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1.
Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition
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Hyunsook An Daeil Sung Tae‐Min Cho Lee Farrand Seojin Jang Jae Hong Seo Ji Young Kim 《International journal of cancer. Journal international du cancer》2018,143(8):1978-1993
Tumor metastasis remains the cause of 90% of cancer‐related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple‐negative breast cancers (TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)‐like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase‐3/‐7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem‐like traits, concomitant with a reduction in the CD24low/CD44high, CD24high/CD49fhigh subpopulation, ALDH1 activity and mammosphere formation. The BCSC‐enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP‐2 and MMP‐9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC‐like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC. 相似文献
2.
Jonas Wolf Dyah Laksmi Dewi Johannes Fredebohm Karin Müller-Decker Christa Flechtenmacher J?rg D Hoheisel Michael Boettcher 《Breast cancer research : BCR》2013,15(6):R109
Introduction
Breast cancer stem cells are suspected to be responsible for tumour recurrence, metastasis formation as well as chemoresistance. Consequently, great efforts have been made to understand the molecular mechanisms underlying cancer stem cell maintenance. In order to study these rare cells in-vitro, they are typically enriched via mammosphere culture. Here we developed a mammosphere-based negative selection shRNAi screening system suitable to analyse the involvement of thousands of genes in the survival of cells with cancer stem cell properties.Methods
We describe a sub-population expressing the stem-like marker CD44+/CD24-/low in SUM149 that were enriched in mammospheres. To identify genes functionally involved in the maintenance of the sub-population with cancer stem cell properties, we targeted over 5000 genes by RNAi and tested their ability to grow as mammospheres. The identified candidate ATG4A was validated in mammosphere and soft agar colony formation assays. Further, we evaluated the influence of ATG4A expression on the sub-population expressing the stem-like marker CD44+/CD24low. Next, the tumorigenic potential of SUM149 after up- or down-regulation of ATG4A was examined by xenograft experiments.Results
Using this method, Jak-STAT as well as cytokine signalling were identified to be involved in mammosphere formation. Furthermore, the autophagy regulator ATG4A was found to be essential for the maintenance of a sub-population with cancer stem cell properties and to regulate breast cancer cell tumourigenicity in vivo.Conclusion
In summary, we present a high-throughput screening system to identify genes involved in cancer stem cell maintenance and demonstrate its utility by means of ATG4A. 相似文献3.
M Murohashi K Hinohara M Kuroda T Isagawa S Tsuji S Kobayashi K Umezawa A Tojo H Aburatani N Gotoh 《British journal of cancer》2010,102(1):206-212
Background:
Tumour-initiating cells (TICs) or cancer stem cells can exist as a small population in malignant tissues. The signalling pathways activated in TICs that contribute to tumourigenesis are not fully understood.Methods:
Several breast cancer cell lines were sorted with CD24 and CD44, known markers for enrichment of breast cancer TICs. Tumourigenesis was analysed using sorted cells and total RNA was subjected to gene expression profiling and gene set enrichment analysis (GSEA).Results:
We showed that several breast cancer cell lines have a small population of CD24−/low/CD44+ cells in which TICs may be enriched, and confirmed the properties of TICs in a xenograft model. GSEA revealed that CD24−/low/CD44+ cell populations are enriched for genes involved in transforming growth factor-β, tumour necrosis factor, and interferon response pathways. Moreover, we found the presence of nuclear factor-κB (NF-κB) activity in CD24−/low/CD44+ cells, which was previously unrecognised. In addition, NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) prevented tumourigenesis of CD24−/low/CD44+ cells in vivo.Conclusion:
Our findings suggest that signalling pathways identified using GSEA help to identify molecular targets and biomarkers for TIC-like cells. 相似文献4.
5.
