IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment

Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex ex vivo all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the ex vivo metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly via activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy.

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

Scientific Reports ◽

10.1038/srep09170 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 23

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.

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Comparison of the effect of rhodium citrate-associated iron oxide nanoparticles on metastatic and non-metastatic breast cancer cells

Cancer Nanotechnology ◽

10.1186/s12645-019-0052-1 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Natalia Lemos Chaves ◽

Danilo Aquino Amorim ◽

Cláudio Afonso Pinho Lopes ◽

Irina Estrela-Lopis ◽

Julia Böttner ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Breast Cancer Cells ◽

Human Tumor ◽

Metastatic Breast ◽

Cytotoxic Action ◽

Dependent Manner ◽

Metastatic Cells ◽

Mcf 7

Abstract Background Nanocarriers have the potential to improve the therapeutic index of currently available drugs by increasing drug efficacy, lowering drug toxicity and achieving steady-state therapeutic levels of drugs over an extended period. The association of maghemite nanoparticles (NPs) with rhodium citrate (forming the complex hereafter referred to as MRC) has the potential to increase the specificity of the cytotoxic action of the latter compound, since this nanocomposite can be guided or transported to a target by the use of an external magnetic field. However, the behavior of these nanoparticles for an extended time of exposure to breast cancer cells has not yet been explored, and nor has MRC cytotoxicity comparison in different cell lines been performed until now. In this work, the effects of MRC NPs on these cells were analyzed for up to 72 h of exposure, and we focused on comparing NPs’ therapeutic effectiveness in different cell lines to elect the most responsive model, while elucidating the underlying action mechanism. Results MRC complexes exhibited broad cytotoxicity on human tumor cells, mainly in the first 24 h. However, while MRC induced cytotoxicity in MDA-MB-231 in a time-dependent manner, progressively decreasing the required dose for significant reduction in cell viability at 48 and 72 h, MCF-7 appears to recover its viability after 48 h of exposure. The recovery of MCF-7 is possibly explained by a resistance mechanism mediated by PGP (P-glycoprotein) proteins, which increase in these cells after MRC treatment. Remaining viable tumor metastatic cells had the migration capacity reduced after treatment with MRC (24 h). Moreover, MRC treatment induced S phase arrest of the cell cycle. Conclusion MRC act at the nucleus, inhibiting DNA synthesis and proliferation and inducing cell death. These effects were verified in both tumor lines, but MDA-MB-231 cells seem to be more responsive to the effects of NPs. In addition, NPs may also disrupt the metastatic activity of remaining cells, by reducing their migratory capacity. Our results suggest that MRC nanoparticles are a promising nanomaterial that can provide a convenient route for tumor targeting and treatment, mainly in metastatic cells.

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S100A4 released from highly bone-metastatic breast cancer cells plays a critical role in osteolysis

Bone Research ◽

10.1038/s41413-019-0068-5 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Haemin Kim ◽

Bongjun Kim ◽

Sang Il Kim ◽

Hyung Joon Kim ◽

Brian Y. Ryu ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Bone Loss ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Critical Role ◽

Bone Destruction ◽

Metastatic Breast ◽

Breast Cancer Patients

Abstract Bone destruction induced by breast cancer metastasis causes severe complications, including death, in breast cancer patients. Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis. Tumor-derived factors play fundamental roles in this form of communication. To identify soluble factors released from cancer cells in bone metastasis, we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells. This subline (mtMDA) showed a markedly elevated ability to secrete S100A4 protein, which directly stimulated osteoclast formation via surface receptor RAGE. Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo. Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts. Furthermore, the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells. In addition, administration of an anti-S100A4 monoclonal antibody (mAb) that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice. Taken together, our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.

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Breast cancer–associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells

Science Signaling ◽

10.1126/scisignal.aax4585 ◽

2020 ◽

Vol 13 (652) ◽

pp. eaax4585 ◽

Cited By ~ 1

Author(s):

Valentí Gómez ◽

Thomas R. Eykyn ◽

Rami Mustapha ◽

Fabián Flores-Borja ◽

Victoria Male ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Succinate Dehydrogenase ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Ex Vivo ◽

Metabolic Enzyme ◽

Metastatic Progression ◽

Anti Inflammatory

Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.

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Imaging Breast Cancer Cells and Tissues Using Peptide-Labeled Fluorescent Silica Nanoparticles

Journal of Nanoscience and Nanotechnology ◽

10.1166/jnn.2008.18282 ◽

2008 ◽

Vol 8 (5) ◽

pp. 2483-2487

Author(s):

Ping Wu ◽

Xiaoxiao He ◽

Kemin Wang ◽

Weihong Tan ◽

Ding Ma ◽

...

Keyword(s):

Breast Cancer ◽

Silica Nanoparticles ◽

Cancer Cells ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Tumor Tissue ◽

Ex Vivo ◽

Rgd Peptide ◽

Tissue Samples

The imaging of tumor cells and tumor tissue samples is very important for cancer detection and therapy. We have taken advantages of fluorescent silica nanoparticles (FSiNPs) coupled with a molecular recognition element that allows for effective in vitro and ex vivo imaging of tumor cells and tissues. In this study, we report on the targeting and imaging of MDA-MB-231 human breast cancer cells using arginine-glycine-aspartic acid (RGD) peptide-labeled FSiNPs. When linked with RGD peptide using the cyanogen bromide (CNBr) method, the FSiNPs exhibited high target binding to αvβ3 integrin receptor (ABIR)-positive MDA-MB-231 breast cancer cells in vitro. Further study regarding the ex vivo imaging of tumor tissue samples was also carried out by intravenously injecting RGD peptide-labeled FSiNPs into athymic nude mice bearing the MDA-MB-231 tumors. Tissue images demonstrated that the high integrin αvβ3 expression level of the MDA-MB-231 tumors was clearly visible due to the special targeting effects of the RGD peptide-labeled FSiNPs, and the tumor fluorescence reached maximum intensity at 1 h postinjection. Our results break new ground for using FSiNPs to optically image tumors, and may also broaden the applications of silica nanoparticles in biomedicine.

