TRANSFORMING GROWTH FACTOR BETA IN THE DIFFERENTIATION OF NEUROBLASTOMA AND PNET

在最近的一项免疫组织化学研究中，我们发现， 成神经细胞瘤细胞的TGF-β 1、2和3，除了良好的 神经节神经母细胞瘤和正常 神经节 相反，几乎所有原始神经外胚层肿瘤（PNET） 表达了不同数量的TGF-β 1和3。 无TGF-β 在神经母细胞瘤细胞的条件培养基中也发现了分泌物 细胞系，与使用基于TGF-β的生物测定的PNET细胞系相反 水貂肺成纤维细胞DNA合成抑制。 这些数据 表明TGF-β在人类细胞分化中可能发挥作用 神经母细胞瘤 下文将进一步探讨这一假设。 方法：（1）研究TGF-β的表达和分泌， 神经母细胞瘤和PNET细胞系分化前后， 已知的分化剂，如视黄酸和TPA。(2)直接 外源性TGF-β对未分化和 将确定分化的神经母细胞瘤细胞培养物。（三） 将使用阻断抗体和反义TGF-β寡核苷酸 调节TGF-β对神经母细胞瘤和PNET细胞的可能作用 体外 初步数据显示，TGF-β 1-mRNA在SH- 用TPA或TPA处理培养物后的SY 5 Y神经母细胞瘤细胞 维甲酸，两者都促进分化。 相比之下，IMR- 32个神经母细胞瘤细胞，表现出最小的形态分化 用同样的药物治疗的小鼠只显示TGF-β 1 mRNA水平的轻度增加。

In a recent immunohistochemical study, we found lack of expression of TGF-beta1, 2, and 3 by neuroblastoma cells, except for well differentiated ganglion cells in ganglioneuroblastomas and in normal ganglia. In contrast, almost all primitive neuroectodermal tumors (PNET) expressed variable amounts of TGF-beta1 and 3. Absence of TGF-beta secretion was also found in conditioned media from neuroblastoma cell lines, in contrast to PNET cell lines using a bioassay based on TGF-beta inhibition of DNA synthesis in mink lung fibroblasts. These data suggested a possible role of TGF-beta in the differentiation of human neuroblastoma. This hypothesis will be further pursued in the following ways: (1) TGF-beta expression and secretion will be studied in neuroblastoma and PNET cell lines before and after differentiation with known differentiating agents, such as retinoic acid and TPA. (2) Direct effects of exogenously added TGF-beta in undifferentiated and differentiated neuroblastoma cell cultures will be determined. (3) Blocking antibodies and antisense TGF-beta oligonucleotides will be used to modulate possible actions of TGF-beta on neuroblastoma and PNET cells in vitro. Preliminary data have shown induction of TGF-beta1-mRNA in SH- SY5Y neuroblastoma cells following treatment of cultures with TPA or retinoic acid, both of which promoted differentiation. In contrast, IMR- 32 neuroblastoma cells which showed minimal morphologic differentiation with the same agents showed only mild increase in TGF-beta1 mRNA levels.