Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: Its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer

Jeremy J.W. Chen, Pei Li Yao, Ang Yuan, Tse-Ming Hong, Chia Tung Shun, Min Liang Kuo, Yung Chie Lee, Pan Chyr Yang

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Abstract

Purpose: To evaluate the interaction between tumorinfiltrating macrophages and cancer cells and its effect on the expression of a potent angiogenic factor, interleukin-8 (IL-8), tumor angiogenesis, and patient outcome in nonsmall cell lung cancer (NSCLC). Experimental Design: We measured tumor IL-8 mRNA expression (by real-time quantitative reverse transcriptionPCR), intratumor microvessel counts, and tumor-infiltrating macrophage density (by immunohistochemical staining) in 35 NSCLC surgical specimens and correlated with the patient's clinical outcome. We then investigated the interaction between macrophages (cell line THP-1) and six different human cancer cell lines (four NSCLCs, one osteosarcoma, and one hepatoma) and its effect on IL-8 mRNA expression using a macrophage/cancer cell coculture system, IL-8 mRNA expression in lung cancer cells, and macrophages being measured separately after coculture in the presence or absence of six anti-inflammatory agents, i.e., pentoxifylline, aspirin, indomethacin, dexamethasone, celecoxib (a selective cyclooxygenase-2 inhibitor), and pyrrolidine dithiocarbamate, a specific nuclear factor κB (NF-κB) inhibitor. NF-κB transcriptional activity and protein levels were measured by reporter gene assay and Western blot. Results: The tumor-infiltrating macrophage density correlated significantly and positively with tumor IL-8 mRNA expression and intratumor microvessel counts and significantly and negatively with patient survival. In addition, after cell-cell interaction in cancer cell:macrophage cocultures, marked IL-8 mRNA expression was induced in lung cancer cells (∼270-fold) and, to a lesser degree, in macrophages (4.5-fold). The increase in IL-8 mRNA expression correlated with the in vitro metastatic potential of the cancer cells. All six anti-inflammatory agents suppressed induction of IL-8 mRNA expression in lung cancer cells by > 90%, four (pentoxifylline, celecoxib, pyrrolidine dithiocarbamate, and dexamethasone) having a dose-dependent effect. NF-κB transcriptional regulation and protein levels were simultaneously increased in the nuclei of cancer cells in macrophage/cancer cell cocultures, this effect also being suppressed by all six anti-inflammatory agents. Conclusions: The interaction between infiltrating macrophages and cancer cells up-regulates IL-8 mRNA expression, especially in the cancer cells; this may contribute greatly to the increased tumor angiogenesis and adverse outcome in NSCLC patients with a high density of tumorinfiltrating macrophages. Anti-inflammatory agents can suppress the induction of IL-8 mRNA expression seen in lung cancer cells after coculture with macrophages, and this suppression is mediated, in part, through the NF-κB pathway.

Original languageEnglish
Pages (from-to)729-737
Number of pages9
JournalClinical Cancer Research
Volume9
Issue number2
Publication statusPublished - 2003 Feb 1

