The improved targeting of an aspirin prodrug albumin-based nanosystem for visualizing and inhibiting lung metastasis of breast cancer

2020 ◽  
Vol 8 (21) ◽  
pp. 5941-5954
Author(s):  
Wancun Zhang ◽  
Lili Xia ◽  
Xiangyu Ren ◽  
Mengyuan Cui ◽  
Tianguang Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis

The nanoplatform FA-BSA@DA was developed for the loading of the aspirin prodrug DA and for the subsequent visualization and inhibition of breast cancer metastasis to the lung.

scholarly journals The AIB1 Oncogene Promotes Breast Cancer Metastasis by Activation of PEA3-Mediated Matrix Metalloproteinase 2 (MMP2) and MMP9 Expression

2008 ◽  
Vol 28 (19) ◽  
pp. 5937-5950 ◽  
Author(s):  
Li Qin ◽  
Lan Liao ◽  
Aisling Redmond ◽  
Leonie Young ◽  
Yuhui Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinase ◽  
Tumor Cells ◽  
Lung Metastasis ◽  
Cancer Metastasis ◽  
Three Dimensional ◽  
Mammary Tumorigenesis ◽  
Breast Cancer Metastasis ◽  
Matrix Metalloproteinase 2 ◽  
Human Breast

ABSTRACT Amplified-in-breast cancer 1 (AIB1) is an overexpressed transcriptional coactivator in breast cancer. Although overproduced AIB1 is oncogenic, its role and underlying mechanisms in metastasis remain unclear. Here, mammary tumorigenesis and lung metastasis were investigated in wild-type (WT) and AIB1−/− mice harboring the mouse mammary tumor virus-polyomavirus middle T (PyMT) transgene. All WT/PyMT mice developed massive lung metastasis, but AIB1−/−/PyMT mice with comparable mammary tumors had significantly less lung metastasis. The recipient mice with transplanted AIB1−/−/PyMT tumors also had much less lung metastasis than the recipient mice with transplanted WT/PyMT tumors. WT/PyMT tumor cells expressed mesenchymal markers such as vimentin and N-cadherin, migrated and invaded rapidly, and formed disorganized cellular masses in three-dimensional cultures. In contrast, AIB1−/−/PyMT tumor cells maintained epithelial markers such as E-cadherin and ZO-1, migrated and invaded slowly, and still formed polarized acinar structures in three-dimensional cultures. Molecular analyses revealed that AIB1 served as a PEA3 coactivator and formed complexes with PEA3 on matrix metalloproteinase 2 (MMP2) and MMP9 promoters to enhance their expression in both mouse and human breast cancer cells. In 560 human breast tumors, AIB1 expression was found to be positively associated with PEA3, MMP2, and MMP9. These findings suggest a new alternative strategy for controlling the deleterious roles of these MMPs in breast cancer by inhibiting their upstream coregulator AIB1.

scholarly journals Aiduqing formula inhibits breast cancer metastasis by suppressing TAM/CXCL1-induced Treg differentiation and infiltration

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jing Li ◽  
Shengqi Wang ◽  
Neng Wang ◽  
Yifeng Zheng ◽  
Bowen Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Lung Metastasis ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Luciferase Reporter ◽  
Immune Balance ◽  
Gene Assay

Abstract Background Metastasis represents the leading cause of death in patients with breast cancer. Traditional Chinese medicine is particularly appreciated for metastatic diseases in Asian countries due to its benefits for survival period prolongation and immune balance modulation. However, the underlying molecular mechanisms remain largely unknown. This study aimed to explore the antimetastatic effect and immunomodulatory function of a clinical formula Aiduqing (ADQ). Methods Naive CD4+ T cells, regulatory T cells (Tregs), and CD8+ T cells were sorted by flow cytometry. Then, breast cancer cells and these immune cells were co-cultured in vitro or co-injected into mice in vivo to simulate their coexistence. Flow cytometry, ELISA, qPCR, double luciferase reporter gene assay, and chromatin immunoprecipitation assay were conducted to investigate the immunomodulatory and antimetastatic mechanisms of ADQ. Results ADQ treatment by oral gavage significantly suppressed 4T1-Luc xenograft growth and lung metastasis in the orthotopic breast cancer mouse model, without noticeable hepatotoxicity, nephrotoxicity, or hematotoxicity. Meanwhile, ADQ remodeled the immunosuppressive tumor microenvironment (TME) by increasing the infiltration of tumor-infiltrating lymphocytes (TILs) and cytotoxic CD8+ T cells, and decreasing the infiltration of Tregs, naive CD4+ T cells, and tumor-associated macrophages (TAMs). Molecular mechanism studies revealed that ADQ remarkably inhibited CXCL1 expression and secretion from TAMs and thus suppressed the chemotaxis and differentiation of naive CD4+ T cells into Tregs, leading to the enhanced cytotoxic effects of CD8+ T cells. Mechanistically, TAM-derived CXCL1 promoted the differentiation of naive CD4+ T cells into Tregs by transcriptionally activating the NF-κB/FOXP3 signaling. Lastly, mouse 4T1-Luc xenograft experiments validated that ADQ formula inhibited breast cancer immune escape and lung metastasis by suppressing the TAM/CXCL1/Treg pathway. Conclusions This study not only provides preclinical evidence supporting the application of ADQ in inhibiting breast cancer metastasis but also sheds novel insights into TAM/CXCL1/NF-κB/FOXP3 signaling as a promising therapeutic target for Treg modulation and breast cancer immunotherapy.

