Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis |
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Authors: | Toshihiro Seike Kyota Fujita Yukiko Yamakawa Mizuho A Kido Soichi Takiguchi Norihiro Teramoto Haruo Iguchi Mami Noda |
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Institution: | (1) Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;(2) Department of Oral Anatomy and Cell Biology, Graduate School of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan;(3) Institute for Clinical Research, National Kyushu Cancer Center, Fukuoka 811-1395, Japan;(4) Division of Pathology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime 791-0280, Japan;(5) Clinical Research Institute, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime 791-0280, Japan; |
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Abstract: | The incidence of brain metastasis is increasing, however, little is known about molecular mechanism responsible for lung cancer-derived
brain metastasis and their development in the brain. In the present study, brain pathology was examined in an experimental
model system of brain metastasis as well as in human brain with lung cancer metastasis. In an experimental model, after 3–6 weeks
of intracardiac inoculation of human lung cancer-derived (HARA-B) cells in nude mice, wide range of brain metastases were
observed. The brain sections showed significant increase in glial fibrillary acidic protein (GFAP)-positive astrocytes around
metastatic lesions. To elucidate the role of astrocytes in lung cancer proliferation, the interaction between primary cultured
mouse astrocytes and HARA-B cells was analyzed in vitro. Co-cultures and insert-cultures demonstrated that astrocytes were
activated by tumor cell-oriented factors; macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8) and plasminogen
activator inhibitor-1 (PAI-1). Activated astrocytes produced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1
β (IL-1β), which in turn promoted tumor cell proliferation. Semi-quantitative immunocytochemistry showed that increased expression
of receptors for IL-6 and its subunits gp130 on HARA-B cells. Receptors for TNF-α and IL-1β were also detected on HARA-B cells
but down-regulated after co-culture with astrocytes. Insert-culture with astrocytes also stimulated the proliferation of other
lung cancer-derived cell lines (PC-9, QG56, and EBC-1). These results suggest that tumor cells and astrocytes stimulate each
other and these mutual relationships may be important to understand how lung cancer cells metastasize and develop in the brain. |
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