Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma.
Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma.
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DOI：
10.1186/1471-2407-6-237
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发表时间：
2006-10-05
期刊：
影响因子：
3.8
通讯作者：
Squire, Jeremy A.
中科院分区：
文献类型：
--
作者：
Dalla-Torre, Cristiane A.;Yoshimoto, Maisa;Lee, Chung-Hae;Joshua, Anthony M.;de Toledo, Silvia R. C.;Petrilli, Antonio S.;Andrade, Joyce A. D.;Chilton-MacNeill, Susan;Zielenska, Maria;Squire, Jeremy A.
骨肉瘤是一种侵袭性很强的肿瘤，具有转移和侵袭周围组织的倾向。确定骨肉瘤侵袭和转移潜能的分子决定因素可能会指导制定合理的策略，以设计针对导致骨肉瘤的途径的特异性治疗。在这项研究中，我们使用通路聚焦的低密度表达cDNA阵列来筛选与肿瘤进展相关的候选基因。所选基因在骨肉瘤患者肿瘤样本上的表达模式通过实时PCR验证，并与临床和病理数据进行关联。THBS3、SPARC和SPP1是骨肉瘤中差异表达的基因。特别是，THBS3在诊断时转移患者的活检中表达水平显著高（p = 0.0001），这是诊断时总生存期、无事件生存期和无复发生存期较差的预测因子。化疗后，肿瘤过表达THBS3的患者无复发生存率较差。来自43例患者的骨肉瘤样本中有51/55（96.3%）存在SPARC高表达，并与最差无事件生存率（p = 0.03）和无复发生存率（p = 0.07）相关。53例骨肉瘤中有47例（89%）发现SPP1过表达，这与诊断时更好的总生存率、无事件生存率和无复发生存率相关。在这项研究中，三个基因被鉴定出与转移和侵袭的表型作用相关的差异基因表达模式。有趣的是，它们都编码参与细胞外重塑的蛋白质，这表明它们在骨肉瘤的进展中具有潜在的作用。这是首次报道THBS3基因作为肿瘤进展的刺激物。高水平的THBS3维持血管生成的能力。高水平的SPARC不是肿瘤进展所必需的，但却是肿瘤生长和维持所必需的。SPP1在骨肉瘤的肿瘤进展中不是必需的，它可能与炎症反应和骨重塑有关，是一个很好的生物标志物。
Osteosarcoma is a very aggressive tumor with a propensity to metastasize and invade surrounding tissue. Identification of the molecular determinants of invasion and metastatic potential may guide the development of a rational strategy for devising specific therapies that target the pathways leading to osteosarcoma. In this study, we used pathway-focused low density expression cDNA arrays to screen for candidate genes related to tumor progression. Expression patterns of the selected genes were validated by real time PCR on osteosarcoma patient tumor samples and correlated with clinical and pathological data. THBS3, SPARC and SPP1 were identified as genes differentially expressed in osteosarcoma. In particular, THBS3 was expressed at significantly high levels (p = 0.0001) in biopsies from patients with metastasis at diagnosis, which is a predictor of worse overall survival, event-free survival and relapse free survival at diagnosis. After chemotherapy, patients with tumors over-expressing THBS3 have worse relapse free survival. High SPARC expression was found in 51/55 (96.3%) osteosarcoma samples derived from 43 patients, and correlated with the worst event-free survival (p = 0.03) and relapse free survival (p = 0.07). Overexpression of SPP1 was found in 47 of 53 (89%) osteosarcomas correlating with better overall survival, event-free survival and relapse free survival at diagnosis. In this study three genes were identified with pattern of differential gene expression associated with a phenotypic role in metastasis and invasion. Interestingly all encode for proteins involved in extracellular remodeling suggesting potential roles in osteosarcoma progression. This is the first report on the THBS3 gene working as a stimulator of tumor progression. Higher levels of THBS3 maintain the capacity of angiogenesis. High levels of SPARC are not required for tumor progression but are necessary for tumor growth and maintenance. SPP1 is not necessary for tumor progression in osteosarcoma and may be associated with inflammatory response and bone remodeling, functioning as a good biomarker.
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