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Interleukin-8
Non-Small Cell Lung Carcinoma
Up-Regulation
Macrophages
Survival
Neoplasms
Messenger RNA
Coculture Techniques
Celecoxib
Lung Neoplasms
Anti-Inflammatory Agents
Pentoxifylline
Microvessels
Dexamethasone
Cell Line
Cyclooxygenase 2 Inhibitors
Angiogenesis Inducing Agents
Osteosarcoma
Cell Nucleus
Reporter Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chen, Jeremy J.W. ; Yao, Pei Li ; Yuan, Ang ; Hong, Tse-Ming ; Shun, Chia Tung ; Kuo, Min Liang ; Lee, Yung Chie ; Yang, Pan Chyr. / Up-regulation of tumor interleukin-8 expression by infiltrating macrophages : Its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 2. pp. 729-737.
@article{c595485f1336405b827aacb4615f0b9f,
title = "Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: Its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer",
abstract = "Purpose: To evaluate the interaction between tumorinfiltrating macrophages and cancer cells and its effect on the expression of a potent angiogenic factor, interleukin-8 (IL-8), tumor angiogenesis, and patient outcome in nonsmall cell lung cancer (NSCLC). Experimental Design: We measured tumor IL-8 mRNA expression (by real-time quantitative reverse transcriptionPCR), intratumor microvessel counts, and tumor-infiltrating macrophage density (by immunohistochemical staining) in 35 NSCLC surgical specimens and correlated with the patient's clinical outcome. We then investigated the interaction between macrophages (cell line THP-1) and six different human cancer cell lines (four NSCLCs, one osteosarcoma, and one hepatoma) and its effect on IL-8 mRNA expression using a macrophage/cancer cell coculture system, IL-8 mRNA expression in lung cancer cells, and macrophages being measured separately after coculture in the presence or absence of six anti-inflammatory agents, i.e., pentoxifylline, aspirin, indomethacin, dexamethasone, celecoxib (a selective cyclooxygenase-2 inhibitor), and pyrrolidine dithiocarbamate, a specific nuclear factor κB (NF-κB) inhibitor. NF-κB transcriptional activity and protein levels were measured by reporter gene assay and Western blot. Results: The tumor-infiltrating macrophage density correlated significantly and positively with tumor IL-8 mRNA expression and intratumor microvessel counts and significantly and negatively with patient survival. In addition, after cell-cell interaction in cancer cell:macrophage cocultures, marked IL-8 mRNA expression was induced in lung cancer cells (∼270-fold) and, to a lesser degree, in macrophages (4.5-fold). The increase in IL-8 mRNA expression correlated with the in vitro metastatic potential of the cancer cells. All six anti-inflammatory agents suppressed induction of IL-8 mRNA expression in lung cancer cells by > 90{\%}, four (pentoxifylline, celecoxib, pyrrolidine dithiocarbamate, and dexamethasone) having a dose-dependent effect. NF-κB transcriptional regulation and protein levels were simultaneously increased in the nuclei of cancer cells in macrophage/cancer cell cocultures, this effect also being suppressed by all six anti-inflammatory agents. Conclusions: The interaction between infiltrating macrophages and cancer cells up-regulates IL-8 mRNA expression, especially in the cancer cells; this may contribute greatly to the increased tumor angiogenesis and adverse outcome in NSCLC patients with a high density of tumorinfiltrating macrophages. Anti-inflammatory agents can suppress the induction of IL-8 mRNA expression seen in lung cancer cells after coculture with macrophages, and this suppression is mediated, in part, through the NF-κB pathway.",
author = "Chen, {Jeremy J.W.} and Yao, {Pei Li} and Ang Yuan and Tse-Ming Hong and Shun, {Chia Tung} and Kuo, {Min Liang} and Lee, {Yung Chie} and Yang, {Pan Chyr}",
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month = "2",
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volume = "9",
pages = "729--737",
journal = "Clinical Cancer Research",
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Up-regulation of tumor interleukin-8 expression by infiltrating macrophages : Its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. / Chen, Jeremy J.W.; Yao, Pei Li; Yuan, Ang; Hong, Tse-Ming; Shun, Chia Tung; Kuo, Min Liang; Lee, Yung Chie; Yang, Pan Chyr.

In: Clinical Cancer Research, Vol. 9, No. 2, 01.02.2003, p. 729-737.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Up-regulation of tumor interleukin-8 expression by infiltrating macrophages

T2 - Its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer

AU - Chen, Jeremy J.W.

