Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts.
Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.
Cancer Research-UK Stromal-Tumor Interaction Group, Paterson Institute for Cancer Research, The University of Manchester, Manchester M20 4BX, United Kingdom.
Yasushi
Y
Kojima
Ahmet
A
Acar
Elinor Ng
EN
Eaton
Kieran T
KT
Mellody
Christina
C
Scheel
Ittai
I
Ben-Porath
Tamer T
TT
Onder
Zhigang C
ZC
Wang
Andrea L
AL
Richardson
Robert A
RA
Weinberg
Akira
A
Orimo
D000818:Animals; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D058628:Myofibroblasts / Q000473:pathology*; D009361:Neoplasm Invasiveness; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta