Discovery of Endothelial to Mesenchymal Transition as a Source for Carcinoma-Associated Fibroblasts

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 A-smooth muscle actin (ASMA)-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-B1 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-loxStop-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. [Cancer Res 2007;67(21):10123-8]

Roles of TGF-β family signaling in stem cell renewal and differentiation

“…Inhibition of endogenous TGF-β and activin signaling by kinase inhibitors of the type I receptors for TGF-β/activin/Nodal not only facilitates proliferation and sheet formation of MESECs but also induces the expression of stabilin and LYVE-1, both of which are markers for sinusoidal endothelial cells [51]. Furthermore, longterm culture of MESECs with TGF-β2 results in the endothelial-mesenchymal transition (EndMT) [52], an event that is also observed during cardiac development and the formation of cancer-associated fibroblasts [53,54]. These results suggest that TGF-β family members play important roles in the proliferation, sheet formation, and subsequent differentiation of MESECs.…”

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

“…The latent TGFβ from gastric fibroblasts and scirrhous gastric cancer cells may be activated by u-PA from scirrhous gastric cancer cells. TGFβ produced from gastric fibroblasts and cancer cells themselves affect the invasiveness of scirrhous gastric cancer cells by inducing a morphologic change to a spindle shape known as the epithelial-to-mesenchymal transition (EMT) [28]. Cancer cells undergoing the EMT develop invasive and migratory abilities [29][30][31].…”

CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

“…19 A huge variety of cell types such as epithelial cells, mesenchymal stem cells, resident fibroblasts or endothelial cells have been reported to be able to transdifferentiate into CAFs through epithelial-mesenchymal transition (EMT), mesothelial-to-mesenchymal transition (MMT), or endothelial-mesenchymal transition (EndMT). [20][21][22][23][24] All these models for CAF development assume exogenous stimuli that initiate transformation and, in most cases, are thought to be sent from adjacent cancer cells in form of growth factors, such as TGF-ß and CXCL12. 23 There is experimental evidence that the CAF phenotype can also be initiated by intrinsic factors.…”