Targeting disseminated estrogen-receptor-positive breast cancer cells in bone marrow
Autor: | Henry R. Haley, Shrila Rajendran, Alyssa C. Cutter, Tanner H. Robison, Brock Humphries, Johanna M. Buschhaus, Avinash S. Bevoor, Samantha S. Eckley, Kathryn E. Luker, Gary D. Luker |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research Stromal cell Thioredoxin-Disulfide Reductase Cell Survival Cell Culture Techniques Estrogen receptor Breast Neoplasms Biology Article 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Bone Marrow Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Genetics medicine Animals Humans Enzyme Inhibitors Molecular Biology Protein kinase B Cancer Mesenchymal Stem Cells medicine.disease Neoplastic Cells Circulating Xenograft Model Antitumor Assays Coculture Techniques 030104 developmental biology medicine.anatomical_structure Receptors Estrogen 030220 oncology & carcinogenesis Cancer cell Cancer research MCF-7 Cells Female Bone marrow Neoplasm Recurrence Local Heterocyclic Compounds 3-Ring Tamoxifen medicine.drug |
Zdroj: | Oncogene |
ISSN: | 1476-5594 |
Popis: | Estrogen receptor-positive (ER+) breast cancer can recur up to 20 years after initial diagnosis. Delayed recurrences arise from disseminated tumors cells (DTCs) in sites such as bone marrow that remain quiescent during endocrine therapy and subsequently proliferate to produce clinically detectable metastases. Identifying therapies that eliminate DTCs and/or effectively target cells transitioning to proliferation promises to reduce risk of recurrence. To tackle this problem, we utilized a 3D co-culture model incorporating ER+ breast cancer cells and bone marrow mesenchymal stem cells to represent DTCs in a bone marrow niche. 3D co-cultures maintained cancer cells in a quiescent, viable state as measured by both single-cell and population-scale imaging. Single-cell imaging methods for metabolism by fluorescence lifetime (FLIM) of NADH and signaling by kinases Akt and ERK revealed that breast cancer cells utilized oxidative phosphorylation and signaling by Akt to a greater extent both in 3D co-cultures and a mouse model of ER+ breast cancer cells in bone marrow. Using our 3D co-culture model, we discovered that combination therapies targeting oxidative phosphorylation via the thioredoxin reductase (TrxR) inhibitor, D9, and the Akt inhibitor, MK-2206, preferentially eliminated breast cancer cells without altering viability of bone marrow stromal cells. Treatment of mice with disseminated ER+ human breast cancer showed that D9 plus MK-2206 blocked formation of new metastases more effectively than tamoxifen. These data establish an integrated experimental system to investigate DTCs in bone marrow and identify combination therapy against metabolic and kinase targets as a promising approach to effectively target these cells and reduce risk of recurrence in breast cancer. |
Databáze: | OpenAIRE |
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