Source: Annual Congress 2010 - Pathology of lung cancer

Abstract

The skeleton is a frequent target of lung cancer metastasis, and the site of disease that produces the greatest morbidity. Approximately 30% to 40% of patients with advanced lung cancer will develop bone metastasis, resulting in a significant deleterious impact on both morbidity and survival. This study analyzed the soluble factors secreted by lung cancer cells which are responsible for increasing osteoclast differentiation. Addition of recombinant human interleukin-8 (rhIL-8), present in large amounts in A549-condition medium (CM) and NCI-H460-CM, mimicked the inductive effect of A549-CM and NCI-H460-CM on osteoclastogenesis. Induction of osteoclast differentiation by lung cancer-derived CM and rhIL-8 was associated with increased phospholipase D (PLD) activation, and the activations of protein kinase C (PKC)α /βII, ERK1/2 and AKT/the mammalian target of rapamycin (mTOR). Blocking PLD by a specific inhibitor significantly decreased osteoclast formation by inhibiting PKCs activation and subsequently attenuating the phosphorylation of ERK1/2. PLD inhibitor also completely decreased AKT and mTOR phosphorylation, whereas phosphatidyl-inositol-3-kinase (PI3K) inhibitor only partially decreased mTOR phosphorylation, suggesting that mTOR activation is through both a PI3K/AKT-dependent and independent manner. In addition, blocking AKT and ERK1/2 by a specific inhibitor also suppressed lung cancer-derived CM and rhIL-8-induced osteoclast differentiation. Our study suggests that inhibition of IL-8 or IL-8-mediated PLD/PKC/ERK1/2 or PLD/AKT signaling is an attractive therapeutic target for osteolytic bone metastases in lung cancer patients.

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Y. L. Hsu, J. Y. Hung, Y. C. Ko, C. H. Hung, M. S. Huang, P. L. Kuo (Taiwan). Lung cancer-derived IL-8 increased osteoclastogenesis via phospholipase D signaling pathway. Eur Respir J 2010; 36: Suppl. 54, 3267

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