Dewaele Barbara, Maggiani Francesca, Floris Giuseppe, Ampe Michele, Vanspauwen Vanessa, Wozniak Agnieszka, Debiec-Rychter Maria, Sciot Raf
Clin Sarcoma Res. 2011 Jul 25;1(1):4. doi: 10.1186/2045-3329-1-4.
Chordomas are rare neoplasms, arising from notochordal remnants in the midline skeletal axis, for which the current treatment is limited to surgery and radiotherapy. Recent reports suggest that receptor tyrosine kinases (RTK) might be essential for the survival or proliferation of chordoma cells, providing a rationale for RTK targeted therapy. Nevertheless, the reported data are conflicting, most likely due to the assorted tumor specimens used for the studies and the heterogeneous methodological approaches. In the present study, we performed a comprehensive characterization of this rare entity using a wide range of assays in search for relevant therapeutic targets.
Histopathological features of 42 chordoma specimens, 21 primary and 21 advanced, were assessed by immunohistochemistry and fluorescent in situ hybridization (FISH) using PDGFRB, CSF1R, and EGFR probes. Twenty-two of these cases, for which frozen material was available (nine primary and 13 advanced tumors), were selectively analyzed using the whole-genome 4.3K TK-CGH-array, phospho-kinase antibody array or Western immunoblotting. The study was supplemented by direct sequencing of KIT, PDGFRB, CSF1R and EGFR.
We demonstrated that EGFR is frequently and the most significantly activated RTK in chordomas. Furthermore, concurrent to EGFR activation, the tumors commonly reveal co-activation of alternative RTK. The consistent activation of AKT, the frequent loss of the tumor suppressor PTEN allele, the recurrent activation of upstream RTK and of downstream effectors like p70S6K and mTOR, all indicate the PI3K/AKT pathway as an important mediator of transformation in chordomas.
Given the complexity of the signaling in chordomas, combined treatment regimens targeting multiple RTK and downstream effectors are likely to be the most effective in these tumors. Personalized therapy with careful selection of the patients, based on the molecular profile of the specific tumor, is anticipated.
脊索瘤是一种罕见的肿瘤，起源于中轴骨骼的脊索残余组织，目前的治疗方法仅限于手术和放疗。最近的报告表明，受体酪氨酸激酶（RTK）可能对脊索瘤细胞的存活或增殖至关重要，这为RTK靶向治疗提供了理论依据。然而，报告的数据相互矛盾，很可能是由于用于研究的肿瘤标本种类繁多以及方法学方法的异质性。在本研究中，我们使用多种检测方法对这种罕见实体进行了全面表征，以寻找相关的治疗靶点。
通过免疫组织化学和荧光原位杂交（FISH），使用PDGFRB、CSF1R和EGFR探针评估42例脊索瘤标本（21例原发性和21例晚期）的组织病理学特征。其中22例有冷冻材料可用的病例（9例原发性肿瘤和13例晚期肿瘤），使用全基因组4.3K TK-CGH阵列、磷酸激酶抗体阵列或Western免疫印迹进行选择性分析。该研究通过对KIT、PDGFRB、CSF1R和EGFR的直接测序进行补充。
我们证明，EGFR是脊索瘤中频繁且最显著激活的RTK。此外，与EGFR激活同时，肿瘤通常显示出其他RTK的共激活。AKT的持续激活、肿瘤抑制基因PTEN等位基因的频繁缺失、上游RTK和下游效应分子如p70S6K和mTOR的反复激活，均表明PI3K/AKT途径是脊索瘤转化的重要介质。
鉴于脊索瘤信号传导的复杂性，针对多种RTK和下游效应分子的联合治疗方案可能对这些肿瘤最有效。预计将根据特定肿瘤的分子特征，对患者进行仔细选择的个性化治疗。
