Originally published as JCO Early Release 10.1200/JCO.2005.12.172 on December 14 2004
Journal of Clinical Oncology, Vol 23, No 5 (February 10), 2005: pp. 953-964
© 2005 American Society of Clinical Oncology.
Tumor-Associated Macrophages: The Double-Edged Sword in Cancer Progression
Jeremy J.W. Chen,
Yi-Chen Lin,
Pei-Li Yao,
Ang Yuan,
Hsang-Yu Chen,
Chia-Tung Shun,
Meng-Feng Tsai,
Chun-Houh Chen,
Pan-Chyr Yang
From the Institutes of Biomedical Sciences and Molecular Biology, National Chung Hsing University, Taichung; Center for Genomic Medicine, National Taiwan University College of Medicine; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine; Graduate Institute of Epidemiology, National Taiwan University, Taipei; Department of Forensic Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine; Institute of Statistical Science and Institute of Biomedical Sciences, Academia Sinica; and National Health Research Institute, Taipei, Taiwan, Republic of China
Address reprint requests to Pan-Chyr Yang, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan S Rd, Taipei, Taiwan 100, R.O.C.; e-mail: pcyang{at}ha.mc.ntu.edu.tw.
PURPOSE: Inflammation plays a critical role in cancer progression. In this study we investigate the pro-tumorigenic activities and gene expression profiles of lung cancer cells after interaction with macrophages.
MATERIALS AND METHODS: We measured intratumoral microvessel counts and macrophage density in 41 lung cancer tumor specimens and correlated these with the patients' clinical outcome. The interaction between macrophages and cancer cell lines was assessed using a transwell coculture system. The invasive potential was evaluated by in vitro invasion assay. The matrix-degrading activity was assayed by gelatin zymography. The microarray was applied to a large-scale analysis of the genes involved in the interaction, as well as to monitor the gene expression profiles of lung cancer cells responding to anti-inflammatory drugs in cocultures.
RESULTS: The macrophage density positively correlated with microvessel counts and negatively correlated with patient relapse-free survival (P < .05). After coculture with macrophages, lung cancer cell lines exhibited higher invasive potentials and matrix-degrading activities. We identified 50 genes by microarray that were upregulated more than two-fold in cancer cells after coculture. Northern blot analyses confirmed some gene expression such as interleukin-6, interleukin-8, and matrix metalloproteinase 9. The two-dimensional hierarchical clustering also demonstrated that the gene expression profiles of lung cancer cells responding to various anti-inflammatory drugs in cocultures are distinct.
CONCLUSION: The interaction of lung cancer cells and macrophages can promote the invasiveness and matrix-degrading activity of cancer cells. Our results also suggest that a great diversity of gene expression occurs in this interaction, which may assist us in understanding the process of cancer metastasis.
Supported by the National Science Council (NSC 91-3112-P-005-008–Y; NSC91-3112-P-002-017-Y) and National Health Research Institutes of the Republic of China through the National Research Program for Genomic Medicine Grant (NHRI92A1-NSCLC09-5).
Presented in part at the 94th Meeting of the American Association for Cancer Research, Washington, DC, July 11-14, 2003.
Drs Chen, Lin, Yao, and Yuan contributed equally to this work.
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
This article has been cited by other articles:
|
|
|
|
 
M. Skrzypski, E. Jassem, M. Taron, J. J. Sanchez, P. Mendez, W. Rzyman, G. Gulida, D. Raz, D. Jablons, M. Provencio, et al.