scholarly journals Dexamethasone enhances the lung metastasis of breast cancer via a PI3K-SGK1-CTGF pathway

Oncogene ◽  
2021 ◽  
Author(s):  
Yujing Zhang ◽  
Gang Shi ◽  
Hantao Zhang ◽  
Qi Xiong ◽  
Fuyi Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Breast Cancer Cell ◽  
Lung Metastasis ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Treatment

AbstractDexamethasone (Dex), as a pretreatment agent, is widely used to attenuate the side effects of chemotherapy in breast cancer treatment. However, whether and how Dex affects breast cancer metastasis remain to be furtherly understood. In this study, we established several mouse breast cancer metastatic models to study the effect of Dex in vitro and in vivo. Transwell, Western Blot and RNA interference were applied to study the molecular mechanism of Dex in promoting breast cancer cell migration. Meanwhile, the effect of Dex on lung metastasis of breast cancer in Dex combined with PTX chemotherapy was discussed. Our results confirmed that Dex could promote breast cancer cell metastasis both in vitro and in vivo. Mechanistic studies revealed that this pro-metastatic effect of Dex was mediated by the GR-PI3K-SGK1-CTGF pathway in tumor cells. Ligation of Dex and glucocorticoid receptor (GR) on tumor cells activated the PI3K signaling pathway and upregulated serum glucocorticoid-inducible kinase 1 (SGK1) expression, and then increased the expression of connective tissue growth factor (CTGF) through Nedd4l-Smad2. Moreover, Dex was the leading factor for lung metastasis in a standard regimen for breast cancer treatment with paclitaxel and Dex. Importantly, targeting SGK1 with the inhibitor GSK650394 remarkably reduced lung metastasis in this regimen. Our present data provide new insights into Dex-induced breast cancer metastasis and indicate that SGK1 could be a candidate target for the treatment of breast cancer metastasis.

scholarly journals USP12 promotes breast cancer angiogenesis by maintaining midkine stability

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Bin Sheng ◽  
Zichao Wei ◽  
Xiaowei Wu ◽  
Yi Li ◽  
Zhihua Liu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Lung Metastasis ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Umbilical Vein ◽  
Breast Cancer Metastasis ◽  
Mouse Lung ◽  
Breast Cancer Patients

AbstractDeubiquitinases (DUBs) have important biological functions, but their roles in breast cancer metastasis are not completely clear. In this study, through screening a series of DUBs related to breast cancer distant metastasis-free survival (DMFS) in the Kaplan-Meier Plotter database, we identified ubiquitin-specific protease 12 (USP12) as a key deubiquitinating enzyme for breast cancer metastasis. We confirmed this via an orthotopic mouse lung metastasis model. We revealed that the DMFS of breast cancer patients with high USP12 was worse than that of others. Knockdown of USP12 decreased the lung metastasis ability of 4T1 cells, while USP12 overexpression increased the lung metastasis ability of these cells in vivo. Furthermore, our results showed that the supernatant from USP12-overexpressing breast cancer cells could promote angiogenesis according to human umbilical vein endothelial cell (HUVEC) migration and tube formation assays. Subsequently, we identified midkine (MDK) as one of its substrates. USP12 could directly interact with MDK, decrease its polyubiquitination and increase its protein stability in cells. Overexpression of MDK rescued the loss of angiogenesis ability mediated by knockdown of USP12 in breast cancer cells in vitro and in vivo. There was a strong positive relationship between USP12 and MDK protein expression in clinical breast cancer samples. Consistent with the pattern for USP12, high MDK expression predicted lower DMFS and overall survival (OS) in breast cancer. Collectively, our study identified that USP12 is responsible for deubiquitinating and stabilizing MDK and leads to metastasis by promoting angiogenesis. Therefore, the USP12–MDK axis could serve as a potential target for the therapeutic treatment of breast cancer metastasis.

