scholarly journals EGCG Inhibits Adipose-Derived Mesenchymal Stem Cells Differentiation into Adipocytes and Prevents a STAT3-Mediated Paracrine Oncogenic Control of Triple-Negative Breast Cancer Cell Invasive Phenotype

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1506
Author(s):  
Narjara Gonzalez Suarez ◽  
Sahily Rodriguez Torres ◽  
Amira Ouanouki ◽  
Layal El Cheikh-Hussein ◽  
Borhane Annabi
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cell Differentiation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Stem Cell Differentiation ◽  
Low Grade ◽  
Invasive Phenotype ◽  
Fatty Acid Binding

Obese subjects have an increased risk of developing triple-negative breast cancer (TNBC), in part associated with the chronic low-grade inflammation state. On the other hand, epidemiological data indicates that increased consumption of polyphenol-rich fruits and vegetables plays a key role in reducing incidence of some cancer types. Here, we tested whether green tea-derived epigallocatechin-3-gallate (EGCG) could alter adipose-derived mesenchymal stem cell differentiation into adipocytes, and how this impacts the secretome profile and paracrine regulation of the TNBC invasive phenotype. Here, cell differentiation was performed and conditioned media (CM) from preadipocytes and mature adipocytes harvested. Human TNBC-derived MDA-MB-231 real-time cell migration was performed using the exCELLigence system. Differential gene arrays and RT-qPCR were used to assess gene expression levels. Western blotting was used to assess protein expression and phosphorylation status levels. In vitro vasculogenic mimicry (VM) was assessed with Matrigel. EGCG was found to inhibit the induction of key adipogenic biomarkers, including lipoprotein lipase, adiponectin, leptin, fatty acid synthase, and fatty acid binding protein 4. Increased TNBC-derived MDA-MB-231 cell chemotaxis and vasculogenic mimicry were observed in response to mature adipocytes secretome, and this was correlated with increased STAT3 phosphorylation status. This invasive phenotype was prevented by EGCG, the JAK/STAT inhibitors Tofacitinib and AG490, as well as upon STAT3 gene silencing. In conclusion, dietary catechin-mediated interventions could, in part through the inhibition of adipogenesis and modulation of adipocytes secretome profile, prevent the onset of an obesogenic environment that favors TNBC development.

A fatty acid-binding protein 7/RXRβ pathway enhances survival and proliferation in triple-negative breast cancer

2012 ◽  
Vol 228 (3) ◽  
pp. 310-321 ◽  
Author(s):  
Rong-Zong Liu ◽  
Kathryn Graham ◽  
Darryl D Glubrecht ◽  
Raymond Lai ◽  
John R Mackey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Triple Negative Breast Cancer ◽  
Fatty Acid Binding Protein ◽  
Triple Negative ◽  
Binding Protein ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

scholarly journals TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiahui Xu ◽  
Xiaoli Yang ◽  
Qiaodan Deng ◽  
Cong Yang ◽  
Dong Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Regulatory Mechanisms ◽  
Tumor Initiating Cells ◽  
Self Renewal ◽  
Tumor Endothelial Marker 8

AbstractEnhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.

scholarly journals A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wei Xie ◽  
Huijie Zhao ◽  
Fengxian Wang ◽  
Yiyun Wang ◽  
Yuan He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Antitumor Effects ◽  
Mouse Xenograft Model

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

scholarly journals 616 CD47 blockade modulates immunosuppressive checkpoint molecules and cellular metabolism to sensitize triple-negative breast cancer tumors to immune checkpoint blockade therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A646-A646
Author(s):  
Elizabeth Stirling ◽  
Adam Wilson ◽  
Katherine Cook ◽  
Alexandra Thomas ◽  
Pierre Triozzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Tumor Burden ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Immunosuppressive Cell

