scholarly journals iPSC-Derived Hereditary Breast Cancer Model Reveals the BRCA1-Deleted Tumor Niche as a New Culprit in Disease Progression

2021 ◽  
Vol 22 (3) ◽  
pp. 1227
Author(s):  
Lucie Portier ◽  
Christophe Desterke ◽  
Diana Chaker ◽  
Noufissa Oudrhiri ◽  
Afag Asgarova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Hereditary Breast Cancer ◽  
Breast Cancer Cells ◽  
Brca1 Gene ◽  
Patient Specific ◽  
Cancer Type

Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a lifetime risk of developing breast and/or ovarian cancer. To model the BRCA1-deleted stroma, we first generated induced pluripotent stem cells (iPSCs) from patients carrying a germline deletion of exon 17 of the BRCA1 gene (BRCA1+/− who, based on their family histories, were at a high risk for cancer. Using peripheral blood mononuclear cells (PBMCs) of these two affected family members and two normal (BRCA1+/+) individuals, we established a number of iPSC clones via non-integrating Sendai virus-based delivery of the four OCT4, SOX2, KLF4, and c-MYC factors. Induced mesenchymal stem cells (iMSCs) were generated and used as normal and pathological stromal cells. In transcriptome analyses, BRCA1+/− iMSCs exhibited a unique pro-angiogenic signature: compared to non-mutated iMSCs, they expressed high levels of HIF-1α, angiogenic factors belonging to the VEGF, PDGF, and ANGPT subfamilies showing high angiogenic potential. This was confirmed in vitro through the increased capacity to generate tube-like structures compared to BRCA1+/+ iMSCs and in vivo by a matrigel plug angiogenesis assay where the BRCA1+/− iMSCs promoted the development of an extended and organized vessel network. We also reported a highly increased migration capacity of BRCA1+/− iMSCs through an in vitro wound healing assay that correlated with the upregulation of the periostin (POSTN). Finally, we assessed the ability of both iMSCs to facilitate the engraftment of murine breast cancer cells using a xenogenic 4T1 transplant model. The co-injection of BRCA1+/− iMSCs and 4T1 breast cancer cells into mouse mammary fat pads gave rise to highly aggressive tumor growth (2-fold increase in tumor volume compared to 4T1 alone, p = 0.01283) and a higher prevalence of spontaneous metastatic spread to the lungs. Here, we report for the first time a major effect of BRCA1 haploinsufficiency on tumor-associated stroma in the context of BRCA1-associated cancers. The unique iMSC model used here was generated using patient-specific iPSCs, which opens new therapeutic avenues for the prevention and personalized treatment of BRCA1-associated hereditary breast cancer.

scholarly journals The in vitro and in vivo effects of mesenchymal stem cells on breast cancer cells

2017 ◽  
Vol 28 ◽  
pp. i15
Author(s):  
T. Herheliuk ◽  
O. Perepelytsina ◽  
O. Yakymchuk ◽  
L. Ostapchenko ◽  
M. Sydorenko
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
In Vivo Effects

scholarly journals Repurposing of Fluvastatin as an Anticancer Agent against Breast Cancer Stem Cells via Encapsulation in a Hyaluronan-Conjugated Liposome

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1133
Author(s):  
Ji Yu ◽  
Dae Shin ◽  
Jin-Seok Kim
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Body Weight Loss ◽  
Breast Cancer Stem Cells ◽  
Anticancer Efficacy

