Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts.
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.
Zeisberg
Elisabeth M
EM
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Potenta
Scott
S
Xie
Liang
L
Zeisberg
Michael
M
Kalluri
Raghu
R
D000818:Animals; D002135:Calcium-Binding Proteins / Q000032:analysis; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000473:pathology*; D005347:Fibroblasts / Q000473:pathology*; D008546:Melanoma, Experimental / Q000473:pathology; D008648:Mesoderm / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D002135:Calcium-Binding Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D053773:Transforming Growth Factor beta1