The cell-cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation.

Abstract

OBJECTIVES:

Small cell lung cancer (SCLC) is an aggressive tumor with a poor prognosis. It is well known that various stromal cells, including macrophages, play a role in tumor progression in several types of malignant tumors; however, the significance of tumor-associated macrophages (TAMs) in SCLC has not been fully elucidated. Signal transducer and activator of transcription 3 (STAT3) is a molecule well-known to be related to tumor progression. In the present study, we investigated the relationship of TAMs and SCLC cells to test the hypothesis that TAMs induce tumor progression in SCLC via STAT3 activation.

MATERIALS AND METHODS:

We performed immunohistochemical analysis using surgically resected tumor specimens and in vitro co-culture experiments using human SCLC cell lines and human monocyte-derived macrophages.

RESULTS:

We first demonstrated via immunostaining that STAT3 activation in tumor cells was predominantly observed in the peripheral areas of tumor nests existing near TAMs in stroma. The indirect co-culture of SCLC cells and macrophages induced STAT3 activation in both cell types, and macrophage-derived culture supernatant (CS) significantly activated STAT3 in SCLC cells. Macrophage-derived CS induced tumor cell proliferation and invasion via STAT3 activation. In addition, chemo-resistance and sphere formation were also increased by macrophage-derived CS. Macrophage-derived interleukin-6 and CC chemokine ligand 4 (CCL4/MIP-1β) were suggested to be associated with STAT3 activation in SCLC cells. CS-induced STAT3 activation in SCLC cells was suppressed by anti-IL-6 receptor antibody, but not by anti-CCL4/MIP-1β antibody.

CONCLUSION:

These results suggest that TAMs are likely involved in SCLC progression via STAT3 activation and TAM-derived IL-6 is indicated to be one of molecules related to STAT3 activation in SCLC cells. Thus, the cell-cell interaction between TAMs and SCLC cells might be a target for therapy.

• Authors: Toyohisa Iriki, Koji Ohnishi, Yukio Fujiwara, Hasita Horlad, Yoichi Saito, Cheng Pan, Koei Ikeda, Takeshi Mori, Makoto Suzuki, Hidenori Ichiyasu, Hirotsugu Kohrogi, Motohiro Takeya, Yoshihiro Komohara
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 106 Pg. 22-32 (04 2017) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 28285690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Chemokine CCL4
• IL6 protein, human
• Interleukin-6
• Receptors, Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Cell Communication (immunology)
• Cell Line, Tumor (metabolism)
• Cell Proliferation
• Chemokine CCL4 (metabolism)
• Disease Progression
• Humans
• Interleukin-6 (metabolism)
• Lung Neoplasms (pathology, surgery)
• Macrophages (immunology)
• Receptors, Interleukin-6 (metabolism)
• STAT3 Transcription Factor (immunology, metabolism)
• Signal Transduction (immunology)
• Small Cell Lung Carcinoma (metabolism, pathology, surgery)