Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.
Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.
Orimo
Akira
A
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Gupta
Piyush B
PB
Sgroi
Dennis C
DC
Arenzana-Seisdedos
Fernando
F
Delaunay
Thierry
T
Naeem
Rizwan
R
Carey
Vincent J
VJ
Richardson
Andrea L
AL
Weinberg
Robert A
RA
D000199:Actins / Q000378:metabolism; D000818:Animals; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002469:Cell Separation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics; D013234:Stem Cells / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4