Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage–Derived VEGFA

Cancer Discovery - Tập 5 Số 9 - Trang 932-943 - 2015
Allison S. Harney1,2,3,4, Esther N. Arwert1,4,5, David Entenberg1,3,4, Yarong Wang4,6, Peng Guo1,4, Bin-Zhi Qian7,8,9, Maja H. Oktay10, Jeffrey W. Pollard8,9, Joan G. Jones11,1,3,10, John S. Condeelis1,3,4
11Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York.
22Department of Radiology, Albert Einstein College of Medicine, New York, New York.
33Integrated Imaging Program, Albert Einstein College of Medicine, New York, New York.
44Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York.
55Tumour Cell Biology Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom.
6Department 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.
76Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York.
87Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, New York, New York.
98MRC Center for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom.
109Department of Pathology, Albert Einstein College of Medicine, New York, New York.
1110Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York.

Tóm tắt

Abstract 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 TIE2hi 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. Significance: Tumor vasculature is abnormal with increased permeability. Here, we show that VEGFA signaling from TIE2hi 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. Cancer Discov; 5(9); 932–43. ©2015 AACR. See related commentary by Kadioglu and De Palma, p. 906. This article is highlighted in the In This Issue feature, p. 893

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Cancer Discovery

Tập 5 Số 9

932-943

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