scholarly journals Increased Cellular Levels of MicroRNA-9 and MicroRNA-221 Correlate with Cancer Stemness and Predict Poor Outcome in Human Breast Cancer

2018 ◽  
Vol 48 (5) ◽  
pp. 2205-2218 ◽  
Author(s):  
Chun-Wen Cheng ◽  
Jyh-Cherng Yu ◽  
Yi-Hsien Hsieh ◽  
Wen-Ling Liao ◽  
Jia-Ching Shieh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Side Population ◽  
Migration And Invasion ◽  
Cell Renewal ◽  
Poor Outcome

Background /Aims: Recent studies of microRNA (miRNA) involvement in tumorigenesis have indicated the critical role of these non-coding small RNAs in malignant transformation, but the prognostic role, if any, of miRNAs in breast cancer remains undetermined. Therefore, we assessed the prognostic significance of microRNA-9 (miR-9) and miR-221 in breast cancer toward the goal of understanding the contribution(s) of these miRNAs to cancer cell stemness. Methods: The level of each of miR-9 and miR-221 in 206 paired laser capture microdissected tumor cells and non-tumor cells was determined by quantitative reverse transcription-PCR (qRT-PCR). The relationship between the miRNA signature and clinicopathological data and prognosis of breast cancer was assessed. Identification of a stem cell-enriched side population was achieved with fluorescence-activated cell sorting and a sphere-forming assay. Wound healing, Boyden chamber assays, and western blotting were used to study the contribution of each miRNA to tumor cell migration and invasion. Results: We found that induction of miR-9 and miR-221 mimics conferred side-population cells to form spheroidal tumor colonies in suspension culture that maintained the mesenchymal stem-cell potential in non-invasive MCF-7 breast cancer cells. In contrast, knockdown of both miR-9 and miR-221 in invasive MDA-MB-231 breast cancer cells dramatically decreased the number of side-population colonies with stem cell-like potency, which reduced the capacity for tumor-cell renewal, invasion, and migration. Clinically, the mean proportion of miR-9- or miR-221-overexpressing cells was significantly greater in tumor cells compared with non-tumor cells (P < 0.05). Increased levels of miR-9 and miR-221 in breast tissue portended a significantly elevated risk of progression to malignancy with respect to larger tumor size, poor differentiation, late-stage evolution, lymph-node metastasis (P < 0.05), and lower overall survival (Ptrend = 0.017; eight-year follow-up). Conclusion: Our findings provide strong evidence that miR-9 and miR-221 can enhance the generation of cancer stem cells to yield an invasive phenotype and that overexpression of these miRNAs predicts a poor outcome for breast cancer patients.

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 Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 35
Author(s):  
Masanobu Tsubaki ◽  
Shuuji Genno ◽  
Tomoya Takeda ◽  
Takuya Matsuda ◽  
Naoto Kimura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Rho Gtpases ◽  
Breast Cancer Cells ◽  
Distant Metastases ◽  
Migration And Invasion ◽  
Tumor Cell Adhesion ◽  
Mechanism Of Inhibition

The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear whether rhosin, a Rho inhibitor, acts by suppressing metastasis by a downstream inhibition of Rho. In this study, we investigated this mechanism of metastasis in highly metastatic melanoma and breast cancer cells, and the mechanism of inhibition of metastasis by rhosin. We found that rhosin suppressed the RhoA and RhoC activation, the nuclear localization of YAP, but did not affect ERK1/2, Akt, or NF-κB activation in the highly metastatic cell lines B16BL6 and 4T1. High expression of YAP was associated with poor overall and recurrence-free survival in patients with breast cancer or melanoma. Treatment with rhosin inhibited lung metastasis in vivo. Moreover, rhosin inhibited tumor cell adhesion to the extracellular matrix via suppression of RHAMM expression, and inhibited SDF-1-induced cell migration and invasion by decreasing CXCR4 expression in B16BL6 and 4T1 cells. These results suggest that the inhibition of RhoA/C-YAP pathway by rhosin could be an extremely useful therapeutic approach in patients with melanoma and breast cancer.

scholarly journals miR205 inhibits stem cell renewal in SUM159PT breast cancer cells

PLoS ONE ◽  
2017 ◽  
Vol 12 (11) ◽  
pp. e0188637 ◽  
Author(s):  
Víctor Mayoral-Varo ◽  
Annarica Calcabrini ◽  
María Pilar Sánchez-Bailón ◽  
Jorge Martín-Pérez
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Renewal ◽  
Stem Cell Renewal

Interactions of breast cancer cells with the microenvironment of the human bone marrow

