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Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Jan 09; Vol. 22 (2). Date of Electronic Publication: 2021 Jan 09. - Publication Year :
- 2021
-
Abstract
- Metastasis accounts for over 90% of cancer-related deaths, yet the mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV-induced proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth. These studies prompt further evaluation of NDPK-mediated EV signaling using targeted genetic silencing approaches.
- Subjects :
- Animals
Cell Line
Cell Line, Tumor
Cell Movement
Endothelial Cells metabolism
Endothelial Cells pathology
Extracellular Vesicles metabolism
Female
Humans
Lung Neoplasms metabolism
Lung Neoplasms pathology
Mice, SCID
NM23 Nucleoside Diphosphate Kinases metabolism
Triple Negative Breast Neoplasms metabolism
Tumor Microenvironment
Mice
Extracellular Vesicles pathology
Lung Neoplasms secondary
Receptors, Purinergic P2Y metabolism
Signal Transduction
Triple Negative Breast Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33435297
- Full Text :
- https://doi.org/10.3390/ijms22020597