scholarly journals The Chemokine Receptor CXCR3 Isoform B Drives Breast Cancer Stem Cells

2019 ◽  
Vol 13 ◽  
pp. 117822341987362 ◽  
Author(s):  
Namita Kundu ◽  
Xinrong Ma ◽  
Regine Brox ◽  
Xiaoxuan Fan ◽  
Tyler Kochel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cell ◽  
Cell Population ◽  
Chemokine Receptor ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Tumor Cell Population ◽  
Isoform B

We are seeking to identify molecular targets that are relevant to breast cancer cells with stem-like properties. There is growing evidence that cancer stem cells (CSCs) are supported by inflammatory mediators expressed in the tumor microenvironment. The chemokine receptor CXCR3 binds the interferon-γ-inducible, ELR-negative CXC chemokines CXCL9, CXCL10, and CXCL11 and malignant cells have co-opted this receptor to promote tumor cell migration and invasion. There are 2 major isoforms of CXCR3: CXCR3A and CXCR3B. The latter is generated from alternative splicing and results in a protein with a longer N-terminal domain. CXCR3 isoform A is generally considered to play a major role in tumor metastasis. When the entire tumor cell population is examined, CXCR3 isoform B is usually detected at much lower levels than CXCR3A and for this, and other reasons, was not considered to drive tumor progression. We have shown that CXCR3B is significantly upregulated in the subpopulation of breast CSCs in comparison with the bulk tumor cell population in 3 independent breast cancer cell lines (MDA-MB-231, SUM159, and T47D). Modulation of CXCR3B levels by knock in strategies increases CSC populations identified by aldehyde dehydrogenase activity or CD44+CD24− phenotype as well as tumorsphere-forming capacity. The reverse is seen when CXCR3B is gene-silenced. CXCL11 and CXCL10 directly induce CSC. We also report that novel CXCR3 allosteric modulators BD064 and BD103 prevent the induction of CSCs. BD103 inhibited experimental metastasis. This protective effect is associated with the reversal of CXCR3 ligand-mediated activation of STAT3, ERK1/2, CREB, and NOTCH1 pathways. We propose that CXCR3B, expressed on CSC, should be explored further as a novel therapeutic target.

scholarly journals A Nuclear-Directed Ribonuclease Variant Targets Cancer Stem Cells and Inhibits Migration and Invasion of Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4350
Author(s):  
Jessica Castro ◽  
Giusy Tornillo ◽  
Gerardo Ceada ◽  
Beatriz Ramos-Neble ◽  
Marlon Bravo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Tumor Cell Lines

Despite the significant advances in cancer research made in recent years, this disease remains one of the leading causes of death worldwide. In part, this is due to the fact that after therapy, a subpopulation of self-renewing tumor cells can survive and promote cancer relapse, resistance to therapies and metastasis. Targeting these cancer stem cells (CSCs) is therefore essential to improve the clinical outcome of cancer patients. In this sense, multi-targeted drugs may be promising agents targeting CSC-associated multifocal effects. We have previously constructed different human pancreatic ribonuclease (RNase) variants that are cytotoxic for tumor cells due to a non-classical nuclear localization signal introduced in their sequence. These cytotoxic RNases affect the expression of multiple genes involved in deregulated metabolic and signaling pathways in cancer cells and are highly cytotoxic for multidrug-resistant tumor cell lines. Here, we show that these cytotoxic nuclear-directed RNases are highly selective for tumor cell lines grown in 3D, inhibit CSCs’ development and diminish the self-renewal capacity of the CSCs population. Moreover, these human RNase variants reduce the migration and invasiveness of highly invasive breast cancer cells and downregulate N-cadherin expression.

scholarly journals An Extract of Taro (Colocasia esculenta) Mediates Potent Inhibitory Actions on Metastatic and Cancer Stem Cells by Tumor Cell-Autonomous and Immune-Dependent Mechanisms

2021 ◽  
Vol 15 ◽  
pp. 117822342110349
Author(s):  
Namita Kundu ◽  
Xinrong Ma ◽  
Stephen Hoag ◽  
Fang Wang ◽  
Ahmed Ibrahim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cell ◽  
Cell Lines ◽  
Nk Cell ◽  
Cancer Therapeutics ◽  
Colocasia Esculenta ◽  
Biologically Active ◽  
Tumor Cell Migration

