scholarly journals Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases

2021 ◽  
Vol 6 ◽  
pp. 52
Author(s):  
Wei Zheng ◽  
Dejian Zhao ◽  
Hui Zhang ◽  
Prameladevi Chinnasamy ◽  
Nicholas Sibinga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Mouse Model ◽  
Calcium Binding ◽  
Lung Metastases ◽  
Metastatic Breast ◽  
Inflammatory Factor ◽  
Interferon Signaling ◽  
Breast Cancer Metastases ◽  
Metastatic Growth

Background: Metastatic breast cancer cells recruit macrophages (metastasis-associated macrophages, or MAMs) to facilitate their seeding, survival and outgrowth. However, a comprehensive understanding of the gene expression program in MAMs and how this program contributes to metastasis remain elusive. Methods: We compared the transcriptomes of MAMs recruited to lung metastases and resident alveolar macrophages (RAMs) and identified a large variety of differentially expressed genes and their associated signaling pathways. Some of the changes were validated using qRT-PCR and immunofluorescence. To probe the functional relevance to metastatic growth, a gene-targeting mouse model of female mice in the C57BL6/J background was used to study allograft inflammatory factor 1 (AIF1, also known as ionized calcium-binding adapter molecule 1 or IBA1). Results: Interferon signaling is one of the most activated pathways in MAMs, with strong upregulation of multiple components of the pathway and a significant enrichment for the gene signatures of interferon-alpha-treated human macrophages. Aif1, an interferon-responsive gene that regulates multiple macrophage activities, was robustly induced in MAMs. Aif1 deficiency in MAMs, however, did not affect development of lung metastases, suggesting that AIF1 indicates MAM activation but is dispensable for regulating metastasis. Conclusions: The drastically different gene expression profile of MAMs as compared to RAMs suggests an important role in promoting metastatic growth. Dissection of the underlying mechanisms and functional validation of potential targets in the profile may provide novel therapeutic strategies for the treatment of metastatic diseases.

scholarly journals Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases

2021 ◽  
Vol 6 ◽  
pp. 52
Author(s):  
Wei Zheng ◽  
Dejian Zhao ◽  
Hui Zhang ◽  
Prameladevi Chinnasamy ◽  
Nicholas Sibinga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Mouse Model ◽  
Calcium Binding ◽  
Lung Metastases ◽  
Metastatic Breast ◽  
Inflammatory Factor ◽  
Interferon Signaling ◽  
Breast Cancer Metastases ◽  
Metastatic Growth

Background: Metastatic breast cancer cells recruit macrophages (metastasis-associated macrophages, or MAMs) to facilitate their seeding, survival and outgrowth. However, a comprehensive understanding of the gene expression program in MAMs and how this program contributes to metastasis remain elusive. Methods: We compared the transcriptomes of MAMs recruited to lung metastases and resident alveolar macrophages (RAMs) and identified a large variety of differentially expressed genes and their associated signaling pathways. Some of the changes were validated using qRT-PCR and immunofluorescence. To probe the functional relevance to metastatic growth, a gene-targeting mouse model of female mice in the C57BL6/J background was used to study allograft inflammatory factor 1 (AIF1, also known as ionized calcium-binding adapter molecule 1 or IBA1). Results: Interferon signaling is one of the most activated pathways in MAMs, with strong upregulation of multiple components of the pathway and a significant enrichment for the gene signatures of interferon-alpha-treated human macrophages. Aif1, an interferon-responsive gene that regulates multiple macrophage activities, was robustly induced in MAMs. Aif1 deficiency in MAMs, however, did not affect development of lung metastases, suggesting that AIF1 indicates MAM activation but is dispensable for regulating metastasis. Conclusions: The drastically different gene expression profile of MAMs as compared to RAMs suggests an important role in promoting metastatic growth. Dissection of the underlying mechanisms and functional validation of potential targets in the profile may provide novel therapeutic strategies for the treatment of metastatic diseases.

scholarly journals Transcriptome analysis of heterogeneity in mouse model of metastatic breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Anastasia A. Ionkina ◽  
Gabriela Balderrama-Gutierrez ◽  
Krystian J. Ibanez ◽  
Steve Huy D. Phan ◽  
Angelique N. Cortez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Metastatic Breast Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Transcriptome Analysis ◽  
Tumor Heterogeneity ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Organ Tropism

