EPIDERMAL GROWTH-FACTOR STIMULATES VASCULAR ENDOTHELIAL GROWTH-FACTOR PRODUCTION BY HUMAN-MALIGNANT GLIOMA-CELLS - A MODEL OF GLIOBLASTOMA-MULTIFORME PATHOPHYSIOLOGY
EPIDERMAL GROWTH-FACTOR STIMULATES VASCULAR ENDOTHELIAL GROWTH-FACTOR PRODUCTION BY HUMAN-MALIGNANT GLIOMA-CELLS - A MODEL OF GLIOBLASTOMA-MULTIFORME PATHOPHYSIOLOGY
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DOI：
10.1091/mbc.4.1.121
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发表时间：
1993-01-01
影响因子：
3.3
通讯作者：
GILLESPIE, GY
中科院分区：
文献类型：
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作者：
GOLDMAN, CK;KIM, J;GILLESPIE, GY
多形性胶质母细胞瘤（GBM）是人类脑肿瘤中最常见和最恶性的肿瘤，其主要组织病理学特征为血管过多、局灶性坏死、持续性脑水肿和细胞快速增殖。通过免疫过氧化物酶和免疫荧光，我们明确地证明了血管内皮生长因子（VEGF）和表皮生长因子受体（EGFr）的存在下，在五个人胶质瘤细胞系（U-251 MG，U-105 MG，D-65 MG，D-54 MG，和CH-235 MG）和八个人GBM肿瘤手术标本。胶质瘤细胞系的体外实验揭示了EGFr活化和VEGF产生之间一致且可靠的关系;即，胶质瘤细胞的EGF（1 - 20 ng/ml）刺激导致生物活性VEGF分泌增加25 - 125%。由EGF刺激的胶质瘤细胞系制备的条件培养基（CM）在人脐静脉内皮细胞（HUVECs）中产生胞浆游离胞内Ca 2+浓度（[Ca 2 +] i）的显著增加。无论是EGF单独或CM从胶质瘤培养物中制备的EGF诱导[Ca 2 +] i增加在HUVECs。用VEGF单克隆抗体A4.6.1预孵育胶质瘤CM，可完全消除HUVEC中VEGF介导的[Ca 2 +] i瞬变。同样，胶质瘤衍生的CM诱导血管性血友病因子从HUVEC释放被A4.6.1预处理完全阻断。这些观察结果为理解GBM肿瘤血管生成、血管通透性增加和细胞增殖的基本细胞病理生理学提供了关键环节。具体而言，EGF激活胶质瘤细胞上表达的EGFr导致胶质瘤细胞分泌VEGF增强。由胶质瘤细胞原位释放的VEGF最可能解释患者中GBM肿瘤的病理组织病理学和临床特征，包括显著的肿瘤血管生成、脑水肿增加和高凝状态，表现为局灶性肿瘤坏死、深静脉血栓形成或肺栓塞。
Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca2+ ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca2+]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGF-mediated [Ca2+]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.