The taro plant, Colocasia esculenta, contains bioactive proteins with potential as cancer therapeutics. Several groups have reported anti-cancer activity in vitro and in vivo of taro-derived extracts (TEs). We reported that TE inhibits metastasis in a syngeneic murine model of Triple-Negative Breast Cancer (TNBC). Purpose: We sought to confirm our earlier studies in additional models and to identify novel mechanisms by which efficacy is achieved. Methods: We employed a panel of murine and human breast and ovarian cancer cell lines to determine the effect of TE on tumor cell viability, migration, and the ability to support cancer stem cells. Two syngeneic models of TNBC were employed to confirm our earlier report that TE potently inhibits metastasis. Cancer stem cell assays were employed to determine the ability of TE to inhibit tumorsphere-forming ability and to inhibit aldehyde dehydrogenase activity. To determine if host immunity contributes to the mechanism of metastasis inhibition, efficacy was assessed in immune-compromised mice. Results: We demonstrate that viability of some, but not all cell lines is inhibited by TE. Likewise, tumor cell migration is inhibited by TE. Using 2 immune competent, syngeneic models of TNBC, we confirm our earlier findings that tumor metastasis is potently inhibited by TE. We also demonstrate, for the first time, that TE directly inhibits breast cancer stem cells. Administration of TE to mice elicits expansion of several spleen cell populations but it was not known if host immune cells contribute to the mechanism by which TE inhibits tumor cell dissemination. In novel findings, we now show that the ability of TE to inhibit metastasis relies on immune T-cell-dependent, but not B cell or Natural Killer (NK)-cell-dependent mechanisms. Thus, both tumor cell-autonomous and host immune factors contribute to the mechanisms underlying TE efficacy. Our long-term goal is to evaluate TE efficacy in clinical trials. Most of our past studies as well as many of the results reported in this report were carried out using an isolation protocol described earlier (TE). In preparation for a near future clinical trial, we have now developed a strategy to isolate an enriched taro fraction, TE-method 2, (TE-M2) as well as a more purified subfraction (TE-M2F1) which can be scaled up under Good Manufacturing Practice (GMP) conditions for evaluation in human subjects. We demonstrate that TE-M2 and TE-M2F1 retain the anti-metastatic properties of TE. Conclusions: These studies provide further support for the continued examination of biologically active components of Colocasia esculenta as potential new therapeutic entities and identify a method to isolate sufficient quantities under GMP conditions to conduct early phase clinical studies.

scholarly journals Dysregulation of Transcription Factor EB Contributes to Cell Proliferation, Metastasis and Stemness in Breast Cancer

2021 ◽  
Author(s):  
Ningwei Fu ◽  
Ning Fan ◽  
Wenchao Luo ◽  
Lijia Lv ◽  
Jing Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Breast Cancer Stem Cells ◽  
Cancer Proliferation ◽  
Mammosphere Formation

Abstract Purpose: TFEB is a key regulator of autophagy-lysosomal biogenesis pathways, while its dysregulation is highly prevalent in various human cancers, but the specific contribution to breast cancer remains poorly understood. The main purpose of this study is to explore the role of TFEB in breast cancer proliferation, metastasis and maintaining breast cancer stem cells (BCSCs) traits, thus uncovering its underlying mechanism.Methods: Bioinformatics, western blotting and immunohistochemical staining were applied to analyze the expression of TFEB in breast cancer. Stable down-regulation TFEB cells were established in MCF-7 and MDA-MB-231 breast cancer cell lines. MTT, clone formation, wound healing, transwell and 3D tumor invasion assays were used to evaluate the proliferation, migration and invasion ability of breast cancer cells. Mammosphere formation, immunocytochemical (ICC) staining were used to detect the effect of down-regulating TFEB on breast cancer stem cells. Results: we demonstrated that higher expression of TFEB was found in breast cancer. TFEB depletion had inhibitory effects on cellular proliferation, migration and invasion of breast cancer cells. Moreover, knockdown TFEB decreased mammosphere formation ability of BCSCs and expression of cancer stem cell markers. Autophagy-lysosomal related proteins were decreased by down regulation of TFEB. Conclusion: we uncovered a critical role of TFEB in breast cancer proliferation and metastasis, and BCSCs self-renewal and stemness. The underlying mechanisms involve in maintaining BCSCs traits, and dysregulating lysosome functions.

scholarly journals Erratum: Corrigendum: Bub1 is required for maintaining cancer stem cells in breast cancer cell lines

