Extracellular Vesicles and Breast Cancer Metastasis

Endothelial Cells, Microvascular Endothelial Cells, and Cardiac Cells

Cardiac cells and endothelial cells are two of the most important cell types that make up the heart tissue and blood vessels of the body’s vascular system. Almost all tissues rely on a blood supply for nutrients and gas exchange, which is supplied by a complex network of blood vessels. Endothelial and microvascular endothelial cells line all blood vessels, large and small, and provide cues to surrounding tissues to support vessel development highlighting the importance of this cell type in angiogenesis – new blood vessels can develop from the walls of existing small vessels by the outgrowth of endothelial cells. In the tumor microenvironment, this can be stimulated by cancer cells to provide vascularization to tumors to support their growth. Tumor cells have been found to directly induce changes in the endothelial cells through soluble factors, adhesion receptors, gap junctions, and extracellular vesicles. The ability of tumor cells to remodel the tumor microenvironment to facilitate further growth and eventual metastasis to distal parts of the body remains an area of active research.

Lifeline® offers a number of normal human endothelial cells and cardiac cells, along with compatible, optimized media products to support these cell types.

• Aortic endothelial cells
• Pulmonary artery endothelial cells
• Coronary artery endothelial cells
• Iliac artery endothelial cells
• Umbilical vein endothelial cells (Primary and 10-Donor Pool)
• Dermal microvascular endothelial cells (Neonatal and Adult)
• Cardiac microvascular endothelial cells
• Cardiac fibroblast cells

Extracellular Vesicles and Their Role in Breast Cancer Metastasis

During cancer progression, tumor cells develop the ability to metastasize, invading surrounding normal tissues and moving through tissue boundaries to form new, distal tumor growths far from the primary tumor site. Tumor-derived extracellular vesicles (EVs) are implicated in tumor invasion by increasing tumor cell motility through degradation of the surrounding extracellular matrix (ECM). In breast cancer metastasis, research suggests that secreted nucleoside diphosphate kinase A and B (NDPK) from breast cancer-derived EVs promotes angiogenesis and pro-metastatic events that initiate the formation of the pre-metastatic niche (PMN), a microenvironment suited to the establishment and expansion of circulating tumor cells (CTCs), but the molecular mechanisms by which this occurs are still unclear.

Duan and Colleagues investigated the role of EV-associated NDPK in modulating the distal microenvironment in favor of PMN formation and metastasis through enhancement of purinergic signaling. EVs isolated from triple-negative breast cancer (MDA-MB-231), found to highly express NDPK were utilized. NDPK gene expression and phosphotransferase activity in MDA-MB-231 and non-cancerous mammary epithelial (HME1) cell line was assessed using flow cytometry, western blot, and ATP assay. A functional role for EV-associated NDPK-B in the PMN was established when EV-associated NDPK was found to activate endothelial cell (Lifeline’s Human Umbilical Vein Endothelial Cells – HUVECs) remodeling in support of cell migration, vascular permeabilization and angiogenesis.

The researchers further assessed the effect of varying MDA-MB-231 EV concentrations on endothelial cell monolayer integrity using a modified Boyden chamber approach where EV treatment of Lifeline’s human lung microvascular endothelial cells (HLMVECs) resulted in increased monolayer permeabilization. These results support the role of EV-secreted NDPK in promoting metastatic outgrowth through modulation of the lung vascular microenvironment in favor of PMN formation.

The results presented here warrant the examination of other ectoenzymes that, along with NDPK, mediate purine metabolism and homeostasis in the tumor microenvironment, including CD39, CD73, adenosine deaminase, and adenylate kinase. High levels of both adenosine and ATP in the tumor microenvironment compared to healthy tissues underscores the importance of their collective roles in remodeling the tumor microenvironment making it more permissive to tumor cell migration and metastasis.

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