Panayiotis A. Theodoropoulos Hara Polioudaki Sofia Agelaki Galatea Kallergi Zacharenia Saridaki Dimitris Mavroudis Vassilis Georgoulias 《Cancer letters》2010
The CD44+/CD24−/low and ALDH1+ cell phenotypes are associated with stemness and enhanced tumorigenic potential in breast cancer. We assessed the expression of CD44, CD24 and ALDH1 on tumor cells circulating in the peripheral blood (CTCs) of patients with metastatic breast cancer using triple-marker immunofluorescence microscopy. Among a total of 1439 CTCs identified in 20 (66.7%) out of 30 patients, 35.2% had the stem-like/tumorigenic phenotype CD44+/CD24−/low, whereas 17.7% of the CTCs analyzed in seven patients, were ALDH1high/CD24−/low. In conclusion, we report the existence of a subpopulation of CTCs with putative stem cell progenitor phenotypes in patients with metastatic breast cancer. 相似文献
6.
Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy 总被引:4,自引:0,他引:4
Introduction
The phenotypic and functional differences between cells that initiate human breast tumors (cancer stem cells) and those that comprise the tumor bulk are difficult to study using only primary tumor tissue. We embarked on this study hypothesizing that breast cancer cell lines would contain analogous hierarchical differentiation programs to those found in primary breast tumors.Methods
Eight human breast cell lines (human mammary epithelial cells, and MCF10A, MCF7, SUM149, SUM159, SUM1315 and MDA.MB.231 cells) were analyzed using flow cytometry for CD44, CD24, and epithelial-specific antigen (ESA) expression. Limiting dilution orthotopic injections were used to evaluate tumor initiation, while serial colony-forming unit, reconstitution and tumorsphere assays were performed to assess self-renewal and differentiation. Pulse-chase bromodeoxyuridine (5-bromo-2-deoxyuridine [BrdU]) labeling was used to examine cell cycle and label-retention of cancer stem cells. Cells were treated with paclitaxol and 5-fluorouracil to test selective resistance to chemotherapy, and gene expression profile after chemotherapy were examined.Results
The percentage of CD44+/CD24- cells within cell lines does not correlate with tumorigenicity, but as few as 100 cells can form tumors when sorted for CD44+/CD24-/low/ESA+. Furthermore, CD44+/CD24-/ESA+ cells can self-renew, reconstitute the parental cell line, retain BrdU label, and preferentially survive chemotherapy.Conclusion
These data validate the use of cancer cell lines as models for the development and testing of novel therapeutics aimed at eradicating cancer stem cells. 相似文献7.
G-protein coupled estrogen receptor (GPER) is a transmembrane receptor that mediates non-genomic effects of
estrogen. This study aimed to investigate the role of GPER in the stemness formation and malignancies in triple
negative breast cancer (TNBC) cells. Spheroids of MDA-MB-468 cells were induced by mammosphere culture,
and the proportion of the CD44+
/CD24−/low stem cell subpopulation was detected. Malignant characteristics,
expression of GPER and stemness-related markers, and tumorigenesis in a xenograft assay were compared
between the mammospheres and adherent cultured cells. The impacts of 17β-estradiol (E2) and the GPER-specific
antagonist G15 were studied in in vitro assays. The proportion of the CD44+
/CD24−/low subpopulation was
increased in the mammospheres of MDA-MB-468 cells, which also showed higher expression of GPER and stemness-related markers than adherent cultured cells. The abilities of spherical colonies to proliferate, invade, and
form colonies in soft agar were enhanced. Spherical cells exhibited stronger tumorigenesis ability than adherent
cells in the xenograft assay. E2 treatment enhanced tumorigenicity of both adherent and spherical cells. Spherical
cells treated with E2 had stronger proliferation, invasion, and colony formation abilities than other groups. Pretreatment with G15 effectively blocked the stimulation by E2. In conclusion, the expression of GPER in TNBC
cells is positively related to stemness and malignant features. 相似文献
8.
