Rempel S A, Golembieski W A, Ge S, Lemke N, Elisevich K, Mikkelsen T, Gutiérrez J A
Henry Ford Midwest Neuro-Oncology Center and the Department of Neurosurgery, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
J Neuropathol Exp Neurol. 1998 Dec;57(12):1112-21. doi: 10.1097/00005072-199812000-00002.
In an attempt to identify genetic alterations occurring early in astrocytoma progression, we performed subtractive hybridization between astrocytoma and glioblastoma cDNA libraries. We identified secreted protein acidic and rich in cysteine (SPARC), a protein implicated in cell-matrix interactions, as a gene overexpressed early in progression. Northern blot and immunohistochemical analyses indicated that transcript and protein were both elevated in all tumor specimens (grades II-IV) examined when compared with levels in normal brain. The level of SPARC expression was found to be tumor-dependent rather than grade-related. Immunohistochemically, SPARC protein was found to be overexpressed in 1) cells in the less cellularly dense regions within the tumor mass, 2) histomorphologically neoplastic-looking cells in adjacent normal brain at the tumor/brain interface, 3) neovessel endothelial cells in both the tumor and adjacent normal brain, and 4) reactive astrocytes in normal brain adjacent to tumor. Using a combination of DNA in situ hybridization and protein immunohistochemical analyses of the human/rat xenograft, SPARC expression was observed in the human glioma cells within the tumor mass, and in cells that invaded along vascular basement membranes and individually into the rat brain parenchyma, suggesting it may be an invasion-related gene. While it remains to be determined whether SPARC functionally contributes to tumor cell invasion, these data suggest that the early onset of increased SPARC expression, though complex, may serve as a signal indicative of neoplastic astrocytic transformation and reactive response to tumor-induced stress.
为了确定星形细胞瘤进展早期发生的基因改变，我们对星形细胞瘤和胶质母细胞瘤的cDNA文库进行了消减杂交。我们鉴定出富含半胱氨酸的酸性分泌蛋白（SPARC），一种与细胞-基质相互作用有关的蛋白，作为进展早期过度表达的基因。Northern印迹和免疫组化分析表明，与正常脑相比，在所有检测的肿瘤标本（II-IV级）中，转录本和蛋白水平均升高。发现SPARC表达水平取决于肿瘤而非分级。免疫组化显示，SPARC蛋白在以下细胞中过度表达：1）肿瘤块内细胞密度较低区域的细胞；2）肿瘤/脑界面处相邻正常脑中组织形态学上呈肿瘤样的细胞；3）肿瘤和相邻正常脑中的新生血管内皮细胞；4）肿瘤相邻正常脑中的反应性星形胶质细胞。通过对人/大鼠异种移植瘤进行DNA原位杂交和蛋白免疫组化分析相结合，在肿瘤块内的人胶质瘤细胞中，以及沿血管基底膜并单独侵入大鼠脑实质的细胞中观察到SPARC表达，提示它可能是一个与侵袭相关的基因。虽然SPARC是否在功能上促进肿瘤细胞侵袭仍有待确定，但这些数据表明，SPARC表达增加的早期出现，尽管复杂，可能是肿瘤性星形胶质细胞转化和对肿瘤诱导应激的反应性信号。
