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 ^@

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, R.O.C.

Drs. Chen, Lin, Yao, and Yuan contributed equally to this work.

^@ 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@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.

Additional References:

1.  Archibald RB, and Frenster JH, "Quantitative Ultrastructural Analysis of In-Vivo Lymphocyte - Reed-Sternberg Cell Interactions in Hodgkin's Disease", Natl. Cancer Inst. Monogr. 36: 239-245 (1973).

2. Masek MA, Rhoades DJ, and Frenster JH, "In-Vivo Macrophage Interactions with Lymphocytes in Hodgkin's Disease", Proc. Am. Assoc. Cancer Res. 14: 8 (1973).

3. Frenster JH, "Phytohemagglutinin-Activated Autochthonous Lymphocytes for Systemic Immunotherapy of Human Neoplasms",  Annals of the New York Academy of Science, vol. 277: pp. 45-51 (1976).

4. Frenster JH, Papalian MM, Masek MA, and Frenster JA, "Electron Microscopic Analysis of Lymph Node Cellular Activity in Hodgkin's Disease", Journal of the National Cancer Institute, Vol. 63, pp. 331-335, Aug. 1979.

5. Rowan RA, Masek MA, Thompson JM, and Frenster JH, "Electron Microscopic Localization of Acid Phosphatase Activity within Hodgkin's Disease Lymph Nodes", Proc. Am. Assoc. Cancer Res. 16: 10 (1975).

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