Mingzhu Huang Yuqing Li Huanle Zhang Feifei Nan 《Journal of experimental & clinical cancer research : CR》2010,29(1):80
Background
Breast cancer stem cells (BCSCs) have been recently identified in breast carcinoma as CD44+CD24- cells, which exclusively retain tumorigenic activity and display stem cell-like properties. Using a mammosphere culture technique, MCF7 mammosphere cells are found to enrich breast cancer stem-like cells expressing CD44+CD24-. The stromal cells are mainly constituted by fibroblasts within a breast carcinoma, yet little is known of the contributions of the stromal cells to BCSCs.Methods
Carcinoma-associated fibroblasts (CAFs) and normal fibroblasts (NFs) were isolated and identified by immunohistochemistry. MCF7 mammosphere cells were co-cultured with different stromal fibroblasts by a transwell cocultured system. Flow cytometry was used to measure CD44 and CD24 expression status on MCF7. ELISA (enzyme-linked immunosorbent assay) was performed to investigate the production of stromal cell-derived factor 1 (SDF-1) in mammosphere cultures subject to various treatments. Mammosphere cells were injected with CAFs and NFs to examine the efficiency of tumorigenity in NOD/SCID mice.Results
CAFs derived from breast cancer patients were found to be positive for α-smooth muscle actin (α-SMA), exhibiting the traits of myofibroblasts. In addition, CAFs played a central role in promoting the proliferation of CD44+CD24- cells through their ability to secrete SDF-1, which may be mediated to SDF-1/CXCR4 signaling. Moreover, the tumorigenicity of mammosphere cells with CAFs significantly increased as compared to that of mammosphere cells alone or with NFs.Conclusion
We for the first time investigated the effects of stromal fibroblasts on CD44+CD24- cells and our findings indicated that breast CAFs contribute to CD44+CD24- cell proliferation through the secretion of SDF-1, and which may be important target for therapeutic approaches. 相似文献9.
Zhi-Jie Hou Xi Luo Wei Zhang Fei Peng Bai Cui Si-Jin Wu Fei-Meng Zheng Jie Xu Ling-Zhi Xu Zi-Jie Long Xue-Ting Wang Guo-Hui Li Xian-Yao Wan Yong-Liang Yang Quentin Liu 《Oncotarget》2015,6(8):6326-6340
Cancer stem-like cell (CS-like cell) is considered to be responsible for recurrence and drug resistance events in breast cancer, which makes it a potential target for novel cancer therapeutic strategy. The FDA approved flubendazole, has been widely used in the treatment of intestinal parasites. Here, we demonstrated a novel effect of flubendazole on breast CS-like cells. Flubendazole inhibited breast cancer cells proliferation in dose- and time-dependent manner and delayed tumor growth in xenograft models by intraperitoneal injection. Importantly, flubendazole reduced CD44high/CD24low subpopulation and suppressed the formation of mammosphere and the expression of self-renewal related genes including c-myc, oct4, sox2, nanog and cyclinD1. Moreover, we found that flubendazole induced cell differentiation and inhibited cell migration. Consistently, flubendazole reduced mesenchymal markers (β-catenin, N-cadherin and Vimentin) expression and induced epithelial and differentiation marker (Keratin 18) expression in breast cancer cells. Mechanism study revealed that flubendazole arrested cell cycle at G2/M phase and induced monopolar spindle formation through inhibiting tubulin polymerization. Furthermore, flubendazole enhanced cytotoxic activity of conventional therapeutic drugs fluorouracil and doxorubicin against breast cancer cells. In conclusion, our findings uncovered a remarkable effect of flubendazole on suppressing breast CS-like cells, indicating a novel utilization of flubendazole in breast cancer therapy. 相似文献
10.
