition to antimicrobial activity, hinokitiol has been reported to possess anti-inflammatory (12,13) and antitumor Hinokitiol inhibits vasculogenic mimicry activity of breast cancer stem/progenitor cells through proteasome-mediated degradation of epidermal growth factor receptor

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“…Breast cancer is considered to be the leading cause of cancer-related death among women all over the world [1]. It was reported that approximately 1.38 million people developed breast cancer in 2008; among all cancers, it was ranked second for morbidity, with 23% of all cancer cases, and its mortality was the fifth highest of all cancers [2].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Effects of HAS-2 Gene Silencing on the Proliferation and Apoptosis of the MCF-7 Human Breast Cancer Cell Line

Zhang¹,

Feng²,

Wang³

et al. 2016

Cell Physiol Biochem

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Background: Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. This study is aimed to investigate the effects of silencing the HAS-2 gene on the proliferation and apoptosis of human breast cancer cells. Methods: MCF-7 cells were collected and assigned into control, scrambled siRNA and HAS-2- siRNA groups. After transfection, the morphological changes in the MCF-7 cells were observed using phase contrast microscopy. qRT-PCR and Western blot assays were used to detect the mRNA and protein expression of apoptosis-related proteins. CCK-8 and flow cytometry were performed to evaluate cell proliferation, the cell cycle and apoptosis. Results: In the control and the scrambled siRNA groups, cells grew adhered to the wall and mainly showed a spindle shape with a clear nucleolus. Compared with the control and scrambled siRNA groups, increases in the number of cells in early apoptosis and metaphase cells in apoptosis were observed in the HAS-2-siRNA group. The HAS-2-siRNA group showed decreased expression of HAS-2 relative to that in the control and scrambled siRNA groups. No significant differences in cell proliferation, cell cycle distribution or apoptosis were noted between the control and scrambled siRNA groups. In the HAS-2-siRNA group, the cell proliferation ability decreased significantly, but the number of cells in the G0/G1 stage, the number of apoptotic cells and the expression of caspase-3 and caspase-9 increased significantly. Conclusion: Our findings indicate that HAS-2 gene silencing may inhibit proliferation and promote apoptosis in the MCF-7 human breast cancer cell line.

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Breast cancer stem cells: Multiple capacities in tumor metastasis

Cited by 154 publications

References 98 publications

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Hinokitiol inhibits vasculogenic mimicry activity of breast cancer stem/progenitor cells through proteasome-mediated degradation of epidermal growth factor receptor

In Vitro Effects of HAS-2 Gene Silencing on the Proliferation and Apoptosis of the MCF-7 Human Breast Cancer Cell Line

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