BackgroundTriple-negative breast cancer(TNBC) lacks druggable targets and has high metastatic incidence. Immune checkpoint blockades (ICB) are FDA approved for TNBC treatment, but therapeutic response and biomarkers are limited. CD47 is an integral membrane protein overexpressed on cancer cells that alters anti-tumor immunosurveillance, resulting in tumor progression. CD47 is involved in metabolic reprogramming but whether CD47 is a marker of progression and its role in ICB response for TNBC remains unknown.MethodsHuman TNBC biopsies were subjected to immunohistochemical analysis to determine CD47 role in TNBC progression. To determine CD47 impact on tumor burden, a carcinogen-induced TNBC model was performed in female wild type(WT) and cd47 null(cd47-/-) C57Bl/6 mice. To evaluate immune infiltrate signaling, tumors underwent spatial tissue proteomics by multiplexing photo-cleavable antibodies in Formalin-Fixed Paraffin-Embedded samples. An orthotopic EMT-6 murine TNBC model was performed to investigate tumor burden for CD47 monotherapy or in combination with anti-PD-L1 therapy.ResultsHuman matched primary, and metastatic TNBC biopsies increased immunoreactivity to CD47, signifying a potential therapeutic target(n=24). CD47 deficiency in the carcinogen-induced DMBA model decreased tumor incidence, weight, and area compared to WT(n=8/group,*p<0.003). Since CD47 can regulate metabolism, tumors underwent metabolomic analysis. Principal component analysis displayed differentially regulated metabolites between WT and cd47-/- tumors. Decreased carnitine conjugated fatty acids and ketone bodies were observed in cd47-/- tumors compared to WT, suggesting decreased fatty acid availability and/or metabolism(n=9/group,*p<0.05). TNBC cell respiratory measurements validated that targeting CD47 shifted metabolic dependency from fatty acid oxidation to glycolysis(n=3,*p<0.05). Kynurenine/tryptophan pathway metabolites, which catabolize Indoleamine-2,3-dioxygenase(IDO1) and involved in anti-PD-1/PD-L1 resistance, were decreased in cd47-/- tumors compared to WT(n=9/group,*p<0.05). Spatial proteomic analysis determined that cd47-/- tumors had elevated immune cell infiltration(CD45+, CD3+), suggesting CD47 absence enhances tumor immunogenicity and immune-mediated tumor ablation. Multiplexing of photo-cleavable antibodies increased protein expression of immune checkpoint molecules(PD-L1,VISTA,B7-H3,BatF3) and immunosuppressive cell types(CD11b+,Ly6c+) in WT tumors compared to cd47-/-, suggesting CD47 absence limits immunosuppressive signaling(n=16/group,*p<0.05). Since anti-PD-L1 therapies are approved to treat TNBC and WT tumors have PD-L1 upregulation, we examined how targeting CD47 would impact tumor burden of mice receiving anti-PD-L1 therapy. Targeting CD47 or PD-L1 as monotherapy decreased tumor burden; however, in combination it further reduced tumor burden compared to anti-PD-L1 treatment due to increased intratumoral granzyme B secreting cytotoxic T cells(n=4–8/group,*p<0.05).ConclusionsOur data indicates that CD47 may serve as a marker of anti-PD-L1 response, and targeting CD47 enhances immunogenicity and decreases immunosuppressive molecules, sensitizing TNBC tumors to anti-PD-L1 therapy to reduce tumor burden.AcknowledgementsDSP is supported by the NCI R21 (CA249349) and the American Cancer Society Research Scholar Grant (133727-RSG-19-150-01-LIB). ERS is supported by the NIAID Immunology and Pathogenesis T32 Training Grant (T32AI007401).Ethics ApprovalAnimal studies were approved by the Institutional Care and Use Committee, Wake Forest Health Sciences.

scholarly journals Obesity Modulates the Gut Microbiome in Triple-Negative Breast Cancer

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3656
Author(s):  
Fokhrul Hossain ◽  
Samarpan Majumder ◽  
Justin David ◽  
Bruce A. Bunnell ◽  
Lucio Miele
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Gut Microbiome ◽  
Triple Negative ◽  
Alpha Diversity ◽  
Low Grade ◽  
Syngeneic Mouse Model ◽  
Variation Of Functional ◽  
Analysis Of Variation ◽  
The Impact

Triple-negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer. Obesity is associated with increased incidence and worse prognosis in TNBC through various potential mechanisms. Recent evidence suggests that the gut microbiome plays a central role in the progression of cancer, and that imbalances or dysbiosis in the population of commensal microbiota can lead to inflammation and contribute to tumor progression. Obesity is characterized by low-grade inflammation, and gut dysbiosis is associated with obesity, chronic inflammation, and failure of cancer immunotherapy. However, the debate on what constitutes a “healthy” gut microbiome is ongoing, and the connection among the gut microbiome, obesity, and TNBC has not yet been addressed. This study aims to characterize the role of obesity in modulating the gut microbiome in a syngeneic mouse model of TNBC. 16S rRNA sequencing and metagenomic analyses were performed to analyze and annotate genus and taxonomic profiles. Our results suggest that obesity decreases alpha diversity in the gut microbiome. Metagenomic analysis revealed that obesity was the only significant factor explaining the similarity of the bacterial communities according to their taxonomic profiles. In contrast to the analysis of taxonomic profiles, the analysis of variation of functional profiles suggested that obesity status, tumor presence, and the obesity–tumor interaction were significant in explaining the variation of profiles, with obesity having the strongest correlation. The presence of tumor modified the profiles to a greater extent in obese than in lean animals. Further research is warranted to understand the impact of the gut microbiome on TNBC progression and immunotherapy.

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