Grinshtein N Datti A Fujitani M Uehling D Prakesch M Isaac M Irwin MS Wrana JL Al-Awar R Kaplan DR 《Cancer research》2011,71(4):1385-1395
Neuroblastoma (NB) is an often fatal pediatric tumor of neural crest origin. We previously isolated NB tumor-initiating cells (NB TIC) from bone marrow metastases that resemble cancer stem cells and form metastatic NB in immunodeficient animals with as few as ten cells. To identify signaling pathways important for the survival and self-renewal of NB TICs and potential therapeutic targets, we screened a small molecule library of 143 protein kinase inhibitors, including 33 in clinical trials. Cytostatic or cytotoxic drugs were identified that targeted PI3K (phosphoinositide 3-kinase)/Akt, PKC (protein kinase C), Aurora, ErbB2, Trk, and Polo-like kinase 1 (PLK1). Treatment with PLK1 siRNA or low nanomolar concentrations of BI 2536 or BI 6727, PLK1 inhibitors in clinical trials for adult malignancies, were cytotoxic to TICs whereas only micromolar concentrations of the inhibitors were cytotoxic for normal pediatric neural stem cells. Furthermore, BI 2536 significantly inhibited TIC tumor growth in a therapeutic xenograft model, both as a single agent and in combination with irinotecan, an active agent for relapsed NB. Our findings identify candidate kinases that regulate TIC growth and survival and suggest that PLK1 inhibitors are an attractive candidate therapy for metastatic NB. 相似文献
11.
Pharmacological inhibition of AKT sensitizes MCF-7 human breast cancer-initiating cells to radiation
Zhan JF Wu LP Chen LH Yuan YW Xie GZ Sun AM Liu Y Chen ZX 《Cellular oncology (Dordrecht)》2011,34(5):451-456
Background
Caner-initiating cells (CICs or cancer stem cells) have been shown both experimentally and clinically to be resistant to radiation. The mechanism underlying radioresistance remains unclear.Methods
In the present study, we screened 51 genes which are potentially important in mediating radioresistance of breast CICs.Results
The expression of AKT1 and AKT2 at protein and mRNA levels was dramatically increased among the screened genes by 8 Gy radiation treatment in MCF-7 mammosphere cells (predominantly CD24–/low/CD44+ CICs), but not in the bulk population of MCF-7 cells (predominantly CD24+/CD44+). Using apoptosis and clonogenic survival assays, we found pharmacological inhibition of AKT with selective inhibitors of AKT sensitized MCF-7 mammosphere cells, but not MCF-7 monolayer cells to radiation.Conclusion
The present findings suggest that treatment with AKT inhibitors prior to ionizing radiation treatment may be a potential benefit to patients with breast cancer, in particular to eradiate breast CICs. 相似文献12.
Victor P Andrade Irina Ostrovnaya Venkatraman E Seshan Mary Morrogh Dilip Giri Narciso Olvera Marina De Brot Monica Morrow Colin B Begg Tari A King 《Breast cancer research : BCR》2012,14(4):1-14
Introduction
Mammary-specific overexpression of Six1 in mice induces tumors that resemble human breast cancer, some having undergone epithelial to mesenchymal transition (EMT) and exhibiting stem/progenitor cell features. Six1 overexpression in human breast cancer cells promotes EMT and metastatic dissemination. We hypothesized that Six1 plays a role in the tumor initiating cell (TIC) population specifically in certain subtypes of breast cancer, and that by understanding its mechanism of action, we could potentially develop new means to target TICs.Methods
We examined gene expression datasets to determine the breast cancer subtypes with Six1 overexpression, and then examined its expression in the CD24low/CD44+ putative TIC population in human luminal breast cancers xenografted through mice and in luminal breast cancer cell lines. Six1 overexpression, or knockdown, was performed in different systems to examine how Six1 levels affect TIC characteristics, using gene expression and flow cytometric analysis, tumorsphere assays, and in vivo TIC assays in immunocompromised and immune-competent mice. We examined the molecular pathways by which Six1 influences TICs using genetic/inhibitor approaches in vitro and in vivo. Finally, we examined the expression of Six1 and phosphorylated extracellular signal-regulated kinase (p-ERK) in human breast cancers.Results
High levels of Six1 are associated with adverse outcomes in luminal breast cancers, particularly the luminal B subtype. Six1 levels are enriched in the CD24low/CD44+ TIC population in human luminal breast cancers xenografted through mice, and in tumorsphere cultures in MCF7 and T47D luminal breast cancer cells. When overexpressed in MCF7 cells, Six1expands the TIC population through activation of transforming growth factor-beta (TGF-β) and mitogen activated protein kinase (MEK)/ERK signaling. Inhibition of ERK signaling in MCF7-Six1 cells with MEK1/2 inhibitors, U0126 and AZD6244, restores the TIC population of luminal breast cancer cells back to that observed in control cells. Administration of AZD6244 dramatically inhibits tumor formation efficiency and metastasis in cells that express high levels of Six1 ectopically or endogenously. Finally, we demonstrate that Six1 significantly correlates with phosphorylated ERK in human breast cancers.Conclusions
Six1 plays an important role in the TIC population in luminal breast cancers and induces a TIC phenotype by enhancing both TGF-β and ERK signaling. MEK1/2 kinase inhibitors are potential candidates for targeting TICs in breast tumors. 相似文献13.