Abstract Background Cancer metastasis is a complex process involving the spread of malignant cells from a primary tumor to distal organs. Understanding this cascade at a mechanistic level could provide critical new insights into the disease and potentially reveal new avenues for treatment. Transcriptome profiling of spontaneous cancer models is an attractive method to examine the dynamic changes accompanying tumor cell spread. However, such studies are complicated by the underlying heterogeneity of the cell types involved. The purpose of this study was to examine the transcriptomes of metastatic breast cancer cells using the well-established MMTV-PyMT mouse model. Methods Organ-derived metastatic cell lines were harvested from 10 female MMTV-PyMT mice. Cancer cells were isolated and sorted based on the expression of CD44low/EpCAMhigh or CD44high/EpCAMhigh surface markers. RNA from each cell line was extracted and sequenced using the NextSeq 500 Illumina platform. Tissue-specific genes were compared across the different metastatic and primary tumor samples. Reads were mapped to the mouse genome using STAR, and gene expression was quantified using RSEM. Single-cell RNA-seq (scRNA-seq) was performed on select samples using the ddSeq platform by BioRad and analyzed using Seurat v3.2.3. Monocle2 was used to infer pseudo-time progression. Results Comparison of RNA sequencing data across all cell populations produced distinct gene clusters. Differential gene expression patterns related to CD44 expression, organ tropism, and immunomodulatory signatures were observed. scRNA-seq identified expression profiles based on tissue-dependent niches and clonal heterogeneity. These cohorts of data were narrowed down to identify subsets of genes with high expression and known metastatic propensity. Dot plot analyses further revealed clusters expressing cancer stem cell and cancer dormancy markers. Changes in relevant genes were investigated across pseudo-time and tissue origin using Monocle2. These data revealed transcriptomes that may contribute to sub-clonal evolution and treatment evasion during cancer progression. Conclusions We performed a comprehensive transcriptome analysis of tumor heterogeneity and organ tropism during breast cancer metastasis. These data add to our understanding of metastatic progression and highlight targets for breast cancer treatment. These markers could also be used to image the impact of tumor heterogeneity on metastases.

scholarly journals Obesity Correlation with Metastases Development and Response to First-Line Metastatic Chemotherapy in Breast Cancer

2015 ◽  
Vol 9 ◽  
pp. CMO.S32812 ◽  
Author(s):  
Mohammed A. Osman ◽  
Bryan T. Hennessy
Keyword(s):  
Breast Cancer ◽  
Survival Data ◽  
Lung Metastases ◽  
Metastatic Breast ◽  
Distant Metastases ◽  
P Value ◽  
First Line ◽  
Breast Cancer Metastases ◽  
Cancer Metastases ◽  
Nonobese Patients

Study Objectives To compare breast cancer metastases between obese and nonobese women and to evaluate the effect of first-line metastatic chemotherapy in each group. Method A retrospective study was performed in an educational institute in Ireland. The study consisted of two parts: the first part was a comparative analysis of metastases development in obese (arm A) and nonobese patients (arm B). The second part was a comparison between both arms in relation to their response to first-line metastatic chemotherapy and their survival data. Results Between 2009 and 2014, we reviewed 118 patients with metastatic breast cancer. All the patients fulfilled our inclusion criteria. In all, 48% of patients were obese and 52% were nonobese. There were no statistically significant differences between the two groups. For arms A and B, the median interval between initial cancer diagnosis and distant metastases development (distant metastases-free survival) was 5.8 versus 7.6 years, respectively ( P value 0.04). Earlier visceral (liver and lung) metastases were observed in obese compared to nonobese women ( P values were 0.05 and 0.04, respectively). The most commonly used chemotherapy was weekly paclitaxel. Our treatments showed significantly better treatment response and better survival results in nonobese women than in obese ones, who were premenopausal with performance state 2, pathological grade 3, and four or more positive lymph nodes. Conclusion Obesity is linked with visceral metastases development, especially lung and liver metastases. Furthermore, first-line metastatic chemotherapy achieved better results in nonobese patients.

scholarly journals Novel Nanoparticle-Based Cancer Treatment, Effectively Inhibits Lung Metastases and Improves Survival in a Murine Breast Cancer Model

2021 ◽  
Vol 11 ◽  
Author(s):  
Sarah Kraus ◽  
Raz Khandadash ◽  
Raphael Hof ◽  
Abraham Nyska ◽  
Ekaterina Sigalov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Magnetic Field ◽  
Lung Metastases ◽  
Metastatic Cancer ◽  
Relative Size ◽  
Clinical Signs ◽  
Metastatic Breast ◽  
The Body ◽  
Alternating Magnetic Field ◽  
Therapeutic Modality