Three-Gene Expression Signature Predicts Survival in Early-Stage Squamous Cell Carcinoma of the Lung
Clin. Cancer Res.,
August 1, 2008;
14(15):
4794 - 4799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Arnold, E. Mira, S. Muneer, G. Korpanty, A. W. Beck, S. E. Holloway, S. Manes, and R. A. Brekken
Forced Expression of MMP9 Rescues the Loss of Angiogenesis and Abrogates Metastasis of Pancreatic Tumors Triggered by the Absence of Host SPARC
Experimental Biology and Medicine,
July 1, 2008;
233(7):
860 - 873.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Dave
Follicular lymphoma and the microenvironment
Blood,
May 1, 2008;
111(9):
4427 - 4428.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-C. Ho, W.-Y. Liao, C.-Y. Wang, Y.-H. Lu, H.-Y. Huang, H.-Y. Chen, W.-K. Chan, H.-W. Chen, and P.-C. Yang
TREM-1 Expression in Tumor-associated Macrophages and Clinical Outcome in Lung Cancer
Am. J. Respir. Crit. Care Med.,
April 1, 2008;
177(7):
763 - 770.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. S. Stearman, L. Dwyer-Nield, M. C. Grady, A. M. Malkinson, and M. W. Geraci
A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment
Cancer Res.,
January 1, 2008;
68(1):
34 - 43.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. D. DuSell, M. Umetani, P. W. Shaul, D. J. Mangelsdorf, and D. P. McDonnell
27-Hydroxycholesterol Is an Endogenous Selective Estrogen Receptor Modulator
Mol. Endocrinol.,
January 1, 2008;
22(1):
65 - 77.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. V. Popovic, R. Sandhoff, T. P. Sijmonsma, S. Kaden, R. Jennemann, E. Kiss, E. Tone, F. Autschbach, N. Platt, E. Malle, et al.
Sulfated Glycosphingolipid as Mediator of Phagocytosis: SM4s Enhances Apoptotic Cell Clearance and Modulates Macrophage Activity
J. Immunol.,
November 15, 2007;
179(10):
6770 - 6782.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D.-M. Kuang, Y. Wu, N. Chen, J. Cheng, S.-M. Zhuang, and L. Zheng
Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes
Blood,
July 15, 2007;
110(2):
587 - 595.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Cheng, D.-H. Huo, D.-M. Kuang, J. Yang, L. Zheng, and S.-M. Zhuang
Human Macrophages Promote the Motility and Invasiveness of Osteopontin-Knockdown Tumor Cells
Cancer Res.,
June 1, 2007;
67(11):
5141 - 5147.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P.-L. Yao, Y.-C. Lin, P. Sawhney, and J. H. Richburg
Transcriptional Regulation of FasL Expression and Participation of sTNF-{alpha} in Response to Sertoli Cell Injury
J. Biol. Chem.,
February 23, 2007;
282(8):
5420 - 5431.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-Y. Chen, S.-L. Yu, C.-H. Chen, G.-C. Chang, C.-Y. Chen, A. Yuan, C.-L. Cheng, C.-H. Wang, H.-J. Terng, S.-F. Kao, et al.
A Five-Gene Signature and Clinical Outcome in Non-Small-Cell Lung Cancer
N. Engl. J. Med.,
January 4, 2007;
356(1):
11 - 20.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-W. Chen, S.-F. Su, C.-T. Chien, W.-H. Lin, S.-L. Yu, C.-C. Chou, J. J. W. Chen, and P.-C. Yang
Titanium dioxide nanoparticles induce emphysema-like lung injury in mice
FASEB J,
November 1, 2006;
20(13):
2393 - 2395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-C. Liu, W.-S. E. Chen, C.-C. Lin, H.-C. Liu, H.-Y. Chen, P.-C. Yang, P.-C. Chang, and J. J.W. Chen
Topology-based cancer classification and related pathway mining using microarray data
Nucleic Acids Res.,
September 1, 2006;
34(14):
4069 - 4080.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-C. Liu, C.-C. Lin, W.-S. E. Chen, H.-Y. Chen, P.-C. Chang, J. J.W. Chen, and P.-C. Yang
CRSD: a comprehensive web server for composite regulatory signature discovery.
Nucleic Acids Res.,
July 1, 2006;
34(Web Server issue):
W571 - W577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-S. Chen, H.-Y. Chang, C.-P. Li, J. M. Liu, and T.-S. Huang
Tumor {beta}-1,4-Galactosyltransferase IV Overexpression Is Closely Associated with Colorectal Cancer Metastasis and Poor Prognosis
Clin. Cancer Res.,
December 15, 2005;
11(24):
8615 - 8622.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