Oihana Iriondo Miriam Rábano Giacomo Domenici Onintza Carlevaris José Antonio López-Ruiz Ignacio Zabalza Edurne Berra Maria dM Vivanco 《Oncotarget》2015,6(31):31721-31739
The heterogeneous nature of breast cancer is a result of intrinsic tumor complexity and also of the tumor microenvironment, which is known to be hypoxic. We found that hypoxia expands different breast stem/progenitor cell populations (cells with increased aldehyde dehydrogenase activity (Aldefluor+), high mammosphere formation capacity and CD44+CD24−/low cells) both in primary normal epithelial and tumor cells. The presence of the estrogen receptor (ER) limits hypoxia-dependent CD44+CD24−/low cell expansion. We further show that the hypoxia-driven cancer stem-like cell enrichment results from a dedifferentiation process. The enhanced mammosphere formation and Aldefluor+ cell content observed in breast cancer cells relies on hypoxia-inducible factor 1α (HIF1α). In contrast, the CD44+CD24−/low population expansion is HIF1α independent and requires prolyl hydroxylase 3 (PHD3) downregulation, which mimics hypoxic conditions, leading to reduced CD24 expression through activation of NFkB signaling. These studies show that hypoxic conditions expand CSC populations through distinct molecular mechanisms. Thus, potential therapies that combine current treatments for breast cancer with drugs that target CSC should take into account the heterogeneity of the CSC subpopulations. 相似文献
14.
Omar M Rahal Lei Nie Li-Chuan Chan Chia-Wei Li Yi-Hsin Hsu Jennifer Hsu Dihua Yu Mien-Chie Hung 《American journal of cancer research》2015,5(12):3624-3634
Our previous study showed that specifically delivering BikDD, a constitutive active mutant of pro-apoptotic protein Bik, to breast cancer cell xenografts in immunocompromised mice has a potent activity against tumor initiating cells (TICs), and that the combination between tyrosine kinase inhibitors (TKI) and BikDD gene therapy yielded synergistic effect on EGFR and HER2 positive breast cancer cells in immunodeficient nude mice. Those encouraging results have allowed us to propose a clinical trial using the liposome-complexing plasmid DNA expressing BikDD gene which has been approved by the NIH RAC Advisory committee. However, it is imperative to test whether systemic delivery of BikDD-expressing plasmid DNAs with liposomes into immunocompetent mice has therapeutic efficacy and tolerable side effects as what we observed in the nude mice model. In this study, we investigated the effects of BikDD gene-therapy on the primary mammary tumors, especially on tumor initiating cells (TICs), of a genetically engineered immunocompetent mouse harboring normal microenvironment and immune response. The effects on TIC population in tumors were determined by FACS analysis with different sets of murine specific TIC markers, CD49fhighCD61high and CD24+Jagged1-. First we showed in vitro that ectopic expression of BikDD in murine N202 cells derived from MMTV-HER2/Neu transgenic mouse tumors induced apoptosis and decreased the number of TICs. Consistently, systemic delivery of VISA-Claudin4-BikDD by liposome complexes significantly inhibited mammary tumor growth and slowed down residual tumor growth post cessation of therapy in MMTV-HER2/Neu transgenic mice compared to the controls. In addition, the anti-tumor effects of BikDD in vivo were consistent with decreased TIC population assessed by FACS analysis and in vitro tumorsphere formation assay of freshly isolated tumor cells. Importantly, systemic administration of BikDD did not cause significant cytotoxic response in standard toxicity assays or body weight changes. Taken together, our findings validated that selective expression of BikDD in the primary mammary tumors in immunocompetent hosts significantly reduced tumor burden and inhibited the residual tumor growth at off-therapy stage by eliminating TICs. Hence, the VISA-Claudin4-BikDD-mediated gene therapy is worthy of further investigation in breast cancer clinical trials. 相似文献
15.
