Otsuka Shinsaku, Hanibuchi Masaki, Ikuta Kenji, Yano Seiji, Goto Hisatsugu, Ogino Hirokazu, Yamada Tadaaki, Kakiuchi Soji, Nishioka Yasuhiko, Takahashi Takashi, Sone Saburo
Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Gradate School, Tokushima, 770-8503, Japan.
Oncol Res. 2009;17(11-12):581-91. doi: 10.3727/096504009789745511.
Lung cancer is commonly associated with multiple-organ metastasis, and bone is a frequent metastatic site for lung cancer. Lung cancer frequently develops osteolytic, and less frequently osteoblastic, metastasis to bone. Osteolytic metastasis models of lung cancer have been reported, but no osteoblastic metastasis model is available for lung cancer. In the present study, we established a reproducible model of human lung cancer with both osteolytic and osteoblastic changes in natural killer cell-depleted severe combined immunodeficient mice. Intravenous inoculation of ACC-LC-319/bone2 cells resulted in the development of metastatic colonies in the lung, liver, and bone of the mice. As assessed sequentially by X-ray photographs, osteolytic bone lesions were observed by day 28, and then osteoblastic lesions were detected by day 35. Histological examination revealed the presence of bony spurs, a hallmark of osteoblastic bone metastasis, where osteoclasts were hardly observed. Treatment with an anti-human vascular endothelial growth factor antibody, bevacizumab, as well as zoledronate, inhibited the number of experimental bone metastases, including osteoblastic changes produced by ACC-LC-319/bone2 cells. These results indicate that our bone metastasis model by ACC-LC319/bone2 might be useful to understand the molecular pathogenesis of osteolytic and osteoblastic metastasis, and to identify molecular targets to control bone metastasis of lung cancer.
肺癌常伴有多器官转移，骨是肺癌常见的转移部位。肺癌常发生溶骨性骨转移，成骨性骨转移较少见。已有肺癌溶骨性转移模型的报道，但尚无肺癌成骨性转移模型。在本研究中，我们在自然杀伤细胞缺陷的严重联合免疫缺陷小鼠中建立了一种可重现的人肺癌模型，该模型同时具有溶骨性和成骨性变化。静脉注射ACC-LC-319/bone2细胞导致小鼠肺、肝和骨中出现转移性菌落。通过X线照片顺序评估，在第28天观察到溶骨性骨病变，然后在第35天检测到成骨性病变。组织学检查显示存在骨剌，这是成骨性骨转移的标志，几乎未观察到破骨细胞。用抗人血管内皮生长因子抗体贝伐单抗以及唑来膦酸治疗可抑制实验性骨转移的数量，包括ACC-LC-319/bone2细胞产生的成骨性变化。这些结果表明，我们用ACC-LC319/bone2建立的骨转移模型可能有助于理解溶骨性和成骨性转移的分子发病机制，并有助于确定控制肺癌骨转移的分子靶点。
