Multifunctional Nanoparticles Loaded with Vascular Endothelial Growth Factor Inhibitors and MED1 siRNA to Inhibit Breast Cancer Progression by Targeting Tumor-Associated Macrophages and Breast Cancer Cells

2021 ◽  
Vol 17 (12) ◽  
pp. 2364-2373
Author(s):  
Song Wang ◽  
Zifeng Luo ◽  
Xinke Zhou ◽  
Chong Wang ◽  
Yuanwei Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Fluorescence Analysis ◽  
Cell Uptake ◽  
Breast Cancer Patients ◽  
Drug Encapsulation ◽  
Vegf Inhibitors ◽  
Proliferation And Invasion

Breast cancer is still threatening many people’ lives, hence novel targeted therapies are urgently required to improve the poor outcome of breast cancer patients. Herein, our study aimed to explore the potential of nanoparticles (NPs)-loaded with VEGF inhibitors and MED1 siRNA for treatment of the disorder. PEG and MTC conjugates were synthesized by ion gelation, and equipped with VEGF inhibitor (siV) and MED1 (siD) siRNA (MT/PC/siV-D NPs). The size and morphology of the NPs were detected by TEM. Agarose gel experiment was performed to detect drug encapsulation rate and NPs stability. Zeta potential was assessed by immunofluorescence assay and cell uptake was detected by fluorescence analysis. After cancer cells were treated with NPs or PBS, cell proliferation and invasion were evaluated with VEGF and MED1 expression was detected by Western blot and RT-qPCR analyses. Animal model was conducted to confirm the role of NPs in tumor growth. Results showed that, the MT/PC/siV-D NPs exhibited great stability, drug encapsulation and internalization ability. The combined NPs caused decreased proliferation and invasion of tumor cells, inducing M2 macrophages to re-polarize to M1 type with declined expression of VEGF and MED1. Moreover, the NPs remarkably alleviated breast tumor progression. The multifunctional NPs equipped with EGF inhibitors and MED1 siRNA can inhibit tumor progression by targeting TAMs and cancer cells during breast cancer.

scholarly journals Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 1918
Author(s):  
Mio Yamaguchi ◽  
Kiyoshi Takagi ◽  
Koki Narita ◽  
Yasuhiro Miki ◽  
Yoshiaki Onodera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Human Breast Carcinoma ◽  
Breast Cancer Patients ◽  
Breast Carcinomas ◽  
Human Breast

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.

scholarly journals Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Yifan Wang ◽  
Ruocen Liao ◽  
Xingyu Chen ◽  
Xuhua Ying ◽  
Guanping Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Invasive Breast Cancer ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Hippo Pathway ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

Abstract Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.

scholarly journals Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells

Oncogene ◽  
2019 ◽  
Vol 39 (7) ◽  
pp. 1543-1556 ◽  
Author(s):  
Ran Cheng ◽  
Sandrine Billet ◽  
Chuanxia Liu ◽  
Subhash Haldar ◽  
Diptiman Choudhury ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Periodontal Diseases ◽  
Metastatic Breast ◽  
Metastatic Progression ◽  
Premetastatic Niche ◽  
Periodontal Inflammation

Abstract Periodontal diseases can lead to chronic inflammation affecting the integrity of the tooth supporting tissues. Recently, a striking association has been made between periodontal diseases and primary cancers in the absence of a mechanistic understanding. Here we address the effect of periodontal inflammation (PI) on tumor progression, metastasis, and possible underlining mechanisms. We show that an experimental model of PI in mice can promote lymph node (LN) micrometastasis, as well as head and neck metastasis of 4T1 breast cancer cells, both in early and late stages of cancer progression. The cervical LNs had a greater tumor burden and infiltration of MDSC and M2 macrophages compared with LNs at other sites. Pyroptosis and the resultant IL-1β production were detected in patients with PI, mirrored in mouse models. Anakinra, IL-1 receptor antagonist, limited metastasis, and MDSC recruitment at early stages of tumor progression, but failed to reverse established metastatic tumors. PI and the resulting production of IL-1β was found to promote CCL5, CXCL12, CCL2, and CXCL5 expression. These chemokines recruit MDSC and macrophages, finally enabling the generation of a premetastatic niche in the inflammatory site. These findings support the idea that periodontal inflammation promotes metastasis of breast cancer by recruiting MDSC in part by pyroptosis-induced IL-1β generation and downstream CCL2, CCL5, and CXCL5 signaling in the early steps of metastasis. These studies define the role for IL-1β in the metastatic progression of breast cancer and highlight the need to control PI, a pervasive inflammatory condition in older patients.