SHON,a novel secreted protein,regulates epithelial–mesenchymal transition through transforming growth factor‐β signaling in human breast cancer cells
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Na Zhang Qian Liang Jingxin Feng Min Yao Jiwei Liu Xiaoxue Li Yu Zhang Jun Lu Baiqu Huang 《International journal of cancer. Journal international du cancer》2015,136(6):1285-1295
The epithelial–mesenchymal transition (EMT) is one of the main mechanisms contributing to the onset of cancer metastasis, and has proven to be associated with breast cancer progression. SHON is a novel secreted hominoid‐specific protein we have previously identified; it is specifically expressed in all human cancer cell lines tested and is oncogenic for human mammary carcinoma cells. Here, we show that ectopic overexpression of SHON in immortalized human mammary epithelial cells is sufficient for cells to acquire the mesenchymal traits, as well as the enhanced cell migration and invasion, along with the epithelial stem cell properties characterized by increased CD44high/CD24low subpopulation and mammosphere‐forming ability. Moreover, we demonstrate that SHON positively activates the autocrine transforming growth factor‐β (TGF‐β) pathway to contribute to EMT, while SHON itself is induced by TGF‐β in mammary epithelial cells. These data are in favor of a SHON‐TGFβ‐SHON‐positive feedback loop that regulates EMT program in breast cancer progression. Finally, examination of the human clinic breast cancer specimens reveals that tumor cells may extracellularly release SHON protein to promote the cancerization of surrounding cells. Together, our findings define an important function of SHON in regulation of EMT via TGF‐β signaling, which is closely associated with the invasive subtypes of human breast cancer. 相似文献
16.
Christin Lund-Andersen Sebastian PatzkeViola Nähse-Kumpf Randi G. Syljuåsen 《Radiotherapy and oncology》2014
Background and purpose
PLK1-inhibitors are emerging as new potential anticancer agents. It is therefore important to explore the combined effects of PLK1-inhibitors with conventional therapies. Based on the functional roles of PLK1 in both mitosis and the G2 checkpoint, we hypothesized that the treatment schedule might influence the combined effects of PLK1-inhibiton and radiation.Materials and methods
Human osteosarcoma U2OS and colorectal cancer HT29 and SW620 cells were treated with the PLK1-inhibitor BI2536 before or after X-ray irradiation (0–6 Gy). Clonogenic assays, flow cytometry, immunofluorescence and mCherry-53BP1 time-lapse imaging were used to assay cell survival, cell cycle progression and DNA damage repair.Results
Treatment with the PLK1-inhibitor for 24 h before radiation caused cells to accumulate in G2/M and resulted in increased radiosensitivity. In contrast, the cytotoxic effects of the two treatments were less-than-additive when cells were treated with the PLK1-inhibitor for 24 h after radiation. This resistance was associated with a prolonged G2 checkpoint causing enhanced repair of the radiation-induced damage and decreased BI2536-mediated mitotic damage.Conclusions
PLK1-inhibitors need to be administrated several hours before radiation to achieve radiosensitization. If PLK1-inhibitors are given after radiation, cell killing is reduced due to the prolonged G2 checkpoint. 相似文献17.
