Trieb K, Lechleitner T, Lang S, Windhager R, Kotz R, Dirnhofer S
Department of Orthopaedics, University of Vienna, Austria.
Hum Pathol. 1998 Oct;29(10):1050-5. doi: 10.1016/s0046-8177(98)90412-9.
Although the therapeutic outcome of osteosarcoma patients has improved dramatically within the last 20 years because of combined neoadjuvant chemotherapy and surgery, the problem of drug resistance remains. Thus far, markers that can predict the response to chemotherapy at the time of biopsy are not available. Heat shock proteins (hsp) 60, 72, and 73 have been shown to play a role in tumor immunity, and our study investigated their expression in human osteosarcomas and nonmalignant bone tumors before neoadjuvant chemotherapy. Immunohistochemical evaluations of hsp expression was performed on paraffin-embedded sections of 45 patients (17 female, 28 male, aged 6.5 to 62 years; mean, 19.4 years) with high-grade osteosarcoma at the time of biopsy, before preoperative chemotherapy. These results were correlated to histological response to chemotherapy, tumor size, age, alkaline phosphatase serum levels, and duration of symptoms. Thirty-four patients (15 male, 19 female, mean age 27 years) with osteoblastoma, osteoid-osteoma, or fibrous dysplasia served as nonmalignant controls. Hsp60 was uniformly found in the cytoplasm of both benign and malignant bone tumors. Nuclear hsp73 expression quantitatively increased in osteosarcoma cells. Hsp72 was significantly overexpressed in osteosarcomas (17 of 45, 38%) compared with nonmalignant bone tumors (1 of 34, 2.9%; P < .001). Hsp72-positive osteosarcomas responded better to neoadjuvant chemotherapy than hsp72-negative cases (P < .001), co-express hsp60, and correlate with higher tumor size (P < .005) and location in the distal femur. No differences were observed relative to age, gender, duration of symptoms, alkaline phosphatase levels, or hsp73 expression between hsp72-positive and hsp72-negative tumors. Hsp72 expression seemed to be a predictive immunohistochemical marker for osteosarcoma, because it is the first marker to prospectively correlate to response to neoadjuvant chemotherapy. It therefore, may be of importance in preoperative therapy regimens for nonresponding high-risk patients.
尽管由于新辅助化疗与手术相结合，骨肉瘤患者的治疗效果在过去20年中有了显著改善，但耐药问题依然存在。迄今为止，尚无能够在活检时预测化疗反应的标志物。热休克蛋白（hsp）60、72和73已被证明在肿瘤免疫中发挥作用，我们的研究调查了它们在新辅助化疗前人类骨肉瘤和非恶性骨肿瘤中的表达情况。对45例活检时患有高级别骨肉瘤的患者（17例女性，28例男性，年龄6.5至62岁；平均19.4岁）术前化疗前石蜡包埋切片进行hsp表达的免疫组织化学评估。这些结果与化疗的组织学反应、肿瘤大小、年龄、血清碱性磷酸酶水平及症状持续时间相关。34例骨母细胞瘤、骨样骨瘤或骨纤维异常增殖症患者（15例男性，19例女性，平均年龄27岁）作为非恶性对照。在良性和恶性骨肿瘤的细胞质中均一致发现hsp60。骨肉瘤细胞中核hsp73表达定量增加。与非恶性骨肿瘤（34例中的1例，2.9%）相比，hsp72在骨肉瘤中显著过表达（45例中的17例，38%；P <.001）。hsp72阳性的骨肉瘤对新辅助化疗的反应优于hsp72阴性病例（P <.001），共同表达hsp60，且与更大的肿瘤大小（P <.005）及位于股骨远端相关。在hsp72阳性和hsp72阴性肿瘤之间，相对于年龄、性别、症状持续时间、碱性磷酸酶水平或hsp73表达未观察到差异。hsp72表达似乎是骨肉瘤的一种预测性免疫组织化学标志物，因为它是首个前瞻性地与新辅助化疗反应相关的标志物。因此，它可能在针对无反应的高危患者的术前治疗方案中具有重要意义。