miR-214 inhibits epithelial–mesenchymal transition of breast cancer cells via downregulation of RNF8

2019 ◽  
Vol 51 (8) ◽  
pp. 791-798 ◽  
Author(s):  
Lu Min ◽  
Chuanyang Liu ◽  
Jingyu Kuang ◽  
Xiaomin Wu ◽  
Lingyun Zhu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Proliferation And Invasion

Abstract MicroRNAs (miRNAs) are a class of endogenous noncoding genes that regulate gene expression at the posttranscriptional level. In recent decades, miRNAs have been reported to play important roles in tumor growth and metastasis, while some reported functions of a specific miRNA in tumorigenesis are contradictory. In this study, we reevaluated the role of miR-214, which has been reported to serve as an oncogene or anti-oncogene in breast cancer metastasis. We found that miR-214 inhibited breast cancer via targeting RNF8, a newly identified regulator that could promote epithelial–mesenchymal transition (EMT). Specifically, the survival rate of breast cancer patients was positively correlated with miR-214 levels and negatively correlated with RNF8 expression. The overexpression of miR-214 inhibited cell proliferation and invasion of breast cancer, while suppression of miR-214 by chemically modified antagomir enhanced the proliferation and invasion of breast cancer cells. Furthermore, miR-214 could modulate the EMT process via downregulating RNF8. To our knowledge, this is the first report that reveals the role of the miR-214–RNF8 axis in EMT, and our results demonstrate a novel mechanism for miR-214 acting as a tumor suppressor through the regulation of EMT.

Capture of EpCAM-negative and vimentin-positive circulating cancer cells (CCCs) from blood of metastatic breast cancer patients using ApoStream.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21029-e21029
Author(s):  
Christopher Neal ◽  
Sujita Sukumaran ◽  
Vishal Gupta ◽  
Insiya Jafferji ◽  
Dave Hasegawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Laser Scanning ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Circulating Cancer Cells

e21029 Background: Up-regulation of epithelial mesenchymal transition (EMT) and the reduction of epithelial marker expression is associated with invasion, cancer progression, resistance to conventional therapies and poor prognosis. ApoStream, a novel continuous flow dielectrophoresis field-flow fractionation (DEP-FFF) device, was used to enable antibody-independent capture of circulating cancer cells (CCCs,also referred to as circulating tumor cells, CTC) for subsequent phenotyping of EMT markers. Methods: A side-by-side comparison of CellSearch and ApoStream was performed on 10 metastatic breast cancer patients. A multiplexed immunofluorescent assay and laser scanning cytometry analyses were used to unambiguously identify CK+/CD45–/DAPI+ CCCs and quantify their EpCAM and vimentin expression. Results: ApoStream recovered CK+/CD45–/DAPI+ CCCs from each breast cancer patient sample tested (mean=255 CCCs per 7.5 ml blood, see Table). ApoStream consistently recovered significantly higher number of CCCs compared to CellSearch (p=0.024). ApoStream recovered both EpCAM+ and EpCAM– CCCs in 50% and 90% of patients, respectively. Vimentin+ CCCs were isolated from 90% of patients. Conclusions: ApoStream’s higher capture efficiency demonstrated the majority of CCCs from breast cancer patients were EpCAM negative and vimentin-positive. ApoStream technology can be used to monitor CCCs undergoing EMT. [Table: see text]

scholarly journals Crosstalk between Cancer Cells and Fibroblasts for the Production of Monocyte Chemoattractant Protein-1 in the Murine 4T1 Breast Cancer

2021 ◽  
Vol 43 (3) ◽  
pp. 1726-1740
Author(s):  
Mayu Imamura ◽  
Tiantian Li ◽  
Chunning Li ◽  
Masayoshi Fujisawa ◽  
Naofumi Mukaida ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Pdgf Receptor ◽  
Breast Cancer Patients ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
4T1 Cells ◽  
4T1 Breast Cancer

