TY - JOUR
T1 - Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion
AU - Orimo, Akira
AU - Gupta, Piyush B.
AU - Sgroi, Dennis C.
AU - Arenzana-Seisdedos, Fernando
AU - Delaunay, Thierry
AU - Naeem, Rizwan
AU - Carey, Vincent J.
AU - Richardson, Andrea L.
AU - Weinberg, Robert A.
N1 - Funding Information:
We would like to thank Dr. Todd R. Golub for help of DNA microarray experiment and critical reading of this manuscript, Drs. Ittai Ben-Porath, Kimberly Hartwell, Christina Scheel, Nir Hacohen, Konrad Hochedlinger, and Chengcheng Zhang for critical reading of this manuscript and Drs. Paul Matsudaira, S.A. Mani, and Sridhar Ramaswamy for helpful experimental suggestions and data analysis and members of R.A.W.’s laboratory for helpful comments and discussion. We appreciate Dr. Charlotte Kuperwasser’s assistance in the isolation of fibroblasts from human breast tissues, Dr. Tasuku Honjo for gift of the human SDF-1 cDNA, and Dr. Ittai Ben-Porath for a pLKO1- GFP -siRNA vector. This work was supported by Merck/MIT (R.A.W.), NIH/NCI grant R21CA87081-02 (R.A.W.), the Ludwig Trust (R.A.W.), the Breast Cancer Research Foundation (R.A.W.), Uehara Memorial Foundation (A.O.), Sankyo Foundation of Life Science (A.O.), and a US Army Pre-doctoral Breast Cancer Fellowship DAMD17-02-1-0468 (P.B.G). R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor. This work was conducted utilizing the W.M. Keck Foundation Biological imaging facility at the Whitehead Institute.
PY - 2005/5/6
Y1 - 2005/5/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2005.02.034
DO - 10.1016/j.cell.2005.02.034
M3 - Article
C2 - 15882617
AN - SCOPUS:18844428327
SN - 0092-8674
VL - 121
SP - 335
EP - 348
JO - Cell
JF - Cell
IS - 3
ER -