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Responsiveness of Stromal Fibroblasts to IFN- Blocks Tumor Growth via Angiostasis¹

Yu Lu,^2* Wei Yang,^2* Chuan Qin, Lianfeng Zhang, Jingjing Deng,^* Shubai Liu,^* and Zhihai Qin^3*

^*National Laboratory of Biomacromolecules, China-Japan Joint Laboratory of Structural Virology and Immunology, and Graduate School of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, and Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

The importance of stromal cells for tumor is akin to soil for seed. However, the interaction among these cells is far from understood. In this study, we show that stromal fibroblasts exist not only during tumor progression but also during regression stage, together with immune effector cells. Coinjection of stromal fibroblasts with tumor cells often promotes tumor growth. However, the presence of IFN- significantly impairs the ability of these cells to promote tumor growth due to a reduced angiogenesis. The mechanism relies mainly on the IFN--mediated down-regulation of vascular endothelial growth factor production by fibroblasts. The results reveal a novel link between immune cells and nonbone marrow-derived stromal cells, and define stromal fibroblasts as the main targets of IFN- in tumor immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant KSCX2-YW-R-42 from the Chinese Academy of Sciences, Grants 30771972 and 30700287 from the National Natural Science Foundation of China, Grants 2006CB504304, 2006CB910901, and 2009CB918900 from the Ministry of Science and Technology of China, and by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Y.L. and W.Y. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Zhihai Qin, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China. E-mail address: zhihai{at}ibp.ac.cn

⁴ Abbreviations used in this paper: VEGF, vascular endothelial growth factor; ECM, extracellular matrix; CAF, carcinoma-associated fibroblast; SDF-1, stromal cell-derived factor 1; -SMA, -smooth muscle actin; MEF, mouse embryonic fibroblast; FSP1, fibroblast specific protein 1; MMP, matrix metalloproteinase; MCA, methylcholanthrene.

⁵ The online version of this article contains supplemental material.