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

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

Correspondence and requests for reprints should be addressed to Dr. Pan-Chyr Yang, M.D., Ph.D., Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan 100, Republic of China. E-mail: pcyang{at}ntu.edu.tw

Rationale: Triggering receptor expressed on myeloid cells (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 the 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 ELISA and Western blot, we measured soluble TREM-1 levels in 65 pleural effusions of various etiologies. We evaluated TREM-1–positive cells by immunocytochemistry in malignant pleural effusion and in lung tumor versus adjacent normal tissue in surgical specimens from 68 patients with non–small cell lung cancer (NSCLC). TREM-1 expression was correlated with patient survival. TREM-1 expression in primary isolated peripheral blood macrophages cocultured with lung cancer cell lines was determined by quantitative real-time reverse transcriptase–polymerase chain reaction.

Measurements and Main Results: Soluble TREM-1 and tumor-associated macrophage TREM-1 expression was increased in malignant pleural effusions in patients with NSCLC. Lung cancer cells could directly up-regulate TREM-1 and proinflammatory cytokine (tumor necrosis factor-, IL-1β) expression in primary isolated peripheral blood macrophages in coculture experiments. Increased TREM-1–positive tumor-associated macrophages in tumor tissue of patients with NSCLC 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 (hazard ratio, 2.72; 95% confidence interval, 1.33–5.57; 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 patients with NSCLC. TREM-1 and the inflammatory response may play an important role in cancer progression.

Key Words: TREM-1 • non-small cell lung cancer • macrophage • inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject TREM-1 is a novel molecule for the triggering and amplification of inflammatory response and a new biomarker for sepsis. The role of TREM-1 in cancer progression is unknown. What This Study Adds to the Field TREM-1 is expressed in tumor-associated macrophages (TAM) in malignant effusion and tumor tissue of non–small cell lung cancer. Lung cancer cells directly up-regulate TREM-1 expression in macrophages of patients with lung cancer. TREM-1 expression in TAM is associated with cancer recurrence and poor survival of patients.