Fluvastatin (FLUVA), which is a common anti-hypercholesterolemia drug, exhibits potential anticancer activity as it suppresses the proliferation, angiogenesis, and metastasis of breast cancer cells via inhibiting 3-hydroxy-methyl glutaryl-coenzyme A (HMG-CoA) reductase. In this study, hyaluronan-conjugated FLUVA-encapsulating liposomes (HA-L-FLUVA) were evaluated for their anticancer efficacy in vitro and in vivo. The particle size, zeta potential, and encapsulation efficiency of HA-L-FLUVA were 158.36 ± 1.78 nm, −24.85 ± 6.26 mV, and 35%, respectively. Growth inhibition of breast cancer stem cells (BCSCs) by HA-L-FLUVA was more effective than that by free FLUVA. The half maximal inhibitory concentration (IC50) values of FLUVA, L-FLVUA, and HA-L-FLUVA were 0.16, 0.17, and 0.09 μM, respectively. The in vivo anticancer effect of HA-L-FLUVA in combination with doxorubicin (DOX) was more effective than that of free FLUVA, free DOX, and HA-L-FLUVA. The longest survival of mice was achieved by treatment with FLUVA (15 mg/kg) and HA-L-FLUVA (15 mg/kg) + DOX (3 mg/kg), followed by HA-L-FLUVA (15 mg/kg), Dulbecco’s phosphate buffered saline, and DOX (3 mg/kg). No more than 10% body weight loss was observed in the mice injected with FLUVA, indicating that the drug was not toxic. Taken together, these results indicate that HA-L-FLUVA could serve as an effective anticancer drug by inhibiting the growth of both breast cancer cells and cancer stem cells.

scholarly journals The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations With Similar Efficiencies

2022 ◽  
Author(s):  
Anastasia L Berg ◽  
Ashley Rowson-Hodel ◽  
Michelle Hu ◽  
Michael Keeling ◽  
Hao Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ex Vivo ◽  
Chemotherapeutic Agents ◽  
Cell Death Pathway ◽  
Amphiphilic Drug ◽  
Hexamethylene Amiloride

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species, but acts poorly toward non-transformed cells derived from multiple tissues. Here we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. Our observations expose a key vulnerability intrinsic to cancer stem cells, and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

scholarly journals miR-1275 Targets MDK/AKT Signaling to Inhibit Breast Cancer Chemoresistance by Lessening the Properties of Cancer Stem Cells

2021 ◽  
Author(s):  
Xu Han ◽  
Ge Ma ◽  
Xinyang Wang ◽  
Jingyue Fu ◽  
Jingyi Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Akt Signaling ◽  
Plasma Samples ◽  
Knock Out

Abstract Background: Chemoresistance is a major obstacle in the neoadjuvant chemotherapy (NCT) of locally advanced breast cancer (LABC). Identification of miRNAs as prognostic biomarkers may help overcome chemoresistance of breast cancer (BC). The aim of this study was to evaluate the expression level of miR-1275 in plasma samples and the biological functions in the chemoresistance of BC.Methods: The expression levels of miR-1275 in plasma samples and cells were measured by RT-qPCR. The associations between the expression levels of miR-1275 and clinicopathological features were studied. CRISPR/Cas9-mediated gene editing was used to construct miR-1275 knock-out cells. CCK-8, colony formation assays, epirubicin accumulation assay and xenograft tumor models were used to detect the sensitivity of breast cancer cells to epirubicin in vitro and in vivo. Mammosphere formation assay, flow cytometry analysis and western blot analyses were used to evaluate the effects of miR-1275 on cancer stem cells (CSCs) characteristics in BC cells. Dual-luciferase reporter, RNA pulldown, ELISA and IHC were used to verify the relationship between the expression of miR-1275 and Midkine (MDK). Results: We found that miR-1275 was significantly downregulated in plasma from patients resistant to chemotherapy with LABC and in chemoresistant breast cancer cell lines, while patients with low levels of miR-1275 show poor overall survival. Mir-1275 knock-out promoted chemoresistance in breast cancer cells by increasing the properties of cancer stem cells in vitro and in vivo. Mechanistically, we identified that Midkine was determined to be direct downstream protein of miR-1275 which initiated PI3K/Akt signaling in breast cancer cells.Conclusions: We demonstrated that the high expression level of miR-1275 in plasma predicted better response to NCT. The reduction of miR-1275 promoted BC cells chemoresistance by increasing CSC properties via targeting MDK/AKT axis. The potential of miR-1275 as a new prognostic biomarker and therapeutic target of breast cancer patients was identified.

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