Lama Gina, Mangiola Annunziato, Anile Carmelo, Sabatino Giovanni, De Bonis Pasquale, Lauriola Libero, Giannitelli Cecilia, La Torre Giuseppe, Jhanwar-Uniyal Meena, Sica Gigliola, Maira Giulio
Institute of Histology and Embryology, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
Int J Oncol. 2007 Jun;30(6):1333-42.
Anomalies of growth factor signaling have been reported in malignant human gliomas. The extracellular signal-regulated kinases (ERKs) play a crucial role in transducing growth factor signals to the nucleus and are involved in a wide range of biological responses, including cell proliferation, differentiation and motility. ERK1/2 is expressed and activated in glioblastoma multiforme (GBM). However, no information is available in literature concerning the presence and activity of ERK1/2 in the peritumor tissue. In the present study, we evaluated by immunohistochemistry total and phosphorylated (t and p) ERK1/2 expression in 31 cases of primary GBM and in tissue surrounding the enhanced lesion at different distances up to 3.5 cm from the tumor margin. Total ERK1/2 was, as expected, uniformly expressed not only in GBM but in the areas around the tumor also, which showed higher levels of immunolabeling. ERK1/2 activation was observed in GBM as well as in peritumor tissue, with no statistical difference in the level of the enzymatic activities. In particular, in the peritumor tissue pERK1/2 was present independently of neoplastic cells not only in reactive astrocytes, but in apparently normal glial cells also. These results indicate that ERK1/2 pathway may participate in GBM growth and progression. In addition, they strongly suggest that ERK1/2 stimulation may be linked not only to tissue reactivity to tumor invasion, but also to cell motility or represent per se a sign of transformation. Finally, our findings highlight the meaning of the extension of neoplasm fingers beyond the outer margin of GBM. Patients with neoplastic cells at <10% or without neoplastic cells in peritumor areas showed a higher survival time compared with those with neoplastic elements at > or = 10%. In addition, a percentage > or = 10 of neoplastic elements in peritumor tissue was associated with an approximately 4-fold increased death risk.
在恶性人类胶质瘤中已报道生长因子信号传导异常。细胞外信号调节激酶（ERKs）在将生长因子信号转导至细胞核中起关键作用，并参与广泛的生物学反应，包括细胞增殖、分化和运动。ERK1/2在多形性胶质母细胞瘤（GBM）中表达并被激活。然而，文献中没有关于肿瘤周围组织中ERK1/2的存在和活性的信息。在本研究中，我们通过免疫组织化学评估了31例原发性GBM以及距肿瘤边缘不同距离（最远达3.5 cm）的强化病变周围组织中总ERK1/2和磷酸化（t和p）ERK1/2的表达。正如预期的那样，总ERK1/2不仅在GBM中均匀表达，在肿瘤周围区域也如此，这些区域显示出更高的免疫标记水平。在GBM以及肿瘤周围组织中均观察到ERK1/2激活，酶活性水平无统计学差异。特别是，在肿瘤周围组织中，pERK1/2不仅存在于反应性星形胶质细胞中，也存在于明显正常的神经胶质细胞中，且与肿瘤细胞无关。这些结果表明ERK1/2通路可能参与GBM的生长和进展。此外，它们强烈表明ERK1/2刺激不仅可能与组织对肿瘤侵袭的反应性有关，还可能与细胞运动有关，或者本身代表一种转化迹象。最后，我们的研究结果突出了GBM外缘之外肿瘤指状延伸的意义。肿瘤周围区域肿瘤细胞<10%或无肿瘤细胞的患者与肿瘤细胞≥10%的患者相比，生存时间更长。此外，肿瘤周围组织中肿瘤成分百分比≥10%与死亡风险增加约4倍相关。
