scholarly journals Spontaneous fusion of MSC with breast cancer cells can generate tumor dormancy

2021 ◽  
Author(s):  
Catharina Melzer ◽  
Juliane von der Ohe ◽  
Tianjiao Luo ◽  
Ralf Hass
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Fusion ◽  
Cancer Cell ◽  
Tumor Heterogeneity ◽  
Breast Cancer Cells ◽  
Tumor Development ◽  
Cell Populations ◽  
Hybrid Cells

Abstract Background: A variety of different tumors including breast cancer cells can closely interact with mesenchymal stroma/stem-like cells (MSC) in the tumor microenvironment eventually resulting in cell fusion and formation of new hybrid cancer cell populations displaying altered properties. Methods: Lentiviral-transduced MDA-MB-231 cherry breast cancer cells and MSC GFP were co-cultured and a resulting hybrid cancer cell population (MDA-MSC-hyb5) was isolated. Characterization was performed for marker expression and short tandem repeat (STR) fragment analysis compared to the parental cells. Moreover, in vivo tumor development and metastatic capacity of MDA-MSC-hyb5 was studied and unique properties were analyzed by RNA microarray expression analyses compared to other breast cancer hybrid populations. Potential chemotherapeutic sensitivity was carried out in tumor explant cultures of MDA-MSC-hyb5 cells. Results: Direct cellular interactions of MDA-MB-231 cherry breast cancer cells with human MSC GFP in a co-culture model resulted in spontaneous cell fusion by generation of MDA-MSC-hyb5 cherry GFP breast cancer hybrid cells. Proliferative capacity of MDA-MSC-hyb5 cells was about 1.8-fold enhanced when compared to the parental MDA-MB-231 cherry breast cancer cells. In contrast to a spontaneous MDA-MB-231 cherry -induced tumor development in vivo within 18.8 days MDA-MSC-hyb5 cells initially remained quiescent in a dormancy-like state. At distinct time points up to about a half year later after injection NODscid mice started to develop MDA-MSC-hyb5 cell-induced tumors. Following tumor initiation, formation of metastases in various different organs occurred rapidly within about 10.5 days. Changes in gene expression levels were evaluated by RNA-microarray analysis and revealed certain increase in dormancy-associated transcripts in MDA-MSC-hyb5. Chemotherapeutic responsiveness of MDA-MSC-hyb5 cells was partially enhanced as compared to MDA-MB-231 cells, however, some resistance e.g. for taxol was detectable in cancer hybrid cells. Moreover, drug response partially changed during tumor development of MDA-MSC-hyb5 cells suggesting unstable in vivo phenotypes of MDA-hyb5 cells with increased tumor heterogeneity. Conclusions: The spontaneous formation of cancer hybrid cell populations like MDA-MSC-hyb5 by cell fusion contributes to tumorigenic diversification by acquisition of new properties such as altered chemotherapeutic responsiveness. The unique tumor dormancy of MDA-MSC-hyb5 cells not observed in other breast cancer hybrid cells so far markedly increases tumor heterogeneity.

scholarly journals Spontaneous Fusion of MSC with Breast Cancer Cells Can Generate Tumor Dormancy

2021 ◽  
Vol 22 (11) ◽  
pp. 5930
Author(s):  
Catharina Melzer ◽  
Juliane von der Ohe ◽  
Tianjiao Luo ◽  
Ralf Hass
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Development ◽  
Cellular Interactions ◽  
Hybrid Cells ◽  
Induced Tumors ◽  
Culture Model ◽  
Gene Expression Levels

Direct cellular interactions of MDA-MB-231cherry breast cancer cells with GFP-transduced human mesenchymal stroma/stem-like cells (MSCGFP) in a co-culture model resulted in spontaneous cell fusion by the generation of MDA-MSC-hyb5cherry GFP breast cancer hybrid cells. The proliferative capacity of MDA-MSC-hyb5 cells was enhanced about 1.8-fold when compared to the parental MDA-MB-231cherry breast cancer cells. In contrast to a spontaneous MDA-MB-231cherry induced tumor development in vivo within 18.8 days, the MDA-MSC-hyb5 cells initially remained quiescent in a dormancy-like state. At distinct time points after injection, NODscid mice started to develop MDA-MSC-hyb5 cell-induced tumors up to about a half year later. Following tumor initiation, however, tumor growth and formation of metastases in various different organs occurred rapidly within about 10.5 days. Changes in gene expression levels were evaluated by RNA-microarray analysis and revealed certain increase in dormancy-associated transcripts in MDA-MSC-hyb5. Chemotherapeutic responsiveness of MDA-MSC-hyb5 cells was partially enhanced when compared to MDA-MB-231 cells. However, some resistance, e.g., for taxol was detectable in cancer hybrid cells. Moreover, drug response partially changed during the tumor development of MDA-MSC-hyb5 cells; this suggests the presence of unstable in vivo phenotypes of MDA-hyb5 cells with increased tumor heterogeneity.