scholarly journals CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages

2015 ◽  
Vol 212 (7) ◽  
pp. 1043-1059 ◽  
Author(s):  
Takanori Kitamura ◽  
Bin-Zhi Qian ◽  
Daniel Soong ◽  
Luca Cassetta ◽  
Roy Noy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Lung Metastasis ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Inflammatory Monocytes ◽  
Chemokine Ligand ◽  
Cc Chemokine Ligand 2 ◽  
Chemokine Ligand 2

Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.

scholarly journals Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Xuanmao Jiao ◽  
Min Wang ◽  
Zhao Zhang ◽  
Zhiping Li ◽  
Dong Ni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Lung Metastasis ◽  
Intracellular Signaling ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Binding Characteristics ◽  
Large Patient ◽  
Humanized Monoclonal Antibody

Abstract Background Triple-negative breast cancer (BCa) (TNBC) is a deadly form of human BCa with limited treatment options and poor prognosis. In our prior analysis of over 2200 breast cancer samples, the G protein-coupled receptor CCR5 was expressed in > 95% of TNBC samples. A humanized monoclonal antibody to CCR5 (leronlimab), used in the treatment of HIV-infected patients, has shown minimal side effects in large patient populations. Methods A humanized monoclonal antibody to CCR5, leronlimab, was used for the first time in tissue culture and in mice to determine binding characteristics to human breast cancer cells, intracellular signaling, and impact on (i) metastasis prevention and (ii) impact on established metastasis. Results Herein, leronlimab was shown to bind CCR5 in multiple breast cancer cell lines. Binding of leronlimab to CCR5 reduced ligand-induced Ca+ 2 signaling, invasion of TNBC into Matrigel, and transwell migration. Leronlimab enhanced the BCa cell killing of the BCa chemotherapy reagent, doxorubicin. In xenografts conducted with Nu/Nu mice, leronlimab reduced lung metastasis of the TNBC cell line, MB-MDA-231, by > 98% at 6 weeks. Treatment with leronlimab reduced the metastatic tumor burden of established TNBC lung metastasis. Conclusions The safety profile of leronlimab, together with strong preclinical evidence to both prevent and reduce established breast cancer metastasis herein, suggests studies of clinical efficacy may be warranted.

scholarly journals Curcumae Radix Extract Decreases Mammary Tumor-Derived Lung Metastasis via Suppression of C-C Chemokine Receptor Type 7 Expression

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 410 ◽  
Author(s):  
Pelin Kaya ◽  
Sang Lee ◽  
Young Lee ◽  
Sun Kwon ◽  
Hyun Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Mammary Tumor ◽  
Chemokine Receptor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Receptor Type ◽  
Primary Breast Tumor ◽  
Mcf7 Cells ◽  
Metastatic Activity

Curcumae radix is the dry root of Curcuma longa L. (turmeric) that can be used either as a spice or traditional medicine. The aim of this study was to investigate the survival benefits and the anti-metastatic activity of curcumae radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice—a mouse model of breast cancer metastasis. In vitro wound scratch assay revealed that CRE treatment inhibited cell motility and cell migration in a dose-dependent manner. To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT transgenic female virgin mice were used and randomly divided into two groups. For survival curve analysis, CRE was administered in a dose of 50 mg/kg to 8–20-week-old mice. Interestingly, CRE treatment significantly increased the median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment decreased tumor burden and inhibited cell proliferation in primary breast tumor, and also suppressed mammary tumor-derived lung metastasis. The size of the lung metastases substantially decreased in the CRE-treated group compared with the ones in the control group. Curcumae radix extract showed anti-metastatic activity through regulating the expression of metastasis markers including C-C Chemokine Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and c-jun. We demonstrated that these metastatic regulators were decreased when CCR7 expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results of this study show that curcumae radix exerts antitumor and anti-metastatic activities, and we suggest that curcumae radix might be a potential supplement for the treatment and prevention of breast cancer metastasis.

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