Lyons Susan A, O'Neal Jeffrey, Sontheimer Harald
TransMolecular, Inc., Birmingham, Alabama 35294, USA.
Glia. 2002 Aug;39(2):162-73. doi: 10.1002/glia.10083.
Highly migratory neuroectodermal cells share a common embryonic origin with cells of the central nervous system (CNS). They include enteric, parasympathetic, sympathoadrenal, and sensory neurons of the peripheral nervous system, Schwann cells, melanocytes, endocrine cells, and cells forming connective tissue of the face and neck. Because of their common embryologic origin, these cells and the tumors that derive from them can share genetic and antigenic phenotypes with gliomas, tumors derived from CNS glia. We recently discovered that chlorotoxin (ClTx), a 4-kD peptide purified from Leiurus quinquestriatus scorpion, is a highly specific marker for glioma cells in biopsy tissues (Soroceanu et al. Cancer Res 58:4871-4879, 1998) that can target tumors in animal models. We report on the specificity of ClTx as a marker for tumors of neuroectodermal origin that include peripheral neuroectodermal tumors (PNET) and gliomas. Specifically, we histochemically stained frozen and paraffin tissue sections of human biopsy tissues from 262 patients with a synthetically manufactured and biologically active ClTx bearing an N-terminal biotin. The vast majority (74 of 79) of primary human brain tumors investigated showed abundant binding of ClTx with greater than 90% ClTx-positive cells in each section. By comparison, 32 biopsies of uninvolved brain used for comparison were largely ClTx-negative, with only a few isolated reactive astrocytes showing some ClTx binding. However, as with gliomas, the vast majority of PNETs examined showed specific ClTx binding (31 of 34). These include medulloblastomas (4 of 4), neuroblastomas (6 of 7), ganglioneuromas (4 of 4), melanomas (7 of 7), adrenal pheochromocytomas (5 of 6), primitive PNET (1), small cell lung carcinoma (2 of 3), and Ewing's sarcoma (2 of 2). Under identical staining conditions, normal tissues from brain, skin, kidney, and lung were consistently negative for ClTx. These results suggest that chlorotoxin is a reliable and specific histopathological marker for tumors of neuroectodermal origin and that chlorotoxin derivatives with cytolytic activity may have therapeutic potential for these cancers.
高迁移性神经外胚层细胞与中枢神经系统（CNS）的细胞有着共同的胚胎起源。它们包括外周神经系统的肠神经元、副交感神经元、交感肾上腺神经元和感觉神经元、施万细胞、黑素细胞、内分泌细胞以及形成面部和颈部结缔组织的细胞。由于它们共同的胚胎学起源，这些细胞以及由它们衍生而来的肿瘤可与神经胶质瘤（源自CNS神经胶质的肿瘤）共享遗传和抗原表型。我们最近发现，从以色列金蝎中纯化得到的一种4-kD肽——氯毒素（ClTx），是活检组织中胶质瘤细胞的一种高度特异性标志物（Soroceanu等人，《癌症研究》58:4871 - 4879，1998年），它能够在动物模型中靶向肿瘤。我们报告了ClTx作为神经外胚层起源肿瘤标志物的特异性，这些肿瘤包括外周神经外胚层肿瘤（PNET）和神经胶质瘤。具体而言，我们用一种合成制造且具有生物活性、N端带有生物素的ClTx对262例患者的人活检组织的冷冻和石蜡组织切片进行了组织化学染色。在所研究的绝大多数（79例中的74例）原发性人脑肿瘤中，每个切片都显示ClTx有大量结合，ClTx阳性细胞超过90%。相比之下，用于对照的32例未受累脑活检组织大多为ClTx阴性，只有少数孤立的反应性星形胶质细胞显示出一些ClTx结合。然而，与神经胶质瘤一样，所检查的绝大多数PNET也显示出特异性的ClTx结合（34例中的31例）。这些肿瘤包括髓母细胞瘤（4例中的4例）、神经母细胞瘤（7例中的6例）、神经节神经瘤（4例中的4例）、黑色素瘤（7例中的7例）、肾上腺嗜铬细胞瘤（6例中的5例）、原始PNET（1例）、小细胞肺癌（3例中的2例）和尤因肉瘤（2例中的2例）。在相同的染色条件下，来自脑、皮肤、肾和肺的正常组织对ClTx始终呈阴性。这些结果表明，氯毒素是神经外胚层起源肿瘤可靠且特异的组织病理学标志物，具有细胞溶解活性的氯毒素衍生物可能对这些癌症具有治疗潜力。