scholarly journals In Vivo Cell Fusion between Mesenchymal Stroma/Stem-Like Cells and Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 185 ◽  
Author(s):  
Catharina Melzer ◽  
Juliane von der Ohe ◽  
Ralf Hass
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Fusion ◽  
Breast Cancer Cells ◽  
Rare Event ◽  
Tumor Formation ◽  
Hybrid Cells ◽  
Mesenchymal Stroma

Cellular communication within the tumor microenvironment enables important interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem-like cells (MSC). These interactions were monitored in vivo following co-injection of GFP-labeled human MSC together with mcherry-labeled MDA-MB-231 breast cancer cells in NODscid mice. Within 14 days of tumor development the number of initially co-injected MSC had significantly declined and spontaneous formation of breast cancer/MSC hybrid cells was observed by the appearance of double fluorescing cells. This in vivo fusion displayed a rare event and occurred in less than 0.5% of the tumor cell population. Similar findings were observed in a parallel in vitro co-culture. Characterization of the new cell fusion products obtained after two consecutive flow cytometry cell sorting and single cell cloning revealed two populations, termed MDA-hyb3 and MDA-hyb4. The breast cancer fusion cells expressed both, GFP and mcherry and displayed more characteristics of the MDA-MB-231 cells than of the parental MSC. While little if any differences were determined in the proliferative capacity, a significant delay of MDA-hyb3 cells in tumor formation was observed when compared to the parental MDA-MB-231 cells. Moreover, MDA-hyb3 cells developed an altered pattern of distant organ metastases. These findings demonstrated dynamic tumor changes by in vivo and in vitro fusion with the development of new breast cancer hybrid cells carrying altered tumorigenic properties. Consequently, cancer cell fusion contributes to progressively increasing tumor heterogeneity which complicates a therapeutic regimen.

scholarly journals Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1366
Author(s):  
Russell Hughes ◽  
Xinyue Chen ◽  
Natasha Cowley ◽  
Penelope D. Ottewell ◽  
Rhoda J. Hawkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Accessory Cell ◽  
Cancer Cell Survival

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

scholarly journals Matrix Metalloproteinase 8 (Collagenase 2) Induces the Expression of Interleukins 6 and 8 in Breast Cancer Cells

2013 ◽  
Vol 288 (23) ◽  
pp. 16282-16294 ◽  
Author(s):  
Sally Thirkettle ◽  
Julie Decock ◽  
Hugh Arnold ◽  
Caroline J. Pennington ◽  
Diane M. Jaworski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinase ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines

Matrix metalloproteinase 8 (MMP-8) is a tumor-suppressive protease that cleaves numerous substrates, including matrix proteins and chemokines. In particular, MMP-8 proteolytically activates IL-8 and, thereby, regulates neutrophil chemotaxis in vivo. We explored the effects of expression of either a WT or catalytically inactive (E198A) mutant version of MMP-8 in human breast cancer cell lines. Analysis of serum-free conditioned media from three breast cancer cell lines (MCF-7, SK-BR-3, and MDA-MB-231) expressing WT MMP-8 revealed elevated levels of IL-6 and IL-8. This increase was mirrored at the mRNA level and was dependent on MMP-8 catalytic activity. However, sustained expression of WT MMP-8 by breast cancer cells was non-permissive for long-term growth, as shown by reduced colony formation compared with cells expressing either control vector or E198A mutant MMP-8. In long-term culture of transfected MDA-MB-231 cells, expression of WT but not E198A mutant MMP-8 was lost, with IL-6 and IL-8 levels returning to base line. Rare clonal isolates of MDA-MB-231 cells expressing WT MMP-8 were generated, and these showed constitutively high levels of IL-6 and IL-8, although production of the interleukins was no longer dependent upon MMP-8 activity. These studies support a causal connection between MMP-8 activity and the IL-6/IL-8 network, with an acute response to MMP-8 involving induction of the proinflammatory mediators, which may in part serve to compensate for the deleterious effects of MMP-8 on breast cancer cell growth. This axis may be relevant to the recognized ability of MMP-8 to orchestrate the innate immune system in inflammation in vivo.

