Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells
Anitha K. Shenoy, … , Lung-Ji Chang, Jianrong Lu
Anitha K. Shenoy, … , Lung-Ji Chang, Jianrong Lu
Published October 10, 2016
Citation Information: J Clin Invest. 2016;126(11):4174-4186. https://doi.org/10.1172/JCI86623.
View: Text | PDF
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

×

Figure 3

EMT cancer cells express pericyte markers in vitro and in vivo.

Options: View larger image (or click on image) Download as PowerPoint
EMT cancer cells express pericyte markers in vitro and in vivo. (A) Quan...
(A) Quantitative RT-PCR analysis of expression of indicated pericyte markers in various epithelial, mesenchymal, and EMT cells. Error bars represent SD (n = 3). (B) Immunofluorescence staining of indicated EMT and pericyte markers in DCIS-Snail-ER cells that were treated with DMSO or 4HT. α-Smooth muscle actin (SMA) is a marker for a subpopulation of pericytes and smooth muscle cells. Scale bars: 50 μm. (C) Inducible EMT cancer cells express pericyte marker NG2 in vivo. DCIS-Snail-ER cells were mixed with DCIS cells (1:4, as in Figure 1) for tumor transplantation. Tumor-bearing mice were treated with tamoxifen (tam). Tumor sections were fixed with acetone, followed by immunostaining with anti-NG2 and anti-Snail antibodies for pericytes and DCIS-Snail-ER cancer cells, respectively. Scale bars: 50 μm. (D) Spontaneous EMT cancer cells express the pericyte marker NG2 in vivo. GFP-tagged neuT epithelial tumor cells were orthotopically implanted in mice. Tumor sections were fixed with acetone and immunostained with anti-NG2 antibody (for pericytes) and anti-GFP antibody (for tumor cells). Scale bars: 25 μm.