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Published ahead of print on December 20, 2007, doi:10.1164/rccm.200704-641OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 7, April 2008, 763-770

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Submitted on April 30, 2007
Accepted on December 20, 2007

TREM-1 Expression in Tumor-associated Macrophages and Clinical Outcome in Lung Cancer

Chao-Chi Ho1, Wei-Yu Liao1, Cheng-Yi Wang2, Yin-Hsiu Lu3, Hsin-Yi Huang4, Hsuan-Yu Chen5, Wing-Kai Chan6, Huei-Wen Chen7, and Pan-Chyr Yang8*

1 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Taiwan; Department of Emergency Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Taiwan, 2 Department of Internal Medicine, Catholic Cardinal Hsien Tien Hospital, Fu-Jen Catholic University, Taipei, Taiwan, Taiwan, 3 National Taiwan University College of Medicine, Center for Genomic Medicine, Taipei, Taiwan, Taiwan, 4 Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Taiwan, 5 National Taiwan University College of Medicine, Center for Genomic Medicine, Taipei, Taiwan, Taiwan; Institute of Statistical Sciences, Academia Sinica, Taipei, Taiwan, Taiwan, 6 Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, Taiwan, 7 Department and Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan, Taiwan, 8 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Taiwan

* To whom correspondence should be addressed. E-mail: pcyang{at}ntu.edu.tw.

Rationale: Triggering receptor expressed on myeloid cells 1 (TREM-1) is a molecule crucial for the triggering and amplification of inflammatory response and a new biomarker for sepsis. Tumor-associated macrophages and inflammation in tumor microenvironment are also involved in cancer progression. Objectives: To determine the role of TREM-1 in tumor-associated macrophage and cancer progression. Methods: Using enzyme-link immunosorbent assay (ELISA) and Western blot, we measured soluble TREM-1 (sTREM-1) level in 65 pleural effusions of various etiologies. We evaluated TREM-1 positive cells by immnocytochemistry in malignant pleural effusion and in lung tumor versus adjacent normal tissue in surgical specimens from 68 NSCLC patients. TREM-1 expression was correlated with patient survival. TREM-1 expression in primary isolated peripheral blood macrophages co-cultured with lung cancer cell-lines was determined by quantitative real-time RT-PCR. Measurements and Main Results: sTREM-1 and tumor- associated macrophage TREM-1 expression were increased in malignant pleural effusions in non-small cell lung cancer (NSCLC) patients. Lung cancer cells could directly up-regulate TREM-1 and pro-inflammatory cytokines (tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-1{beta} (IL-1{beta})) expression in primary isolated peripheral blood macrophages in co-culture experiments. Increased TREM-1 positive tumor-associated macrophages in tumor tissue of NSCLC patients were associated with reduced disease-free (P=0.011) and overall survival (P=0.004). Multivariate Cox regression analysis indicated that TREM-1 was an independent predictor of patient survival (HR= 2.72, 95% CI=1.33 to 5.57, P=0.006). Conclusions: Cancer cells can directly up-regulate TREM-1 expression in patients' macrophages. TREM-1 expression in tumor-associated macrophages is associated with cancer recurrence and poor survival of NSCLC patients. TREM-1 and the inflammatory response may play an important role in cancer progression.
Key words: TREM-1, tumor-associated macrophage, cancer progression, lung cancer, survival.






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Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2007 American Thoracic Society