Abstract
Treating metastasis has been challenging due to tumors complexity and heterogeneity. This complexity is partly related to the crosstalk between tumor and its microenvironment. Endothelial cells -the building blocks of tumor vasculature- have been shown to have additional roles in cancer progression than angiogenesis and supplying oxygen and nutrients. Here, we show an alternative role for endothelial cells in supporting breast cancer growth and spreading independent of their vascular functions. Using endothelial cells and breast cancer cell lines MDA-MB231 and MCF-7, we developed co-culture systems to study the influence of tumor endothelium on breast tumor development by both in vitro and in vivo approaches. Our results demonstrated that endothelial cells conferred survival advantage to tumor cells under complete starvation and enriched the CD44HighCD24Low/- stem cell population in tumor cells. Moreover, endothelial cells enhanced the pro-metastatic potential of breast cancer cells. The in vitro and in vivo results concordantly confirmed a role for endothelial Jagged1 to promote breast tumor through notch activation. Here, we propose a role for endothelial cells in enhancing breast cancer progression, stemness, and pro-metastatic traits through a perfusion-independent manner. Our findings may be beneficial in developing novel therapeutic approaches.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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CD24 Antigen / metabolism
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Line, Tumor
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Cell Survival
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Cells, Cultured
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Cellular Microenvironment*
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Coculture Techniques
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Endothelial Cells / cytology
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Endothelial Cells / metabolism*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Hyaluronan Receptors / metabolism
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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MCF-7 Cells
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Microscopy, Confocal
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Neoplasm Metastasis
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Receptors, Notch / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Serrate-Jagged Proteins
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Transcription Factor HES-1
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Transplantation, Heterologous
Substances
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Basic Helix-Loop-Helix Transcription Factors
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CD24 Antigen
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Calcium-Binding Proteins
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Homeodomain Proteins
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Hyaluronan Receptors
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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Receptors, Notch
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Serrate-Jagged Proteins
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Transcription Factor HES-1
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HES1 protein, human
Grants and funding
This publication was made possible by grants from the Qatar National Research Fund under its National Priorities Research Program award number NPRP 09-1174-3-291, NPRP 4-640-1-096, and NPRP 09-1087-3-274. Its contents are solely the responsibility of the authors and do not necessarily represent the views of the Qatar National Research Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.