Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression.
Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression.
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DOI：
10.1186/1471-2164-10-625
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发表时间：
2009-12-23
期刊：
影响因子：
4.4
通讯作者：
Khanna C
中科院分区：
文献类型：
--
作者：
Paoloni M;Davis S;Lana S;Withrow S;Sangiorgi L;Picci P;Hewitt S;Triche T;Meltzer P;Khanna C
肺转移仍然是骨肉瘤最常见的死亡原因。事实上，新诊断的骨肉瘤患者的5年生存率在20多年来没有显著变化。进一步了解这种侵袭性儿科癌症的转移和耐药机制是必要的。宠物狗自然发展成骨肉瘤提供了一个新的机会模型转移的发展和进展。考虑到犬骨肉瘤的加速生物学，我们假设直接比较犬和小儿骨肉瘤的表达谱可能有助于确定新的转移相关肿瘤靶点，这些靶点在单独研究人类癌症时被遗漏。使用平行寡核苷酸阵列平台，鉴定和标准化物种之间共有的直系同源物。骨肉瘤的表达特征不能区分犬和人类疾病的分层聚类。跨物种目标挖掘确定了两个基因，白细胞介素-8（IL-8）和溶质载体家族1（神经胶质高亲和力谷氨酸转运蛋白），成员3（SLC 1A 3），它们在狗中均匀表达，但不是在所有儿科骨肉瘤患者样本中。在一个独立的儿童骨肉瘤患者群体中，这些基因的表达与不良结局相关（分别为p = 0.020和p = 0.026）。儿童骨肉瘤组织中IL-8和SLC 1A 3蛋白表达的验证进一步支持了这些新靶点的潜在价值。正在进行的评估将验证这些目标及其相关途径的生物学意义。总的来说，这些数据支持人类和犬骨肉瘤之间的强烈相似性，并强调了比较肿瘤学方法作为提高我们对癌症生物学和治疗的理解的一种手段所提供的机会。
Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Using parallel oligonucleotide array platforms, shared orthologues between species were identified and normalized. The osteosarcoma expression signatures could not distinguish the canine and human diseases by hierarchical clustering. Cross-species target mining identified two genes, interleukin-8 (IL-8) and solute carrier family 1 (glial high affinity glutamate transporter), member 3 (SLC1A3), which were uniformly expressed in dog but not in all pediatric osteosarcoma patient samples. Expression of these genes in an independent population of pediatric osteosarcoma patients was associated with poor outcome (p = 0.020 and p = 0.026, respectively). Validation of IL-8 and SLC1A3 protein expression in pediatric osteosarcoma tissues further supported the potential value of these novel targets. Ongoing evaluation will validate the biological significance of these targets and their associated pathways. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapies.
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