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 7

Spontaneous EMT cancer cells are essential for pericyte coverage and integrity of tumor vasculature.

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Spontaneous EMT cancer cells are essential for pericyte coverage and int...
NeuT tumor cells were infected with lentiviral control vector or SMA-DTA to eliminate EMT cells, and orthotopically injected into mice. Statistical differences were determined by 2-tailed Student’s t test. (A) Pericyte coverage in tumor sections was determined by immunostaining of pericytes with anti-NG2 antibody and ECs with anti-MECA32 antibody. Scale bars: 50 μm. Histograms (right) of pericyte coverage and vessel density in control and SMA-DTA neuT tumors. Error bars represent SD (n = 5). **P < 0.01. (B) Tumor vascular permeability was visualized by intravenously infusing tumor-bearing mice with FITC-dextran dye (green). Tumor sections were stained for ECs with anti-CD34 antibody. Scale bars: 100 μm. Quantification of relative vascular leakiness is on the right. Error bars represent SD (n = 4). **P < 0.01. (C) Growth rate of control and SMA-DTA neuT tumors. Tumor volumes were measured at indicated time points. Error bars represent SD (n = 5). *P < 0.05. (D) A schematic model for the behavior and function of EMT carcinoma cells in tumor growth.