Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2<sup>hi</sup> macrophage–derived VEGFA

Allison S. Harney, Esther N. Arwert, David R. Entenberg, Yarong Wang, Peng Guo, Bin Zhi Qian, Maja H. Oktay, Jeffrey W. Pollard, Joan G. Jones, John S. Condeelis

Research output: Contribution to journalArticle

171 Citations (Scopus)

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 TIE2<sup>hi</sup> 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 TIE2<sup>hi</sup> 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.

Original languageEnglish (US)
Pages (from-to)932-943
Number of pages12
JournalCancer Discovery
Volume5
Issue number9
DOIs
StatePublished - Sep 1 2015

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Capillary Permeability
Tumor Microenvironment
Neoplasm Metastasis
Neoplasms
Macrophages
Breast Neoplasms
Cellular Microenvironment
Recurrence
Photons
Blood Vessels
Microscopy
Permeability
Endothelial Cells

ASJC Scopus subject areas

  • Oncology

Cite this

Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2<sup>hi</sup> macrophage–derived VEGFA. / Harney, Allison S.; Arwert, Esther N.; Entenberg, David R.; Wang, Yarong; Guo, Peng; Qian, Bin Zhi; Oktay, Maja H.; Pollard, Jeffrey W.; Jones, Joan G.; Condeelis, John S.

In: Cancer Discovery, Vol. 5, No. 9, 01.09.2015, p. 932-943.

Research output: Contribution to journalArticle

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