Dyson Vision Research Institute, Weill Medical College of Cornell University, New York, New York, USA.
Am J Pathol. 2010 Jul;177(1):424-35. doi: 10.2353/ajpath.2010.090512. Epub 2010 May 27.
Retinoblastomas consist of cone-like neoplastic cells and diverse non-neoplastic cells whose roles in tumorigenesis have not been defined. Here, we investigated the glial cells that constitute 2% to 3% of the cells in retinoblastoma tumors, including their origin, their relationship to a potential retinoblastoma stem cell population, and their effects on tumor cell proliferation. Retinoblastoma glia consistently expressed the retinal astrocyte marker Pax2 but inconsistently expressed the Müller cell and occasional astrocyte marker CRALBP. Many of the glia expressed the stem cell-associated Sox2 but nevertheless were non-neoplastic as they coexpressed Rb and/or retained two RB1 alleles. Conversely, the glia were distinct from the non-neoplastic cells that strongly expressed the stem cell-associated ABCG2. Adherent Pax2(+),Sox2(+),Rb(+) glia readily grew from explanted retinoblastomas and produced soluble factors that enhanced the proliferation of cocultured retinoblastoma cells. This effect was emulated by normal retinal glia and appeared to be mediated by insulin-like growth factor binding protein-5 (IGFBP-5), as it was mimicked by recombinant IGFBP-5 and mitigated by neutralizing IGFBP-5 antibody. As glia-derived IGFBP-5 was earlier found to promote photoreceptor survival, our findings indicate that retinal astrocytes enhance the proliferation of cone-like retinoblastoma cells by deploying a factor that also provides trophic support to the tumor cells' non-neoplastic counterparts. These observations suggest that a tissue-specific microenvironmental feature cooperates with oncogenic mutations in a cancer cell of origin to promote retinoblastoma tumorigenesis.
视网膜母细胞瘤由圆锥状肿瘤细胞和多种非肿瘤细胞组成，但其在肿瘤发生中的作用尚未确定。在这里，我们研究了构成视网膜母细胞瘤肿瘤中 2%至 3%细胞的神经胶质细胞，包括其起源、与潜在的视网膜母细胞瘤干细胞群体的关系，以及对肿瘤细胞增殖的影响。视网膜母细胞瘤神经胶质细胞始终表达视网膜星形胶质细胞标志物 Pax2，但不一致地表达 Müller 细胞和偶尔的星形胶质细胞标志物 CRALBP。许多神经胶质细胞表达与干细胞相关的 Sox2，但它们是非肿瘤性的，因为它们共同表达 Rb 并/或保留两个 RB1 等位基因。相反，神经胶质细胞与强烈表达与干细胞相关的 ABCG2 的非肿瘤细胞不同。从离体培养的视网膜母细胞瘤中容易获得贴壁的 Pax2(+)、Sox2(+)、Rb(+)神经胶质细胞，并产生可溶性因子，增强共培养的视网膜母细胞瘤细胞的增殖。这种效应被正常视网膜神经胶质细胞模拟，似乎是由胰岛素样生长因子结合蛋白-5（IGFBP-5）介导的，因为重组 IGFBP-5 模拟了这种效应，中和 IGFBP-5 抗体减轻了这种效应。由于先前发现神经胶质细胞衍生的 IGFBP-5 可促进光感受器的存活，我们的发现表明，视网膜星形胶质细胞通过部署一种因子来增强圆锥状视网膜母细胞瘤细胞的增殖，该因子也为肿瘤细胞的非肿瘤对应物提供营养支持。这些观察结果表明，组织特异性微环境特征与癌症起源细胞中的致癌突变协同作用，促进视网膜母细胞瘤的发生。
