Copin Marie-Christine, Lesaffre Marie, Berbon Mélanie, Doublet Louis, Leroy Catherine, Tresch Emmanuelle, Porte Henri, Vicogne Jérôme, B Cortot Alexis, Dansin Eric, Tulasne David
Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France; Univ. Lille, Institut de Pathologie, CHU Lille, Avenue Oscar Lambret, F-59000 Lille, France.
Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
Lung Cancer. 2016 Nov;101:59-67. doi: 10.1016/j.lungcan.2016.09.009. Epub 2016 Sep 14.
The receptor tyrosine kinase MET is essential to embryonic development and organ regeneration. Its deregulation is associated with tumorigenesis. While MET gene amplification and mutations leading to MET self-activation concern only a few patients, a high MET level has been found in about half of the non-small cell lung cancers (NSCLCs) tested. How this affects MET activation in tumors is unclear. Also uncertain is the prognostic value, in cancer, of a phenomenon well described in cell models: MET shedding, i.e. its cleavage by membrane proteases leading to release of a soluble fragment into the medium.
A prospective cohort of 39 NSCLC patients was constituted at diagnosis or soon after. Normal tissues, tumor tissues, and blood samples were obtained. This allowed, for the same patient, synchronous determination of (i) the MET level in the tumor, (ii) receptor phosphorylation, and (iii) the concentration of soluble MET fragment (sMET) in the serum.
After confirming the adequacy of an ELISA for measuring the serum level of sMET, we found no correlation between this level and the concentration of MET in tumors, as evaluated by immunohistochemistry and western blotting. Nevertheless, all but one tumor displaying a high MET level also displayed receptor phosphorylation, restricted to a small number of tumor cells.
Our results thus demonstrate that the serum level of sMET is not indicative of the amount of MET present in the tumor cells and cannot be used as a biomarker for therapeutic purposes. However, MET scoring of tumor biopsies could be a first step prior to determination of MET receptor activation in high-MET tumors.
受体酪氨酸激酶MET对胚胎发育和器官再生至关重要。其失调与肿瘤发生相关。虽然MET基因扩增和导致MET自激活的突变仅涉及少数患者，但在约一半检测的非小细胞肺癌（NSCLC）中发现MET水平较高。尚不清楚这如何影响肿瘤中的MET激活。同样不确定的是，在癌症中，细胞模型中已充分描述的一种现象——MET脱落（即其被膜蛋白酶切割导致可溶性片段释放到培养基中）的预后价值。
在诊断时或诊断后不久建立了一个由39例NSCLC患者组成的前瞻性队列。获取了正常组织、肿瘤组织和血液样本。这使得对于同一患者能够同步测定：（i）肿瘤中的MET水平，（ii）受体磷酸化，以及（iii）血清中可溶性MET片段（sMET）的浓度。
在确认一种ELISA方法用于测量血清sMET水平的适用性后，我们发现该水平与通过免疫组织化学和蛋白质印迹法评估的肿瘤中MET浓度之间无相关性。然而，除一例肿瘤外，所有MET水平高的肿瘤也都显示受体磷酸化，且仅限于少数肿瘤细胞。
因此，我们的结果表明血清sMET水平不能指示肿瘤细胞中MET的含量，不能用作治疗目的的生物标志物。然而，对肿瘤活检进行MET评分可能是在高MET肿瘤中确定MET受体激活之前的第一步。