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is shown to promote the progression of breast cancer. We previously identified cancer cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential regulator of MCP-1 production in the murine 4T1 breast cancer, but it played a minimum role in overall MCP-1 production. Here, we evaluated the crosstalk between 4T1 cells and fibroblasts. When fibroblasts were co-cultured with 4T1 cells or stimulated with the culture supernatants of 4T1 cells (4T1-sup), MCP-1 production by fibroblasts markedly increased. 4T1 cells expressed mRNA for platelet-derived growth factor (PDGF)-a, b and c, and the PDGF receptor inhibitor crenolanib almost completely inhibited 4T1-sup-induced MCP-1 production by fibroblasts. However, PDGF receptor antagonists failed to reduce MCP-1 production in tumor-bearing mice. Histologically, 4T1 tumors contained a small number of αSMA-positive fibroblasts, and Mcp-1 mRNA was mainly associated with macrophages, especially those surrounding necrotic lesions on day 14, by in situ hybridization. Thus, although cancer cells have the capacity to crosstalk with fibroblasts via PDGFs, this crosstalk does not play a major role in MCP-1 production or cancer progression in this model. Unraveling complex crosstalk between cancer cells and stromal cells will help us identify new targets to help treat breast cancer patients.

scholarly journals miR-338-3p Is Regulated by Estrogens through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts (CAFs)

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 203 ◽  
Author(s):  
Adele Vivacqua ◽  
Anna Sebastiani ◽  
Anna Miglietta ◽  
Damiano Rigiracciolo ◽  
Francesca Cirillo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancer Patients ◽  
Expression Of Genes ◽  
Taqman Array

Estrogens acting through the classic estrogen receptors (ERs) and the G protein estrogen receptor (GPER) regulate the expression of diverse miRNAs, small sequences of non-coding RNA involved in several pathophysiological conditions, including breast cancer. In order to provide novel insights on miRNAs regulation by estrogens in breast tumor, we evaluated the expression of 754 miRNAs by TaqMan Array in ER-negative and GPER-positive SkBr3 breast cancer cells and cancer-associated fibroblasts (CAFs) upon 17β-estradiol (E2) treatment. Various miRNAs were regulated by E2 in a peculiar manner in SkBr3 cancer cells and CAFs, while miR-338-3p displayed a similar regulation in both cell types. By METABRIC database analysis we ascertained that miR-338-3p positively correlates with overall survival in breast cancer patients, according to previous studies showing that miR-338-3p may suppress the growth and invasion of different cancer cells. Well-fitting with these data, a miR-338-3p mimic sequence decreased and a miR-338-3p inhibitor sequence rescued the expression of genes and the proliferative effects induced by E2 through GPER in SkBr3 cancer cells and CAFs. Altogether, our results provide novel evidence on the molecular mechanisms by which E2 may regulate miR-338-3p toward breast cancer progression.

scholarly journals LncRNA DANCR contributes to tumor progression via targetting miR-216a-5p in breast cancer: lncRNA DANCR contributes to tumor progression

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Weiyang Tao ◽  
Chunyang Wang ◽  
Bifa Zhu ◽  
Guoqiang Zhang ◽  
Da Pang
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cell Line ◽  
Breast Cancer Cells ◽  
Biological Effects ◽  
Tumor Promoter ◽  
Aberrant Expression ◽  
Proliferation And Invasion

Abstract Breast cancer, the most frequently occurring malignant tumor, has high mortality rate, especially triple-negative breast cancer (TNBC). LncRNA-differentiation antagonizing non-protein coding RNA (lncRNA DANCR) has been found that its aberrant expression was associated with tumor progression and it was promising to be a potential target for cancer therapy. The goal of the present study was to explore the biological effects and underlying mechanism of DANCR in breast cancer. Our results showed that DANCR was up-regulated in TNBC tissues and breast cancer cells compared with normal breast tissues and cells, and higher DANCR level suggested poorer prognosis, implying that it was promising to be a novel biomarker used for TNBC diagnosis and prognosis. To better research the functions and mechanism of DANCR on breast cancer cells, we selected two cell lines used for next study: one TNBC cell line–MDA-MB-231 and one ER-positive breast cancer cell line–MCF-7. Further study indicated that DANCR overexpression significantly promoted cell proliferation and invasion in vitro and contributed to tumor growth in vivo. To deeply understand its molecular mechanism, miRNA-216a-5p was identified as a target of DANCR by bioinformatic analysis. Experiments demonstrated that miRNA-216a-5p interacted with DANCR and its inhibitor could weaken the influences induced by DANCR knockdown for cancer cells, including cell proliferation and invasion, and the expression of Nanog, SOX2, and OCT4. Therefore, DANCR might act as a tumor promoter by targetting miRNA-216a-5p, which might provide a potential therapy target for breast cancer treatment.