scholarly journals PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner

2018 ◽  
Vol 50 (6) ◽  
pp. 2108-2123 ◽  
Author(s):  
Ruifang Gao ◽  
Yanhua Liu ◽  
Dan Li ◽  
Jing Xun ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Tumor Metastasis ◽  
Dependent Manner ◽  
Fructose 2

Background/Aims: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells. Methods: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT-PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively. Results: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling. Conclusion: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer.

scholarly journals Breast cancer cell-derived extracellular vesicles transfer miR-182-5p and promote breast carcinogenesis via the CMTM7/EGFR/AKT axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Chong Lu ◽  
Yu Zhao ◽  
Jing Wang ◽  
Wei Shi ◽  
Fang Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Akt Signaling ◽  
Cancer Tissues

Abstract Background Extracellular vesicles (EVs) derived from tumor cells are implicated in the progression of malignancies through the transfer of molecular cargo microRNAs (miRNAs or miRs). We aimed to explore the role of EVs derived from breast cancer cells carrying miR-182-5p in the occurrence and development of breast cancer. Methods Differentially expressed miRNAs and their downstream target genes related to breast cancer were screened through GEO and TCGA databases. miR-182-5p expression was examined in cancer tissues and adjacent normal tissues from patients with breast cancer. EVs were isolated from breast cancer cell line MDA-MB-231 cells and identified. The gain- and loss-of function approaches of miR-182-5p and CKLF-like MARVEL transmembrane domain-containing 7 (CMTM7) were performed in MDA-MB-231 cells and the isolated EVs. Human umbilical vein endothelial cells (HUVECs) were subjected to co-culture with MDA-MB-231 cell-derived EVs and biological behaviors were detected by CCK-8 assay, flow cytometry, immunohistochemical staining, Transwell assay and vessel-like tube formation in vitro. A xenograft mouse model in nude mice was established to observe the tumorigenesis and metastasis of breast cancer cells in vivo. Results miR-182-5p was highly expressed in breast cancer tissues and cells, and this high expression was associated with poor prognosis of breast cancer patients. miR-182-5p overexpression was shown to promote tumor angiogenesis in breast cancer. Moreover, our data indicated that miR-182-5p was highly enriched in EVs from MDA-MD-231 cells and then ultimately enhanced the proliferation, migration, and angiogenesis of HUVECs in vitro and in vivo. Moreover, we found that CMTM7 is a target of miR-182-5p. EVs-miR-182-5p promotes tumorigenesis and metastasis of breast cancer cells by regulating the CMTM7/EGFR/AKT signaling axis. Conclusions Taken altogether, our findings demonstrates that EVs secreted by breast cancer cells could carry miR-182-5p to aggravate breast cancer through downregulating CMTM7 expression and activating the EGFR/AKT signaling pathway.

Abstract 246: Translocation Of Myomirs Via Gap Junction Channels Prevents Cancer Cell Growth

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Laura Graciotti ◽  
Toru Hosoda ◽  
Marcello Rota ◽  
Giulia Borghetti ◽  
Sergio Signore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gap Junctions ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Fold Increase ◽  
Tumor Formation

The adult heart is resistant to cancer formation and the metastatic invasion of distant neoplasms. This biological advantage may be dictated by the molecular properties of myocytes that constitutes 90% of the myocardium. We raised the possibility that microRNAs (miRs) highly expressed in myocytes (myomirs) may translocate via gap junctions to neighboring cancer cells, preventing their growth or inhibiting their survival. First, we established whether overexpression of myomirs interferes with the proliferation and death of MCF7 human breast cancer cells. Infection of MCF7 with lentiviruses carrying miR-1, miR-133a and miR-499 (miR-MCF7) resulted in a 5-fold decrease in Ki67 labeling and a 20% increase in the fraction of cells arrested at G0/G1. In contrast, TdT-positive apoptotic cells averaged 0.5% and did not differ in miR-MCF7 and control cells. To mimic the in vivo condition, EGFP-labeled MCF7 were co-cultured with myocytes and, 4 days later, the expression of myomirs was measured in FACS-sorted MCF7. With respect to baseline, co-cultured MCF7 showed 100-fold, 16-fold, and 27-fold increase in the expression of miR-1, miR-133a and miR-499, respectively. Co-culture of myocytes and MCF7 led to the formation of gap junctions made of connexin 43 (Cx43) and connexin 45 (Cx45). Silencing of Cx43 and Cx45 decreased significantly the expression of myomirs in co-cultured MCF7. Importantly, proximity of MCF7 to myocytes reduced markedly the growth rate of the cancer cells. Subsequently, 1 x 106 MCF7 or miR-MCF7 were injected subcutaneously in NOD-scid mice. At 5 weeks, the tumors developed from miR-MCF7 were 70% smaller than those originated from control MCF7. Two doses of breast cancer cells were injected intramyocardially to establish their in situ tumorigenic effects. Tumor formation was found in all hearts that received 1 x 106 MCF7. Conversely, mice injected with 1 x 105 cells did not show macroscopic evidence of neoplastic lesions. The lack of tumor development in the latter case is consistent with the ability of the heart to prevent neoplasm development when cancer cell colonization is not massive. Our findings document that miR-1, miR-133a and miR-499 translocate from myocytes to cancer cells via gap junctions, inhibiting tumor growth in vitro and in vivo.

