LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Institut Universitaire de Technologie, Angers, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
Eur J Cancer. 2013 Jun;49(9):2253-63. doi: 10.1016/j.ejca.2013.02.020. Epub 2013 Mar 13.
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents for whom the prognosis remains unfavourable despite treatment protocols that combine chemotherapy and surgery. Metalloproteinases decisively contribute to cancer development and promotion by regulating cell growth, angiogenesis or inflammation. However, their role in osteosarcoma remains still unknown.
A screening of a large panel of metalloproteinases and their inhibitors, carried out in osteolytic (K7M2 and POS-1) or osteoblastic (MOS-J) mouse osteosarcoma models, shows that a member of a family of cell surface metallopeptidases, A Disintegrin And Metalloproteinase 12 (ADAM12), is highly expressed in the K7M2 and POS-1 cell lines and weakly expressed in the MOS-J cell line. To investigate whether ADAM12, involved in several pathologic conditions characterised by abnormal cell growth, plays a role in osteosarcoma tumour growth, ADAM12 was overexpressed in MOS-J and downregulated in K7M2 cells.
In vivo experiments demonstrated that ADAM12 favours tumour growth, leading to a significant modification in animal survival. In vitro assays showed that ADAM12 knockdown in K7M2 cells slows cell proliferation. In addition, the study of microarchitectural parameters, assessed by micro-computed tomography (CT) analysis, showed that ADAM12 favours bone osteolysis, as demonstrated both in an ADAM12 overexpressing (MOS-J) and a knockdown (K7M2) model. Histological analysis showed that ADAM12 inhibited osteoblast activity and therefore enhanced bone resorption.
Our study demonstrates that ADAM12 expression not only favours tumour growth but also associates enhanced osteolysis with a significant reduction in animal survival, suggesting that ADAM12 could be a new therapeutic target in osteosarcoma.
骨肉瘤是儿童和青少年中最常见的原发性恶性骨肿瘤，尽管采用了化疗和手术相结合的治疗方案，但预后仍然不佳。金属蛋白酶通过调节细胞生长、血管生成或炎症，对癌症的发生和发展起着决定性的作用。然而，它们在骨肉瘤中的作用仍不清楚。
在溶骨性（K7M2 和 POS-1）或成骨性（MOS-J）小鼠骨肉瘤模型中对大量金属蛋白酶及其抑制剂进行筛选，结果表明细胞表面金属肽酶家族的一个成员 A 型分解素金属蛋白酶 12（ADAM12）在 K7M2 和 POS-1 细胞系中高度表达，而在 MOS-J 细胞系中弱表达。为了研究 ADAM12 是否参与了由异常细胞生长引起的几种病理状况，从而在骨肉瘤肿瘤生长中发挥作用，我们在 MOS-J 中过表达 ADAM12，并在 K7M2 细胞中下调 ADAM12。
体内实验表明 ADAM12 有利于肿瘤生长，导致动物存活率显著改变。体外实验表明 ADAM12 在 K7M2 细胞中的敲低会减缓细胞增殖。此外，通过微计算机断层扫描（CT）分析评估微结构参数的研究表明，ADAM12 促进骨溶解，这在 ADAM12 过表达（MOS-J）和敲低（K7M2）模型中均得到证实。组织学分析表明，ADAM12 抑制成骨细胞活性，从而增强骨吸收。
我们的研究表明，ADAM12 的表达不仅有利于肿瘤生长，而且还与增强的溶骨性作用相关，同时显著降低了动物的存活率，这表明 ADAM12 可能成为骨肉瘤的一个新的治疗靶点。
