Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex
Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex
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DOI：
10.1016/j.ajpath.2010.11.031
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发表时间：
2011-01-01
影响因子：
6
通讯作者：
Crino, Peter B.
中科院分区：
文献类型：
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作者：
Parker, Whitney E.;Orlova, Ksenia A.;Crino, Peter B.
表皮生长因子（EGF）、肝细胞生长因子（HGF）和血管内皮生长因子（VEGF）调节发育中的脑中的血管生成和细胞生长。EGF、HGF和VEGF调节哺乳动物雷帕霉素靶蛋白（mTOR）级联反应的活性，mTOR级联反应是一种调节细胞生长的途径，在结节性硬化症（TSC）中被异常激活。我们假设，表皮生长因子，肝细胞生长因子，血管内皮生长因子，及其受体EGFR，c-Met，和Flt-1的表达，分别将在TSC的改变。我们通过cDNA阵列和免疫组化分析表明，EGF，EGFR，HGF，c-Met和VEGF，但不是Flt-1，mRNA和蛋白质表达上调Tsc 1条件性敲除（Tsc 1（GFAP）CKO）小鼠皮层。重要的是，这些变化密切预测增强表达这些蛋白质在结节和室管膜下巨细胞星形细胞瘤（SEGA）标本TSC。EGF、EGFR、HGF、c-Met和VEGF蛋白以及缺氧诱导因子-1 α（一种调节VEGF水平并受mTOR级联活性调节的转录因子）的表达在15例TSC患者的SEGA（n = 6）和块茎（n = 10）中增强。这些生长因子和生长因子受体在人SEGA和块茎中以及在Tsc 1（GFAP）CKO小鼠中的增强表达可能是块茎和SEGA中细胞生长和增殖增强的原因，并为TSC的治疗开发提供了潜在的靶分子。(Am J Pathol 2011，178：296-305; DOI：10.1016/j.ajpath.2010.11.031）
Epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) regulate angiogenesis and cell growth in the developing brain. EGF, HGF, and VEGF modulate the activity of the mammalian target of rapamycin (mTOR) cascade, a pathway regulating cell growth that is aberrantly activated in tuberous sclerosis complex (TSC). We hypothesized that expression of EGF, HGF, VEGF, and their receptors EGFR, c-Met, and Flt-1, respectively, would be altered in TSC. We show by cDNA array and immunohistochemical analysis that EGF, EGFR, HGF, c-Met, and VEGF, but not Flt-1, rnRNA, and protein expression was up-regulated in Tsc1 conditional knockout (Tsc1(GFAP)CKO) mouse cortex. Importantly, these alterations closely predicted enhanced expression of these proteins in tuber and subependymal giant cell astrocytoma (SEGA) specimens in TSC. Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1 alpha, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n = 6) and tubers (n = 10) from 15 TSC patients. Enhanced expression of these growth factors and growth factor receptors in human SEGAs and tubers and in the Tsc1(GFAP)CKO mouse may account for enhanced cellular growth and proliferation in tubers and SEGAs and provides potential target molecules for therapeutic development in TSC. (Am J Pathol 2011, 178:296-305; DOI: 10.1016/j.ajpath.2010.11.031)