scholarly journals Knockdown of Rab7a suppresses the proliferation, migration, and xenograft tumor growth of breast cancer cells

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Jiming Xie ◽  
Yan Yan ◽  
Fang Liu ◽  
Hongbin Kang ◽  
Fengying Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Colony Formation ◽  
Breast Cancer Cells ◽  
Tumor Development ◽  
Xenograft Tumor ◽  
Cycle Arrest ◽  
G2 Cell Cycle Arrest ◽  
Cancer Tissues

Abstract Breast cancer is a common invasive cancer in women. Ras-related protein Rab-7a (Rab7a) is involved in late endocytic trafficking, while its role in breast cancer is largely unclear. In the present study, we investigated the role of Rab7a in breast cancer. Comparing with adjacent breast tissues, Rab7a expression was increased in breast cancer tissues. Using lentivirus-mediated knockdown strategy, we found that Rab7a silencing inhibited the proliferation and colony formation of MDA-MB-231 cells. Apoptosis and G2 cell cycle arrest were induced in Rab7a knockdown. By contrast, Rab7a suppressed the apoptosis and promoted proliferation and colony formation of MCF-7 cells. The migration of MDA-MB-231 cells was suppressed by Rab7a knockdown. In vivo, depletion of Rab7a inhibited the xenograft tumor development of MDA-MB-231 cells. Altogether, our results highlight the novel function of Rab7a in the proliferation, invasion, and xenograft tumor development of breast cancer cells.

scholarly journals Anillin regulates breast cancer cell migration, growth, and metastasis by non-canonical mechanisms involving control of cell stemness and differentiation

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Dongdong Wang ◽  
Nayden G. Naydenov ◽  
Mikhail G. Dozmorov ◽  
Jennifer E. Koblinski ◽  
Andrei I. Ivanov
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Tumor Growth And Metastasis

Abstract Background Breast cancer metastasis is driven by a profound remodeling of the cytoskeleton that enables efficient cell migration and invasion. Anillin is a unique scaffolding protein regulating major cytoskeletal structures, such as actin filaments, microtubules, and septin polymers. It is markedly overexpressed in breast cancer, and high anillin expression is associated with poor prognosis. The aim of this study was to investigate the role of anillin in breast cancer cell migration, growth, and metastasis. Methods CRISPR/Cas9 technology was used to deplete anillin in highly metastatic MDA-MB-231 and BT549 cells and to overexpress it in poorly invasive MCF10AneoT cells. The effects of anillin depletion and overexpression on breast cancer cell motility in vitro were examined by wound healing and Matrigel invasion assays. Assembly of the actin cytoskeleton and matrix adhesion were evaluated by immunofluorescence labeling and confocal microscopy. In vitro tumor development was monitored by soft agar growth assays, whereas cancer stem cells were examined using a mammosphere formation assay and flow cytometry. The effects of anillin knockout on tumor growth and metastasis in vivo were determined by injecting control and anillin-depleted breast cancer cells into NSG mice. Results Loss-of-function and gain-of-function studies demonstrated that anillin is necessary and sufficient to accelerate migration, invasion, and anchorage-independent growth of breast cancer cells in vitro. Furthermore, loss of anillin markedly attenuated primary tumor growth and metastasis of breast cancer in vivo. In breast cancer cells, anillin was localized in the nucleus; however, knockout of this protein affected the cytoplasmic/cortical events, e.g., the organization of actin cytoskeleton and cell-matrix adhesions. Furthermore, we observed a global transcriptional reprogramming of anillin-depleted breast cancer cells that resulted in suppression of their stemness and induction of the mesenchymal to epithelial trans-differentiation. Such trans-differentiation was manifested by the upregulation of basal keratins along with the increased expression of E-cadherin and P-cadherin. Knockdown of E-cadherin restored the impaired migration and invasion of anillin-deficient breast cancer cells. Conclusion Our study demonstrates that anillin plays essential roles in promoting breast cancer growth and metastatic dissemination in vitro and in vivo and unravels novel functions of anillin in regulating breast cancer stemness and differentiation.

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