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Jeong Yoon Han ◽  
Yu Kyeong Han ◽  
Ga-Young Park ◽  
Sung Dae Kim ◽  
Chang Geun Lee
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines

Anti-lactadherin antibodies in anti-angiogenic cancer therapy of breast cancer stem cells

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14138-14138 ◽  
Author(s):  
A. A. Epenetos ◽  
G. Bower ◽  
M. Deonarain ◽  
L. Bonney
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Human Breast Cancer ◽  
Tumor Vasculature ◽  
Breast Cancer Cell Lines ◽  
Human Breast ◽  
Integrin Receptor ◽  
Receptor Signalling

14138 Background: Angiolix (Hu-Mc3) is a humanized monoclonal antibody that recognizes a migrating adhesion molecule called Lactadherin. This novel antibody has a high affinity for its antigen and recognizes an epitope on Lactadherin which interacts with the the ’RGD’- motif found on integrin receptors on newly formed endothelial cells. Lactadherin binding leads to signalling via a VEGF-independent integrin receptor signalling cascade leading to vascular endothelial cell profileration. Lactadherin binding may also increase the potency of VEGF-VEGF receptor signalling. Methods: We studied the expression of Lactadherin on breast cancer cell lines, the biodistribution of Angiolix in human breast cancer xeografts and its ability to inhibit tumor growth in vivo. Results: Our data show that tumor cells express lactadherin in vivo and that Angiolix could achieve more than 75% growth inhibition of human breast cancer growing as xenografts . Conclusions: In view of the recent finding that cancer stem cells can over-express the pro-angiogenic VEGF and make a major contribution to tumor vasculature proliferation leads to the possibility that Angiolix may be able to act to specifically target breast cancer stem cell and cause tumor regression by blocking the growth of tumor vasculature by its ability to neutralise Lactadherin-integrin receptor binding. [Table: see text]

Apatinib Inhibits Stem Properties and Malignant Biological Behaviors of Breast Cancer Stem Cells by Blocking Wnt/β-catenin Signal Pathway Through Down-regulating LncRNA ROR

2021 ◽  
Vol 21 ◽  
Author(s):  
Baohong Jiang ◽  
Hongbo Zhu ◽  
Liting Tang ◽  
Ting Gao ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Magnetic Beads ◽  
Signal Pathway ◽  
Migration And Invasion ◽  
Pcr Analysis ◽  
Dependent Manner ◽  
Breast Cancer Stem Cells ◽  
Mesenchymal Transition

Background: Cancer stem cells could influence tumor recurrence and metastasis. Objective: To develop a new effective treatment modality targeting breast cancer stem cells (BCSCs), and to explore the role of Apatinib in BCSCs. Methods: BCSCs were isolated from MDA-MB-231 cells by immune magnetic beads method. BCSCs were treated with Apatinib, lentiviral plasmids (lncRNA ROR) and iCRT-3 (Wnt pathway inhibitors). Viability, colony numbers, sphere numbers, apoptosis, migration, invasion of BCSCs were detected by MTT, colony formation, tumor sphere, flow cytometry, wound-healing, transwell assays, respectively. The expressions of markers (ABCG2, CD44, CD90, and CD24), epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, N-cadherin, Vimentin, MMP-2, MMP-9), and Wnt/β-catenin pathway-related proteins (Wnt3a, Wnt5a, β-catenin) in breast cancer stem cells were determined by performing Western blot and qRT-PCR analysis. Results: Apatinib decreased the viability and colony numbers of BCSCs in a concentration-dependent manner, and it also reduced sphere numbers, suppressed migration, invasion and lncRNA ROR expression, and induced apoptosis of BCSCs. However, these results were partially reversed by lncRNA ROR overexpression. Apatinib suppressed stem property, EMT process and Wnt/β-catenin pathway in BCSCs, which was partially reversed by lncRNA ROR overexpression. Moreover, lncRNA ROR overexpression increased the colony and sphere numbers, and promoted the cell viability, apoptosis inhibition, migration and invasion of BCSCs, but these effects were partially reversed by iCRT-3. LncRNA ROR overexpression increased the stem property, EMT process and Wnt/β-catenin pathway, which were partially counteracted by iCRT-3. Conclusion: Apatinib inhibited stem property and malignant biological behaviors of BCSCs by blocking Wnt/β-catenin signal pathway through down-regulating lncRNA ROR.

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