Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA.
Dissemination of tumor cells is an essential step in metastasis. Direct contact between a macrophage, mammalian-enabled (MENA)-overexpressing tumor cell, and endothelial cell [Tumor MicroEnvironment of Metastasis (TMEM)] correlates with metastasis in breast cancer patients. Here we show, using intravital high-resolution two-photon microscopy, that transient vascular permeability and tumor cell intravasation occur simultaneously and exclusively at TMEM. The hyperpermeable nature of tumor vasculature is described as spatially and temporally heterogeneous. Using real-time imaging, we observed that vascular permeability is transient, restricted to the TMEM, and required for tumor cell dissemination. VEGFA signaling from TIE2(hi) TMEM macrophages causes local loss of vascular junctions, transient vascular permeability, and tumor cell intravasation, demonstrating a role for the TMEM within the primary mammary tumor. These data provide insight into the mechanism of tumor cell intravasation and vascular permeability in breast cancer, explaining the value of TMEM density as a predictor of distant metastatic recurrence in patients.


CONCLUSIONS
Tumor vasculature is abnormal with increased permeability. Here, we show that VEGFA signaling from TIE2(hi) TMEM macrophages results in local, transient vascular permeability and tumor cell intravasation. These data provide evidence for the mechanism underlying the association of TMEM with distant metastatic recurrence, offering a rationale for therapies targeting TMEM.
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York. Department of Radiology, Albert Einstein College of Medicine, New York, New York. Integrated Imaging Program, Albert Einstein College of Medicine, New York, New York. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York. allison.harney@einstein.yu.edu john.condeelis@einstein.yu.edu.
Allison S
AS
Harney
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York. Tumour Cell Biology Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom.
Esther N
EN
Arwert
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York. Integrated Imaging Program, Albert Einstein College of Medicine, New York, New York. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York.
David
D
Entenberg
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York.
Yarong
Y
Wang
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York.
Peng
P
Guo
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York. Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, New York, New York. MRC Center for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom.
Bin-Zhi
BZ
Qian
Department of Pathology, Albert Einstein College of Medicine, New York, New York.
Maja H
MH
Oktay
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York. Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, New York, New York. MRC Center for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom.
Jeffrey W
JW
Pollard
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York. Integrated Imaging Program, Albert Einstein College of Medicine, New York, New York. Department of Pathology, Albert Einstein College of Medicine, New York, New York. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York.
Joan G
JG
Jones
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York. Integrated Imaging Program, Albert Einstein College of Medicine, New York, New York. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York. allison.harney@einstein.yu.edu john.condeelis@einstein.yu.edu.
John S
JS
Condeelis
D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D057054:Molecular Imaging; D009389:Neovascularization, Pathologic; D010641:Phenotype; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059008:Time-Lapse Imaging; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000494:pharmacology*
D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2