Jenny E Chu Ying Xia Benjamin Chin-Yee David Goodale Alysha K Croker Alison L Allan 《Neoplasia (New York, N.Y.)》2014,16(2):180-191
Breast cancer preferentially metastasizes to lung, lymph node, liver, bone, and brain. However, it is unclear whether properties of cancer cells, properties of organ microenvironments, or a combination of both is responsible for this observed organ tropism. We hypothesized that breast cancer cells exhibit distinctive migration/growth patterns in organ microenvironments that mirror common clinical sites of breast cancer metastasis and that receptor-ligand interactions between breast cancer cells and soluble organ-derived factors mediate this behavior. Using an ex vivo model system composed of organ-conditioned media (CM), human breast cancer cells (MDA-MB-231, MDA-MB-468, SUM149, and SUM159) displayed cell line-specific and organ-specific patterns of migration/proliferation that corresponded to their in vivo metastatic behavior. Notably, exposure to lung-CM increased migration of all cell lines and increased proliferation in two of four lines (P < .05). Several cluster of differentiation (CD) 44 ligands including osteopontin (OPN) and L-selectin (SELL) were identified in lung-CM by protein arrays. Immunodepletion of SELL decreased migration of MDA-MB-231 cells, whereas depletion of OPN decreased both migration and proliferation. Pretreatment of cells with a CD44-blocking antibody abrogated migration effects (P < .05). “Stemlike” breast cancer cells with high aldehyde dehydrogenase and CD44 (ALDHhiCD44+) responded in a distinct chemotactic manner toward organ-CM, preferentially migrating toward lung-CM through CD44 receptor-ligand interactions (P < .05). In contrast, organ-specific changes in migration were not observed for ALDHlowCD44- cells. Our data suggest that interactions between CD44+ breast cancer cells and soluble factors present in the lung microenvironment may play an important role in determining organotropic metastatic behavior. 相似文献
18.
Yu-Chao Chang Chia-Ing Jan Chih-Yu Peng Yu-Chi Lai Fang-Wei Hu Cheng-Chia Yu 《Oncotarget》2015,6(27):24002-24016
Tumor initiating cells (TICs) possessing cancer stemness were shown to be enriched after therapy, resulting in the relapse and metastasis of head and neck squamous cell carcinomas (HNC). An effective therapeutic approach suppressing the HNC-TICs would be a potential method to improve the treatments for HNC. We observed that the treatment of silibinin (SB) dose dependently down-regulated the ALDH1 activity, CD133 positivity, stemness signatures expression, self-renewal property, and chemoresistance in ALDH1+CD44+ HNC-TICs. Using miRNA-microarray and mechanistic studies, SB increased the expression of microRNA-494 (miR-494) and both Bmi1 and ADAM10 were identified as the novel targets of miR-494. Moreover, overexpression of miR-494 results in a reduction in cancer stemness. However, knockdown of miR-494 in CD44−ALDH1−non-HNC-TICs enhanced cancer stemness and oncogenicity, while co-knockdown of Bmi1 and ADAM10 effectively reversed these phenomena. Mice model showed that SB treatment by oral gavage to xenograft tumors reduced tumor growth and prolonged the survival time of tumor-bearing mice by activation of miR-494-inhibiting Bmi1/ADAM10 expression. Survival analysis indicated that a miR494highBmi1lowADAM10low phenotype predicted a favourable clinical outcome. We conclude that the inhibition of tumor aggressiveness in HNC-TICs by SB was mediated by up-regulation miR-494, suggesting that SB would be a valuable anti-cancer drug for treatment of HNC. 相似文献
19.
Wen-Wei Chang Ruey-Jen Lin John Yu Wen-Ying Chang Chiung-Hui Fu Alan Chuan-Ying Lai Jyh-Cherng Yu Alice L Yu 《Breast cancer research : BCR》2013,15(3):R39