Mawrin Christian, Sasse Tina, Kirches Elmar, Kropf Siegfried, Schneider Thomas, Grimm Christoph, Pambor Claudia, Vorwerk Christian K, Firsching Raimund, Lendeckel Uwe, Dietzmann Knut
Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany.
Clin Cancer Res. 2005 Jun 1;11(11):4074-82. doi: 10.1158/1078-0432.CCR-04-2550.
Activation of intracellular signaling cascades has been implicated in the growth control of benign meningiomas, but their role for meningioma progression and outcome is unknown. Here we determined the expression and function of proteins involved in mitogen-activated protein kinase (MAPK) and phosphinositol-3 kinase (PI3K)/Akt signaling in benign, atypical, and malignant meningiomas and studied their association with clinicopathologic data including meningioma recurrence.
Expression of various MAPK and PI3K signaling proteins was determined in 70 primary meningiomas and, if present, in recurrent tumors by immunohistochemistry and Western blotting. The expression patterns in primary and recurrent tumors were related to clinical data. The effect of MAPK and PI3K pathway inhibition on cell proliferation and apoptosis was determined using a primary malignant meningioma cell culture.
Atypical and malignant meningiomas showed higher levels of phospho-Akt compared with benign tumors, and their proliferation could be inhibited by PI3K blocking using wortmannin. PI3K inhibition did not induce apoptosis in malignant meningioma cells. In contrast, expression of phospho-Raf and phospho-MAPK was decreased in aggressive meningiomas compared with benign tumors, but MAPK inhibition by PD98059 resulted in tumor cell apoptosis and decreased proliferation. Reduced MAPK activation was associated with meningioma recurrence, and PI3K activation was associated with poor preclinical condition and brain invasion of malignant meningiomas.
Both MAPK and PI3K/Akt pathways are activated at different levels in benign and malignant meningiomas. Activation of PI3K/Akt signaling contributes to the aggressive behavior of malignant meningiomas, whereas MAPK activation is involved in both proliferation and apoptosis of malignant meningiomas.
细胞内信号级联反应的激活与良性脑膜瘤的生长控制有关，但其在脑膜瘤进展和预后中的作用尚不清楚。在此，我们确定了丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3激酶（PI3K）/Akt信号通路相关蛋白在良性、非典型和恶性脑膜瘤中的表达及功能，并研究了它们与包括脑膜瘤复发在内的临床病理数据的相关性。
通过免疫组织化学和蛋白质印迹法，在70例原发性脑膜瘤以及复发性肿瘤（若存在）中测定各种MAPK和PI3K信号蛋白的表达。原发性和复发性肿瘤中的表达模式与临床数据相关。使用原发性恶性脑膜瘤细胞培养物确定MAPK和PI3K通路抑制对细胞增殖和凋亡的影响。
与良性肿瘤相比，非典型和恶性脑膜瘤中磷酸化Akt水平更高，使用渥曼青霉素阻断PI3K可抑制其增殖。PI3K抑制未诱导恶性脑膜瘤细胞凋亡。相反，与良性肿瘤相比，侵袭性脑膜瘤中磷酸化Raf和磷酸化MAPK的表达降低，但PD98059抑制MAPK导致肿瘤细胞凋亡并减少增殖。MAPK激活降低与脑膜瘤复发相关，PI3K激活与恶性脑膜瘤的临床前状况差和脑侵袭相关。
MAPK和PI3K/Akt通路在良性和恶性脑膜瘤中均在不同水平被激活。PI3K/Akt信号通路的激活促成了恶性脑膜瘤的侵袭性行为，而MAPK激活参与了恶性脑膜瘤的增殖和凋亡。
