Kaya Mitsunori, Wada Takuro, Nagoya Satoshi, Yamashita Toshihiko
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
J Orthop Sci. 2007 Nov;12(6):562-7. doi: 10.1007/s00776-007-1179-1. Epub 2007 Nov 30.
We have previously offered data suggesting a positive linkage of postoperative up-regulation of systemic angiogenic activity and postoperative progression of pulmonary metastasis in osteosarcoma. The finding that the significant down-regulation of endostatin was critical in angiogenic elevation after primary tumor removal suggests that endostatin is a candidate for antiangiogenic therapy for osteosarcoma.
In the current study, we evaluated the effect of antiangiogenic therapy using endostatin on postoperative progression of pulmonary metastasis from osteosarcoma. Mouse osteosarcoma cell line LM 8 cells were inoculated in subcutaneous layer of nude mice. Two weeks after tumor inoculation, the primary tumor was removed surgically, and antiangiogenic therapy using adenovirus encoding endostatin expression vector (Ad5CMV-mEnd) was performed. Two weeks after the antiangiogenic treatment, pulmonary metastasis was evaluated by counting the number of metastatic nodules. The evaluation of systemic angiogenic activity was performed using Matrigel plug assay.
Two weeks after the viral injection, mice were sacrificed, and the macroscopic pulmonary metastases were counted. Notably, the number of pulmonary metastases was smaller in the mice injected with Ad5CMV-mEnd than in controls, accompanied by significant suppression of systemic angiogenic activity. In addition, the sizes of the pulmonary metastases of the mice injected with Ad5CMV-mEnd were smaller than in the control group.
Our results indicate that antiangiogenic therapy using endostatin has the potential to prevent postoperative progression of pulmonary metastasis from osteosarcoma. Although this therapeutic strategy cannot provide a cure for osteosarcoma, it should enable osteosarcoma patients to coexist with dormant pulmonary metastasis and lead to improvement of their prognosis.
我们之前提供的数据表明骨肉瘤术后全身血管生成活性上调与肺转移术后进展之间存在正相关联系。原发性肿瘤切除后内皮抑素的显著下调对血管生成升高至关重要，这一发现表明内皮抑素是骨肉瘤抗血管生成治疗的一个候选药物。
在本研究中，我们评估了使用内皮抑素进行抗血管生成治疗对骨肉瘤肺转移术后进展的影响。将小鼠骨肉瘤细胞系LM 8细胞接种于裸鼠皮下层。肿瘤接种两周后，手术切除原发性肿瘤，并使用编码内皮抑素表达载体的腺病毒（Ad5CMV-mEnd）进行抗血管生成治疗。抗血管生成治疗两周后，通过计数转移结节的数量评估肺转移情况。使用基质胶栓试验评估全身血管生成活性。
病毒注射两周后，处死小鼠并计数肉眼可见的肺转移灶。值得注意的是，注射Ad5CMV-mEnd的小鼠肺转移灶数量少于对照组，同时全身血管生成活性受到显著抑制。此外，注射Ad5CMV-mEnd小鼠的肺转移灶大小也小于对照组。
我们的结果表明，使用内皮抑素进行抗血管生成治疗有可能预防骨肉瘤肺转移的术后进展。虽然这种治疗策略不能治愈骨肉瘤，但它应能使骨肉瘤患者与潜伏的肺转移灶共存，并改善其预后。