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22097-e22097
Author(s):  
T. Kaiser ◽  
G. Klein ◽  
E. Solomayer ◽  
D. Wallwiener ◽  
T. Fehm
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Breast Cancer Cells ◽  
Migration Assays

e22097 Background: Bone is one of the most favored sites for metastasis of breast cancer cells (BrCa) resulting in the formation of osteolytic and/or osteoblastic lesions. There is increasing evidence that the bone marrow (BM) microenvironment plays a pivotal role in modulating tumor cell homing to the bone, metastasis and progression. However, the molecular crosstalk between BrCa cells and the cellular and extracellular components of the bone marrow leading to osteotropism still remains a poorly characterized step in the metastatic process. Methods: Cell adhesion and migration assays using the invasive MDA-MB-231 and the noninvasive MCF7 BrCa cell lines were performed to investigate the impact of BM components on cellular functions of tumor cells. Results: Cell-matrix adhesion assays showed a strong and concentration-dependent attachment of BrCa cells to several extracellular matrix components present in the human bone marrow such as fibronectin, different laminin isoforms, collagens type I and IV or tenascin-C. Moreover, the BrCa cells attached avidly to the BM-derived primary osteoblasts, whereas the binding to stromal cells was significantly weaker. Notably, cell-cell adhesion experiments with primary osteoclasts revealed an anti-adhesive effect on tumor cell binding leading to no attachment activity of BrCa cells with the cell surface of primary osteoclasts. The influence of cellular components of the BM on tumor cell migration was analyzed by cell migration assays using conditioned media of osteoblasts, osteoclasts and stromal cells or a modified Transwell chamber technique. The migration assays with invasive MDA-MB-231 cells clearly showed that osteoblasts, but not osteoclasts or stromal cells released factors which led to a faster wound closure, suggesting an enhanced migratory ability of the metastatic tumor cells, whereas the migration of nonmetastatic MCF7 cells was unaffected. Conclusions: These data indicate that the crosstalk with osteoblasts affects both the adhesive and the migratory ability of BrCa cells favoring the bone colonization process. Furthermore, the presented experimental conditions may provide useful tools to study effects of antiresorptive drugs like bisphosphonates to improve therapeutic strategies for treatment metastatic bone disease. No significant financial relationships to disclose.

scholarly journals ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Tetsuro Masuda ◽  
Motoyoshi Endo ◽  
Yutaka Yamamoto ◽  
Haruki Odagiri ◽  
Tsuyoshi Kadomatsu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Cxcr4 Expression ◽  
Breast Cancer Patients

Abstract Bone metastasis of breast cancer cells is a major concern, as it causes increased morbidity and mortality in patients. Bone tissue-derived CXCL12 preferentially recruits breast cancer cells expressing CXCR4 to bone metastatic sites. Thus, understanding how CXCR4 expression is regulated in breast cancer cells could suggest approaches to decrease bone metastasis of breast tumor cells. Here, we show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) increases responsiveness of breast cancer cells to CXCL12 by promoting up-regulation of CXCR4 in those cells. In addition, we used a xenograft mouse model established by intracardiac injection of tumor cells to show that ANGPTL2 knockdown in breast cancer cells attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression in those cells, thereby decreasing bone metastasis. Finally, we found that ANGPTL2 and CXCR4 expression levels within primary tumor tissues from breast cancer patients are positively correlated. We conclude that tumor cell-derived ANGPTL2 may increase bone metastasis by enhancing breast tumor cell responsiveness to CXCL12 signaling through up-regulation of tumor cell CXCR4 expression. These findings may suggest novel therapeutic approaches to treat metastatic breast cancer.

scholarly journals Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derived Galectin-3

Blood ◽  
2020 ◽  
Author(s):  
Elmina Mammadova-Bach ◽  
Jesus Gil-Pulido ◽  
Edita Sarukhanyan ◽  
Philipp Burkard ◽  
Sergey Shityakov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Platelet Adhesion ◽  
Platelet Glycoprotein ◽  
Glycoprotein Vi ◽  
Galectin 3

Increasing evidence suggests that platelets play a predominant role in colon and breast cancer metastasis but the underlying molecular mechanisms remain elusive. Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin that triggers platelet activation through immunoreceptor tyrosine-based activation motif (ITAM)-signaling and thereby regulates diverse functions including platelet adhesion, aggregation and procoagulant activity. GPVI has been proposed as a safe antithrombotic target as its inhibition is protective in models of arterial thrombosis with only minor effects on hemostasis. Here, we demonstrate that genetic deficiency of platelet GPVI in mice decreases experimental and spontaneous metastasis of colon and breast cancer cells. Similar results were obtained with mice lacking the spleen-tyrosine kinase Syk in platelets, an essential component of the ITAM-signaling cascade. In vitro and in vivo analyses show that mouse, as well as human GPVI, supports platelet adhesion to colon and breast cancer cells. Using a CRISPR/Cas9-based gene knock-out approach, we identified Galectin-3 as the major counter-receptor of GPVI on tumor cells. In vivo studies demonstrated that the interplay between platelet GPVI and tumor cell-expressed Galectin-3 utilizes ITAM-signaling components in platelets and favors the extravasation of tumor cells. Finally, we showed that JAQ1 F(ab)2-mediated inhibition of GPVI efficiently impairs platelet-tumor cell interaction and tumor metastasis. Our study reveals a new mechanism by which platelets promote the metastasis of colon and breast cancer cells and suggests that GPVI represents a promising target for antimetastatic therapies.

scholarly journals The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling

2021 ◽  
Vol 22 (2) ◽  
pp. 849
Author(s):  
Na Zhang ◽  
Jiafei Ji ◽  
Dandan Zhou ◽  
Xuan Liu ◽  
Xinglin Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Tumor Recurrence ◽  
Breast Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Culture Model

Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial–mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy.

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