scholarly journals BSCI-04. Tumor-educated platelets promote breast cancer brain metastasis and therapeutic resistance

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii1-iii2
Author(s):  
Elie Tabet ◽  
Bakhos Tannous
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Breast ◽  
Therapeutic Resistance ◽  
Mesenchymal Transition ◽  
Breast Cancer Brain Metastasis ◽  
Signaling Axis ◽  
Wild Type Counterpart

Abstract Platelets have been shown to play an important role in systemic and local tumor modulation. Once encountered by tumor cells, platelets are educated to collect and release pro-tumor factors in the tumor/microenvironment, serving as a guiding partner for metastasis. This educational program, however, is not well understood. Here, we show that tumor-educated platelets (TEPs) acquire tumor promoting functions and drive breast cancer progression, metastasis to distal sites including the brain, as well as therapeutic resistance. Importantly, TEPs promoted an increased pro-tumorigenic effect on metastatic breast cancer, compared to their wild-type counterpart, leading to epithelial to mesenchymal transition through NF-κB/STAT3 signaling axis via C/EBPβ transcription factor. Our findings point to the important role of TEPs in breast cancer brain metastasis and therapeutic resistance, which could have a major implication in other tumor types, endorsing TEPs as a potential therapeutic target.

TAMI-07. TUMOR-EDUCATED PLATELETS GUIDE BREAST CANCER BRAIN METASTASIS AND PROMOTE THERAPEUTIC RESISTANCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi199-vi199
Author(s):  
Elie Tabet ◽  
Bakhos Tannous
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Progression ◽  
Metastatic Breast ◽  
Therapeutic Resistance ◽  
Breast Cancer Patients ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Healthy Humans ◽  
Breast Cancer Brain Metastasis

Abstract BACKGROUND Platelets have been shown to play an important role in systemic and local tumor modulation. Once encountered by tumor cells, platelets are educated to collect and release pro-tumor factors in the tumor/microenvironment, serving as a guiding partner for metastasis. This educational program, however, is not well understood. METHODS Wild-type platelets (WTPs) were isolated from blood of healthy humans or mice, whereas tumor-educated platelets (TEPs) were isolated from blood of breast cancer patients or from tumor-bearing donor mice. The tumorigenic and modulatory effect of these two types of platelets on breast cancer was examined in-vitro and in-vivo. RESULTS Here, we show that TEPs acquire tumor promoting functions and drive breast cancer progression, metastasis to distal sites specifically the brain, as well as therapeutic resistance. Importantly, TEPs promoted an increased pro-tumorigenic effect on metastatic breast cancer, compared to their wild-type counterpart, promoting epithelial to mesenchymal transition through NF-κB/STAT3 signaling axis via C/EBPβ transcription factor. CONCLUSION Our findings point to the important role of TEPs in breast cancer brain metastasis and therapeutic resistance, which could have a major implication in other tumor types, endorsing TEPs as a potential therapeutic target.

scholarly journals Epithelial-to-mesenchymal transition of tumor cells: cancer progression and metastasis

2021 ◽  
Author(s):  
Vasileios Vardas ◽  
Eleni Politaki ◽  
Evangelia Pantazaka ◽  
Vassilis Georgoulias ◽  
Galatea Kallergi
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Breast ◽  
Cellsearch System ◽  
Mesenchymal Transition ◽  
Specificity And Sensitivity

