Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells
Anitha K. Shenoy, Yue Jin, Huacheng Luo, Ming Tang, Christine Pampo, Rong Shao, Dietmar W. Siemann, Lizi Wu, Coy D. Heldermon, Brian K. Law, Lung-Ji Chang, Jianrong Lu
Anitha K. Shenoy, Yue Jin, Huacheng Luo, Ming Tang, Christine Pampo, Rong Shao, Dietmar W. Siemann, Lizi Wu, Coy D. Heldermon, Brian K. Law, Lung-Ji Chang, Jianrong Lu
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Research Article Oncology Vascular biology

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

Abstract

Carcinoma cells can acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT). However, the significance of EMT in cancer metastasis has been controversial, and the exact fates and functions of EMT cancer cells in vivo remain inadequately understood. Here, we tracked epithelial cancer cells that underwent inducible or spontaneous EMT in various tumor transplantation models. Unlike epithelial cells, the majority of EMT cancer cells were specifically located in the perivascular space and closely associated with blood vessels. EMT markedly activated multiple pericyte markers in carcinoma cells, in particular PDGFR-β and N-cadherin, which enabled EMT cells to be chemoattracted towards and physically interact with endothelium. In tumor xenografts generated from carcinoma cells that were prone to spontaneous EMT, a substantial fraction of the pericytes associated with tumor vasculature were derived from EMT cancer cells. Depletion of such EMT cells in transplanted tumors diminished pericyte coverage, impaired vascular integrity, and attenuated tumor growth. These findings suggest that EMT confers key pericyte attributes on cancer cells. The resulting EMT cells phenotypically and functionally resemble pericytes and are indispensable for vascular stabilization and sustained tumor growth. This study thus proposes a previously unrecognized role for EMT in cancer.

Authors

Anitha K. Shenoy, Yue Jin, Huacheng Luo, Ming Tang, Christine Pampo, Rong Shao, Dietmar W. Siemann, Lizi Wu, Coy D. Heldermon, Brian K. Law, Lung-Ji Chang, Jianrong Lu

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Figure 6

Spontaneous EMT cancer cells are associated with blood vessels in tumor xenografts and constitute a substantial portion of tumor pericytes.

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Spontaneous EMT cancer cells are associated with blood vessels in tumor ...
(A) NeuT tumor cells were transduced with the SMA-mApple reporter and orthotopically transplanted into mice. Tumors were sectioned. A subpopulation of neuT cells underwent spontaneous EMT in vivo and thus expressed mApple (red). Endothelium was immunostained with anti-CD31 antibody (green). To label functional vasculature, tumor-bearing mice were injected with fluorescent Lycopericon esculentum lectin (green) via the tail vein prior to tumor harvest. Scale bars: 50 μm. (B) Quantification of mApple-expressing neuT tumor cells that are associated with blood vessels in tumor xenografts. Error bars represent SD (n = 4). (C) Spontaneous EMT cancer cells are not enriched at tumor edges. Green fluorescent lectin–perfused tumors from A were sectioned and examined for the localization of mApple-expressing cells (red). Scale bars: 100 μm. (D) Spontaneous EMT cancer cells contribute to tumor pericytes. Lectin-perfused SMA-mApple neuT tumors from A were sectioned and immunostained for pericytes with anti-SMA antibody (pseudocolored, green). Lectin-marked vasculature was pseudocolored white. Spontaneous EMT cells expressed mApple (red). Scale bar: 100 μm. Histograms (right) show the substantial overlap between SMA-positive pericytes and mApple-expressing EMT tumor cells (n = 4).