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EphB4 Tyrosine Kinase Stimulation Inhibits Growth of MDA-MB-231 Breast Cancer Cells in a Dose and Time Dependent Manner

Disease Markers ◽

10.1155/2013/857895 ◽

2013 ◽

Vol 35 ◽

pp. 933-938 ◽

Cited By ~ 7

Author(s):

Farnaz Barneh ◽

Mona Moshayedi ◽

Hamid Mirmohammadsadeghi ◽

Shaghayegh Haghjooy-Javanmard ◽

Ali Mohammad Sabzghabaee ◽

...

Keyword(s):

Breast Cancer ◽

Tyrosine Kinase ◽

Cell Viability ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Dependent Manner ◽

Growth Inhibitory ◽

Therapeutic Value ◽

Dose Dependent ◽

Stimulation Of

Background. EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc.Methods. Cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinB2-Fc. Cell viability was measured on days 3 and 6 following treatment using alamar-blue when cells were in different states of confluence.Results. Stimulation of cells with ephrinB2 did not pose any significant effect on cell viability before reaching confluence, while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose-dependent manner. EphrinB2 treatment did not affect tubular formation and invasion on matrigel.Conclusion. This study showed that EphB4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth-inhibitory properties of EphB4 receptor. It is concluded that growth inhibition has occurred possibly due to long treatment with ligand, a process which leads to receptor downregulation.

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Widespread Alternative Splicing Changes in Metastatic Breast Cancer Cells

Cells ◽

10.3390/cells10040858 ◽

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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The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02898-4 ◽

2021 ◽

Author(s):

Baojuan Han ◽

Lina Dong ◽

Jing Zhou ◽

Yan Yang ◽

Jiaxun Guo ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Metastatic Breast Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

T Lymphocyte ◽

Breast Cancer Cells ◽

Biological Function ◽

Metastatic Breast ◽

Breast Cancer Patients

AbstractThis work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.

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Use of a Lymphatic Drug Delivery System and Sonoporation to Target Malignant Metastatic Breast Cancer Cells Proliferating in the Marginal Sinuses

Scientific Reports ◽

10.1038/s41598-019-49386-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Shigeki Kato ◽

Yuko Shirai ◽

Maya Sakamoto ◽

Shiro Mori ◽

Tetsuya Kodama

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Lymphatic Vessels ◽

Metastatic Breast ◽

High Frequency Ultrasound ◽

Marginal Sinus ◽

Metastatic Cells ◽

Systemic Lymphadenopathy

Abstract Lymph node (LN) metastasis through the lymphatic network is a major route for cancer dissemination. Tumor cells reach the marginal sinuses of LNs via afferent lymphatic vessels (LVs) and form metastatic lesions that lead to distant metastasis. Thus, targeting of metastatic cells in the marginal sinuses could improve cancer treatment outcomes. Here, we investigated whether lymphatic administration of a drug combined with sonoporation could be used to treat a LN containing proliferating murine FM3A breast cancer cells, which are highly invasive, in its marginal sinus. First, we used contrast-enhanced high-frequency ultrasound and histopathology to analyze the structure of LVs in MXH10/Mo-lpr/lpr mice, which exhibit systemic lymphadenopathy. We found that contrast agent injected into the subiliac LN flowed into the marginal sinus of the proper axillary LN (PALN) and reached the cortex. Next, we examined the anti-tumor effects of our proposed technique. We found that a strong anti-tumor effect was achieved by lymphatic administration of doxorubicin and sonoporation. Furthermore, our proposed method prevented tumor cells in the marginal sinus from invading the parenchyma of the PALN and resulted in tumor necrosis. We conclude that lymphatic administration of a drug combined with sonoporation could exert a curative effect in LNs containing metastatic cells in their marginal sinuses.

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Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for metastasis

10.21203/rs.3.rs-493200/v1 ◽

2021 ◽

Author(s):

Nastaran Ghahhari ◽

Magdalena Sznurkowska ◽

Nicolas Hulo ◽

Lilia Bernasconi ◽

Nicola Aceto ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factors ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Ex Vivo ◽

Metastatic Breast ◽

Estrogen Receptor Α ◽

Cooperative Interaction ◽

Mesenchymal Transition

Abstract The epithelial to mesenchymal transition (EMT) has been proposed to contribute to the metastatic spread of breast cancer cells. EMT-promoting transcription factors determine a continuum of different EMT states. In contrast, estrogen receptor α (ERα) helps to maintain the epithelial phenotype of breast cancer cells and its expression is crucial for effective endocrine therapies. Determining whether and how EMT-associated transcription factors such as ZEB1 modulate ERα signaling during early stages of EMT could promote the discovery of novel therapeutic approaches to suppress metastasis. We have discovered that, shortly after induction of EMT and while cells are still epithelial, ZEB1 modulates ERα-mediated transcription induced by estrogen or cAMP signaling in breast cancer cells. Based on these findings and our ex vivo and xenograft results, we suggest that the functional interaction between ZEB1 and ERα may alter the tissue tropism of metastatic breast cancer cells towards bone.

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