Detection and characterization of circulating tumor cells (CTCs) with an epithelial-to-mesenchymal transition (EMT) phenotype is very important as it can contribute to the identification of high-risk for relapse and death patients. However, most of the methods are underestimating CTC numbers, due to their dependence on epithelial markers. In the current study, we evaluated the EMT phenotype in CTCs isolated from breast cancer (BC) patients, using the CellSearch system. Spiking experiments for the evaluation of the specificity and sensitivity of our method were performed using HeLa cells. Sixty-five breast cancer (BC) patients (47 early and 18 metastatic) were enrolled in the study. Vimentin is a mesenchymal marker which indicates tumoral cells acquiring invasive and malignant properties. We studied the vimentin (VIM) expression using the extra channel of the CellSearch system and an anti-vimentin antibody conjugated with FITC. In our present results, we reported the percentage of circulating tumor cells that expressed vimentin in early and in metastatic breast cancer patients. Interestingly, the incidence of cells with a CK-VIM+CD45- phenotype was detected in both settings. These cells were detected in 31.4% of CK-negative (11/35) and 82.3% of CK-positive (10/12) early BC patients. The corresponding numbers for metastatic disease were 15.4% (2/13) and 100% (5/5), respectively. Our results suggest that in CTC-negative patients, potentially undetectable tumor cells could be identified using the FDA-approved CellSearch system, based on the (CK-VIM+CD45-)-phenotype, offering additional information regarding the metastatic dissemination in cancer patients. Further experiments evaluating more biomarkers are necessary to elucidate the mechanisms that regulate tumorigenesis and metastasis.

TAMI-04. OLFACTORY RECEPTOR 5B21 DRIVES BREAST CANCER BRAIN METASTASIS THROUGH STAT3/NFΚB/CEBPΒ PATHWAY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi198-vi199
Author(s):  
Mao Li ◽  
Markus Schweiger ◽  
Daniel Ryan ◽  
Ichiro Nakano ◽  
Litia Carvalho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Mesenchymal Transition ◽  
Breast Cancer Brain Metastasis ◽  
Metastatic Sites ◽  
The Brain

Abstract Olfactory receptors (ORs), responsible for the sense of smell, play an essential role in various physiological processes outside the nasal epithelium, including cancer. In breast cancer, however, the expression and function of ORs remain understudied. We established a breast cancer metastasis model by intracardiac injection of MDA-MB-231 (231P) in immunocompromised mice and produced a series of derivative cell lines from developed metastatic sites, including the brain-seeking clone (231Br). We examined the significance of ORs transcript abundance in primary and metastatic breast cancer to different tissues, including the brain, bone, and lung. While 20 OR transcripts were differentially expressed in distant metastases, OR5B21 displayed high expression in all three metastatic sites with respect to the primary tumor, especially in brain metastasis with 13 fold higher than the primary site. Metastatic clones showed distinguishing higher invasion biological characteristics compared to parental cells in vivo and in vitro. Knockdown of OR5B21 significantly decreased the invasion and migration of MDA-MB-231 Brain-seeking metastatic cell as well as metastasis to different organs, including the brain, while overexpression of OR5B21 had the opposite effect. Mechanistically, OR5B21 expression was associated with epithelial to mesenchymal transition through the STAT3/NFkB/CEBPβ signaling pathway. We propose OR5B21 (and potentially other ORs) as a novel oncogene contributing to breast cancer brain metastasis and a potential target for adjuvant therapy.

scholarly journals Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

2016 ◽  
Vol 113 (48) ◽  
pp. E7749-E7758 ◽  
Author(s):  
Roberto Rangel ◽  
Song-Choon Lee ◽  
Kenneth Hon-Kim Ban ◽  
Liliana Guzman-Rojas ◽  
Michael B. Mann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancer Subtype ◽  
Clinical Importance ◽  
Transposon Mutagenesis ◽  
Phosphatase And Tensin Homolog ◽  
Mesenchymal Transition ◽  
Tensin Homolog ◽  
Cancer Subtype

Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressorTRPS1. Down-regulation ofTRPS1in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression ofSERPINE1andSERPINB2and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

scholarly journals Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3053
Author(s):  
Iulia-Monica Groza ◽  
Cornelia Braicu ◽  
Ancuta Jurj ◽  
Oana Zanoaga ◽  
Raduly Lajos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Survival Rate ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Options ◽  
Overall Survival Rate ◽  
Cancer Genes ◽  
Mesenchymal Transition ◽  
Oncological Diseases