AU - Yao, Pei Li

AU - Yuan, Ang

AU - Hong, Tse-Ming

AU - Shun, Chia Tung

AU - Kuo, Min Liang

AU - Lee, Yung Chie

AU - Yang, Pan Chyr

PY - 2003/2/1

Y1 - 2003/2/1

N2 - Purpose: To evaluate the interaction between tumorinfiltrating macrophages and cancer cells and its effect on the expression of a potent angiogenic factor, interleukin-8 (IL-8), tumor angiogenesis, and patient outcome in nonsmall cell lung cancer (NSCLC). Experimental Design: We measured tumor IL-8 mRNA expression (by real-time quantitative reverse transcriptionPCR), intratumor microvessel counts, and tumor-infiltrating macrophage density (by immunohistochemical staining) in 35 NSCLC surgical specimens and correlated with the patient's clinical outcome. We then investigated the interaction between macrophages (cell line THP-1) and six different human cancer cell lines (four NSCLCs, one osteosarcoma, and one hepatoma) and its effect on IL-8 mRNA expression using a macrophage/cancer cell coculture system, IL-8 mRNA expression in lung cancer cells, and macrophages being measured separately after coculture in the presence or absence of six anti-inflammatory agents, i.e., pentoxifylline, aspirin, indomethacin, dexamethasone, celecoxib (a selective cyclooxygenase-2 inhibitor), and pyrrolidine dithiocarbamate, a specific nuclear factor κB (NF-κB) inhibitor. NF-κB transcriptional activity and protein levels were measured by reporter gene assay and Western blot. Results: The tumor-infiltrating macrophage density correlated significantly and positively with tumor IL-8 mRNA expression and intratumor microvessel counts and significantly and negatively with patient survival. In addition, after cell-cell interaction in cancer cell:macrophage cocultures, marked IL-8 mRNA expression was induced in lung cancer cells (∼270-fold) and, to a lesser degree, in macrophages (4.5-fold). The increase in IL-8 mRNA expression correlated with the in vitro metastatic potential of the cancer cells. All six anti-inflammatory agents suppressed induction of IL-8 mRNA expression in lung cancer cells by > 90%, four (pentoxifylline, celecoxib, pyrrolidine dithiocarbamate, and dexamethasone) having a dose-dependent effect. NF-κB transcriptional regulation and protein levels were simultaneously increased in the nuclei of cancer cells in macrophage/cancer cell cocultures, this effect also being suppressed by all six anti-inflammatory agents. Conclusions: The interaction between infiltrating macrophages and cancer cells up-regulates IL-8 mRNA expression, especially in the cancer cells; this may contribute greatly to the increased tumor angiogenesis and adverse outcome in NSCLC patients with a high density of tumorinfiltrating macrophages. Anti-inflammatory agents can suppress the induction of IL-8 mRNA expression seen in lung cancer cells after coculture with macrophages, and this suppression is mediated, in part, through the NF-κB pathway.

AB - Purpose: To evaluate the interaction between tumorinfiltrating macrophages and cancer cells and its effect on the expression of a potent angiogenic factor, interleukin-8 (IL-8), tumor angiogenesis, and patient outcome in nonsmall cell lung cancer (NSCLC). Experimental Design: We measured tumor IL-8 mRNA expression (by real-time quantitative reverse transcriptionPCR), intratumor microvessel counts, and tumor-infiltrating macrophage density (by immunohistochemical staining) in 35 NSCLC surgical specimens and correlated with the patient's clinical outcome. We then investigated the interaction between macrophages (cell line THP-1) and six different human cancer cell lines (four NSCLCs, one osteosarcoma, and one hepatoma) and its effect on IL-8 mRNA expression using a macrophage/cancer cell coculture system, IL-8 mRNA expression in lung cancer cells, and macrophages being measured separately after coculture in the presence or absence of six anti-inflammatory agents, i.e., pentoxifylline, aspirin, indomethacin, dexamethasone, celecoxib (a selective cyclooxygenase-2 inhibitor), and pyrrolidine dithiocarbamate, a specific nuclear factor κB (NF-κB) inhibitor. NF-κB transcriptional activity and protein levels were measured by reporter gene assay and Western blot. Results: The tumor-infiltrating macrophage density correlated significantly and positively with tumor IL-8 mRNA expression and intratumor microvessel counts and significantly and negatively with patient survival. In addition, after cell-cell interaction in cancer cell:macrophage cocultures, marked IL-8 mRNA expression was induced in lung cancer cells (∼270-fold) and, to a lesser degree, in macrophages (4.5-fold). The increase in IL-8 mRNA expression correlated with the in vitro metastatic potential of the cancer cells. All six anti-inflammatory agents suppressed induction of IL-8 mRNA expression in lung cancer cells by > 90%, four (pentoxifylline, celecoxib, pyrrolidine dithiocarbamate, and dexamethasone) having a dose-dependent effect. NF-κB transcriptional regulation and protein levels were simultaneously increased in the nuclei of cancer cells in macrophage/cancer cell cocultures, this effect also being suppressed by all six anti-inflammatory agents. Conclusions: The interaction between infiltrating macrophages and cancer cells up-regulates IL-8 mRNA expression, especially in the cancer cells; this may contribute greatly to the increased tumor angiogenesis and adverse outcome in NSCLC patients with a high density of tumorinfiltrating macrophages. Anti-inflammatory agents can suppress the induction of IL-8 mRNA expression seen in lung cancer cells after coculture with macrophages, and this suppression is mediated, in part, through the NF-κB pathway.

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