Sarah Nanoparticles (SaNPs) are unique multicore iron oxide-based nanoparticles, developed for the treatment of advanced cancer, following standard care, through the selective delivery of thermal energy to malignant cells upon exposure to an alternating magnetic field. For their therapeutic effect, SaNPs need to accumulate in the tumor. Since the potential accumulation and associated toxicity in normal tissues are an important risk consideration, biodistribution and toxicity were assessed in naïve BALB/c mice. Therapeutic efficacy and the effect on survival were investigated in the 4T1 murine model of metastatic breast cancer. Toxicity evaluation at various timepoints did not reveal any abnormal clinical signs, evidence of alterations in organ function, nor histopathologic adverse target organ toxicity, even after a follow up period of 25 weeks, confirming the safety of SaNP use. The biodistribution evaluation, following SaNP administration, indicated that SaNPs accumulate mainly in the liver and spleen. A comprehensive pharmacokinetics evaluation, demonstrated that the total percentage of SaNPs that accumulated in the blood and vital organs was ~78%, 46%, and 36% after 4, 13, and 25 weeks, respectively, suggesting a time-dependent clearance from the body. Efficacy studies in mice bearing 4T1 metastatic tumors revealed a 49.6% and 70% reduction in the number of lung metastases and their relative size, respectively, in treated vs. control mice, accompanied by a decrease in tumor cell viability in response to treatment. Moreover, SaNP treatment followed by alternating magnetic field exposure significantly improved the survival rate of treated mice compared to the controls. The median survival time was 29 ± 3.8 days in the treated group vs. 21.6 ± 4.9 days in the control, p-value 0.029. These assessments open new avenues for generating SaNPs and alternating magnetic field application as a potential novel therapeutic modality for metastatic cancer patients.

scholarly journals NECAB3 is a differentially expressed gene in human metastatic breast cancer, in the brain and in the lymph nodes.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Lymph Nodes ◽  
Calcium Binding ◽  
Differentially Expressed Gene ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Clinical Problem ◽  
Primary Tumors ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with brain metastasis in humans with metastatic breast cancer. We found that N-terminal EF-hand calcium-binding protein 3, encoded by NECAB3, was among the genes whose expression was most different in the brain and lymph node metastases of patients with metastatic breast cancer. NECAB3 mRNA was present at increased quantities in brain metastatic tissues as compared to primary tumors of the breast. Importantly, expression of NECAB3 in primary tumors was significantly correlated with patient recurrence-free survival in patients with breast cancer. Modulation of NECAB3 expression may be relevant to the biology by which tumor cells metastasize from the breast to the brain while evading immune clearance in the lymph nodes in humans with metastatic breast cancer.

scholarly journals Bronchoalveolar carcinoma as an unsuspected cause for worsening shortness of breath in a patient with metastatic breast cancer

2018 ◽  
pp. bcr-2018-226125
Author(s):  
Sukhdeep Kaur Nagpal ◽  
Michael Flynn ◽  
Claire Ryan ◽  
Catherine Harper-Wynne
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Standard Treatment ◽  
Lung Metastases ◽  
Metastatic Breast ◽  
Multimodality Treatment ◽  
Chest Ct ◽  
Postmortem Examination ◽  
Shortness Of Breath ◽  
Radiological Changes

A 70-year-old woman with lung metastases from a breast cancer presented with worsening cough and dyspnoea. She recently had a pleurodesis for a malignant pleural effusion. Chest CT scans demonstrated various radiological changes leading to diagnostic challenges. Differential diagnoses included empyema, pleural disease progression, pulmonary oedema, pneumonitis, lymphangitis and atypical infections. She deteriorated despite a multimodality treatment strategy. Postmortem examination confirmed that lung changes were consistent with a bronchoalveolar carcinoma unrelated to the known metastatic breast cancer. The eventual knowledge of this diagnosis was reassuring to the treating medical team and a comfort to the relatives who witnessed the lack of response to standard treatment.

scholarly journals Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changhu Lee ◽  
Hyung Won Ryu ◽  
Sahee Kim ◽  
Min Kim ◽  
Sei-Ryang Oh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
Bioactive Component ◽  
Metastatic Growth

AbstractBreast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

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