Breast cancer is one of the most common oncological diseases in women, as its incidence is rapidly growing, rendering it unpredictable and causing more harm than ever before on an annual basis. Alterations of coding and noncoding genes are related to tumorigenesis and breast cancer progression. In this study, several key genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) features were identified. EMT and CSCs are two key mechanisms responsible for self-renewal, differentiation, and self-protection, thus contributing to drug resistance. Therefore, understanding of the relationship between these processes may identify a therapeutic vulnerability that can be further exploited in clinical practice, and evaluate its correlation with overall survival rate. To determine expression levels of altered coding and noncoding genes, The Cancer Omics Atlas (TCOA) are used, and these data are overlapped with a list of CSCs and EMT-specific genes downloaded from NCBI. As a result, it is observed that CSCs are reciprocally related to EMT, thus identifying common signatures that allow for predicting the overall survival for breast cancer genes (BRCA). In fact, common CSCs and EMT signatures, represented by ALDH1A1, SFRP1, miR-139, miR-21, and miR-200c, are deemed useful as prognostic biomarkers for BRCA. Therefore, by mapping changes in gene expression across CSCs and EMT, suggesting a cross-talk between these two processes, we have been able to identify either the most common or specific genes or miRNA markers associated with overall survival rate. Thus, a better understanding of these mechanisms will lead to more effective treatment options.

scholarly journals ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Sara Charmsaz ◽  
Ben Doherty ◽  
Sinéad Cocchiglia ◽  
Damir Varešlija ◽  
Attilio Marino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
In Silico ◽  
Ex Vivo ◽  
Metastatic Breast ◽  
Peptide Mimetic ◽  
Breast Cancer Brain Metastasis

Abstract Background Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. Methods Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target’s natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. Results Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. Conclusion ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

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 ADRENOMEDULIN DI KARSINOMA PAYUDARA DENGAN METASTASIS

2018 ◽  
Vol 21 (2) ◽  
pp. 187
Author(s):  
Stefanus Lembar
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Breast ◽  
Myoepithelial Cells ◽  
Bone Scanning ◽  
High Concentration ◽  
Autocrine Growth ◽  
Cell Cycle Protein ◽  
Human Carcinoma ◽  
Mesenchymal Transition

Metastasis is the leading cause of mortality in patients with breast cancer. The molecular biology behind the metastasis is verycomplex and may require changes in the regulation of the cell cycle, protein that promotes autocrine growth loop, and the protein thatcauses epithelial to mesenchymal transition. More complex, it is clear that the biology of metastasis is partly governed by the non-tumourcells, including fibroblasts, endothelial cells and myoepithelial cells. Adrenomedullin is an autocrine growth factor produced by the renalcarcinoma cells. However, previous studies indicated that adrenomedullin can be secreted in various carcinoma tissue and carcinoma cells.Adrenomedullin may mediate immunosuppression, antiapoptosis, angiogenesis and proliferation, thus it is an important tumour cellsurvival factor underlying human carcinoma genesis. The role of adrenomedullin in the carcinoma genesis, invasion and metastasis hasbeen greatly focused. The aim of this study was to determine the concentration of adrenomedullin in patients with metastatic breast cancer.A total of 64 patients with breast cancer aged 21–90 years (63 women and 1 man) in Jakarta has been participated in this study aftersigning informed consent. Metastasis was confirmed by examination of bone scanning. Concentrations of adrenomedullin were measuredby EnzymeLinked Immunosorbent Assay (ELISA) using a commercial kit. Based on examination of bone scanning, there were 24 (37.5%)subjects with metastasis and 40 (62.5%) nonmetastasis. Mean of the concentrations of adrenomedullin in the subjects with metastasiswas 252.5 (205.0–299.9) pg/mL, while in the nonmetastasis was 203.1 (178.7–227.5) pg/mL. The concentrations of adrenomedullinwere significantly higher in subjects with metastasis than nonmetastasis (p=0.041). High concentration of adrenomedullin in the subjectswith metastasis suggests that adrenomedullin may be more likely to be involved in metastasis.

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