scholarly journals PPARgamma: A Potential Intrinsic and Extrinsic Molecular Target for Breast Cancer Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 543
Author(s):  
Giuseppina Augimeri ◽  
Daniela Bonofiglio
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Tumor Biology ◽  
Peroxisome Proliferator ◽  
Breast Cancer Patients ◽  
Peroxisome Proliferator Activated Receptor ◽  
Extracellular Matrix Components

Over the last decades, the breast tumor microenvironment (TME) has been increasingly recognized as a key player in tumor development and progression and as a promising prognostic and therapeutic target for breast cancer patients. The breast TME, representing a complex network of cellular signaling—deriving from different stromal cell types as well as extracellular matrix components, extracellular vesicles, and soluble growth factors—establishes a crosstalk with cancer cells sustaining tumor progression. A significant emphasis derives from the tumor surrounding inflammation responsible for the failure of the immune system to effectively restrain breast cancer growth. Thus, effective therapeutic strategies require a deeper understanding of the interplay between tumor and stroma, aimed at targeting both the intrinsic neoplastic cells and the extrinsic surrounding stroma. In this scenario, peroxisome proliferator-activated receptor (PPAR) γ, primarily known as a metabolic regulator, emerged as a potential target for breast cancer treatment since it functions in breast cancer cells and several components of the breast TME. In particular, the activation of PPARγ by natural and synthetic ligands inhibits breast cancer cell growth, motility, and invasiveness. Moreover, activated PPARγ may educate altered stromal cells, counteracting the pro-inflammatory milieu that drive breast cancer progression. Interestingly, using Kaplan–Meier survival curves, PPARγ also emerges as a prognostically favorable factor in breast cancer patients. In this perspective, we briefly discuss the mechanisms by which PPARγ is implicated in tumor biology as well as in the complex regulatory networks within the breast TME. This may help to profile approaches that provide a simultaneous inhibition of epithelial cells and TME components, offering a more efficient way to treat breast cancer.

scholarly journals Widespread Alternative Splicing Changes in Metastatic Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 858
Author(s):  
Jagyeong Oh ◽  
Davide Pradella ◽  
Changwei Shao ◽  
Hairi Li ◽  
Namjeong Choi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Expression Levels

Aberrant alternative splicing (AS) is a hallmark of cancer and a potential target for novel anti-cancer therapeutics. Breast cancer-associated AS events are known to be linked to disease progression, metastasis, and survival of breast cancer patients. To identify altered AS programs occurring in metastatic breast cancer, we perform a global analysis of AS events by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq). We demonstrate that, relative to low-metastatic, high-metastatic breast cancer cells show different AS choices in genes related to cancer progression. Supporting a global reshape of cancer-related splicing profiles in metastatic breast cancer we found an enrichment of RNA-binding motifs recognized by several splicing regulators, which have aberrant expression levels or activity during breast cancer progression, including SRSF1. Among SRSF1-regulated targets we found DCUN1D5, a gene for which skipping of exon 4 in its pre-mRNA introduces a premature termination codon (PTC), thus generating an unstable transcript degraded by nonsense-mediated mRNA decay (NMD). Significantly, distinct breast cancer subtypes show different DCUN1D5 isoform ratios with metastatic breast cancer expressing the highest level of the NMD-insensitive DCUN1D5 mRNA, thus showing high DCUN1D5 expression levels, which are ultimately associated with poor overall and relapse-free survival in breast cancer patients. Collectively, our results reveal global AS features of metastatic breast tumors, which open new possibilities for the treatment of these aggressive tumor types.

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