Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts

2007-11-01 | journal article; research paper

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​Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts​
Zeisberg, E. M. ; Potenta, S.; Xie, L.; Zeisberg, M.   & Kalluri, R.​ (2007) 
Cancer Research67(21) pp. 10123​-10128​.​ DOI: https://doi.org/10.1158/0008-5472.CAN-07-3127 

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Authors
Zeisberg, Elisabeth M. ; Potenta, Scott; Xie, Liang; Zeisberg, Michael ; Kalluri, Raghu
Abstract
Activated fibroblasts are associated with many different tumors. Myofibroblasts, activated fibroblasts, and perivascular mesenchymal cells such as pericytes play a role in cancer progression. Many studies suggest that myofibroblasts facilitate tumor growth and cancer progression. The source for myofibroblasts and other activated fibroblasts within the tumors is still debated. Although de novo activation of quiescent fibroblasts into alpha-smooth muscle actin (alpha SMA)-positive myofibroblasts is one likely source, epithelial to mesenchymal transition and bone marrow recruitment are also evolving as possible mechanisms for the emergence of a heterogeneous population of carcinoma-associated fibroblasts. Here, we show that transforming growth factor-beta1 could induce proliferating endothelial cells to undergo a phenotypic conversion into fibroblast-like cells. Such endothelial to mesenchymal transition (EndMT) is associated with the emergence of mesenchymal marker fibroblast-specific protein-1 (FSP1) and down-regulation of CD31/PECAM. Additionally, we show EndMT in tumors using the B16F10 melanoma model and the Rip-Tag2 spontaneous pancreatic carcinoma model. Crossing Tie2-Cre mice with R26Rosa-lox-Stop-lox-LacZ mice allows for irreversible tagging of endothelial cells. We provide unequivocal evidence for EndMT at the invasive front of the tumors in these transgenic mice. Collectively, our results show that EndMT is a unique mechanism for the accumulation of carcinoma-associated fibroblasts and suggest that antiangiogenic treatment of tumors may have a direct effect in decreasing activated fibroblasts that likely facilitate cancer progression.
Issue Date
1-November-2007
Journal
Cancer Research 
ISSN
0008-5472
eISSN
1538-7445
Language
English

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