Targeting stromal remodelling and cancer stem cell plasticity overcomes chemoresistance in metastatic triple negative breast cancer

2019 ◽  
Author(s):  
Aurelie Cazet ◽  
Mun Hui ◽  
Benjamin Elsworth ◽  
Sunny Wu ◽  
Daniel Roden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Plasticity ◽  
Stem Cell Plasticity

scholarly journals Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Aurélie S. Cazet ◽  
Mun N. Hui ◽  
Benjamin L. Elsworth ◽  
Sunny Z. Wu ◽  
Daniel Roden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Plasticity ◽  
Stem Cell Plasticity

scholarly journals Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer

2017 ◽  
Author(s):  
Aurélie S. Cazet ◽  
Mun N. Hui ◽  
Benjamin L. Elsworth ◽  
Sunny Z. Wu ◽  
Daniel Roden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Stem Cell Markers ◽  
Cell Plasticity ◽  
Neoplastic Cells ◽  
Stem Cell Plasticity

ABSTRACTThe cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hh ligand produced by neoplastic cells reprogrammed cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and production of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells, which then acquired a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. Markers of pathway activity correlated with response. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and an exciting new therapeutic target in TNBC.SIGNIFICANCECompared to other breast cancer subtypes, TNBCs are associated with significantly worse patient outcomes. Standard of care systemic treatment for patients with non-BRCA1/2 positive TNBC is cytotoxic chemotherapy. However, the failure of 70% of treated TNBCs to attain complete pathological response reflects the relative chemoresistance of these tumors. New therapeutic strategies are needed to improve patient survival and quality of life. Here, we provide new insights into the dynamic interactions between heterotypic cells within a tumor. Specifically, we establish the mechanisms by which CAFs define cancer cell phenotype and demonstrate that the bidirectional CAF-cancer cell crosstalk can be successfully targeted in mice and humans using anti-stromal therapy.

scholarly journals Isolation and Establishment of a Highly Proliferative, Cancer Stem Cell-Like, and Naturally Immortalized Triple-Negative Breast Cancer Cell Line, KAIMRC2

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1303
Author(s):  
Rizwan Ali ◽  
Hajar Al Zahrani ◽  
Tlili Barhoumi ◽  
Alshaimaa Alhallaj ◽  
Abdullah Mashhour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Line ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Triple Negative ◽  
Cancer Cell Line

In vitro studies of a disease are key to any in vivo investigation in understanding the disease and developing new therapy regimens. Immortalized cancer cell lines are the best and easiest model for studying cancer in vitro. Here, we report the establishment of a naturally immortalized highly tumorigenic and triple-negative breast cancer cell line, KAIMRC2. This cell line is derived from a Saudi Arabian female breast cancer patient with invasive ductal carcinoma. Immunocytochemistry showed a significant ratio of the KAIMRC2 cells’ expressing key breast epithelial and cancer stem cells (CSCs) markers, including CD47, CD133, CD49f, CD44, and ALDH-1A1. Gene and protein expression analysis showed overexpression of ABC transporter and AKT-PI3Kinase as well as JAK/STAT signaling pathways. In contrast, the absence of the tumor suppressor genes p53 and p73 may explain their high proliferative index. The mice model also confirmed the tumorigenic potential of the KAIMRC2 cell line, and drug tolerance studies revealed few very potent candidates. Our results confirmed an aggressive phenotype with metastatic potential and cancer stem cell-like characteristics of the KAIMR2 cell line. Furthermore, we have also presented potent small molecule inhibitors, especially Ryuvidine, that can be further developed, alone or in synergy with other potent inhibitors, to target multiple cancer-related pathways.

scholarly journals Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment

Oncotarget ◽  
2016 ◽  
Vol 7 (31) ◽  
pp. 49349-49367 ◽  
Author(s):  
Wei Bin Fang ◽  
Min Yao ◽  
Gage Brummer ◽  
Diana Acevedo ◽  
Nabil Alhakamy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Gene Silencing ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
M2 Macrophage ◽  
Cell Renewal ◽  
Stem Cell Renewal

Metabolic stress induces GD2+ cancer stem cell-like phenotype in triple-negative breast cancer

2021 ◽  
Author(s):  
Appalaraju Jaggupilli ◽  
Stanley Ly ◽  
Khoa Nguyen ◽  
Vivek Anand ◽  
Bin Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metabolic Stress

scholarly journals GSK3β regulates epithelial-mesenchymal transition and cancer stem cell properties in triple-negative breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Geraldine Vidhya Vijay ◽  
Na Zhao ◽  
Petra Den Hollander ◽  
Mike J. Toneff ◽  
Robiya Joseph ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals Epigenetic Regulation of Cancer Stem Cell Genes in Triple-Negative Breast Cancer

2012 ◽  
Vol 181 (1) ◽  
pp. 257-267 ◽  
Author(s):  
Naofumi Kagara ◽  
Kelly T. Huynh ◽  
Christine Kuo ◽  
Hideyuki Okano ◽  
Myung Shin Sim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Epigenetic Regulation ◽  
Triple Negative

scholarly journals CD133+ cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer

Oncogene ◽  
2012 ◽  
Vol 32 (5) ◽  
pp. 544-553 ◽  
Author(s):  
T J Liu ◽  
B C Sun ◽  
X L Zhao ◽  
X M Zhao ◽  
T Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Vasculogenic Mimicry
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