Department of Internal Medicine, University of Genova, Genoa, Italy.
J Biol Regul Homeost Agents. 2013 Jan-Mar;27(1):143-54.
Glioblastoma multiforme (GBM) is among the most devastating human tumors being rapidly fatal despite aggressive surgery, radiation and chemotherapies. It is characterized by extensive dissemination of tumor cells within the brain that hinders complete surgical resection. GBM tumor initiating-cells (TICs) are a rare subpopulation of cells responsible for tumor development, growth, invasiveness and recurrence after chemotherapy. TICs from human GBM can be selected in vitro using the same conditions permissive for the growth of normal neural cells, of which share some features including marker expression, self-renewal capacity, long-term proliferation, and ability to differentiate into neuronal and glial cells. EGFR overexpression and its constitutive activation is one of the most important signaling alteration identified in GBM, and its pharmacological targeting represents an attractive therapeutic goal. We previously demonstrated that human GBM TICs have different sensitivity to the EGFR kinase inhibitors erlotinib and gefitinib, depending on the differential modulation of downstream signaling cascades. In this work we investigated the mechanisms of resistance to erlotinib in two human GBM TIC cultures, analyzing EGF and bFGF individual contribution to proliferation, clonogenicity, and migration. We demonstrated the presence of a small cell subpopulation whose proliferation is supported by EGF and a larger one mainly dependent on bFGF. Thus, insensitivity to EGFR kinase inhibitors as far as TIC proliferation results from a predominant FGFR activation that hides the inhibitory effects induced on EGFR signaling. Conversely, EGF and bFGF induced cell migration with similar efficacy. In addition, unlike neural stem/progenitors cells, the removal of chondroitin sulphate proteoglycans from cell surface was unable to discern EGF- and bFGF-dependent subpopulations in GBM TICs.
多形性胶质母细胞瘤（GBM）是最具破坏性的人类肿瘤之一，尽管进行了积极的手术、放疗和化疗，但其仍迅速致命。它的特点是肿瘤细胞在大脑内广泛扩散，阻碍了完全的手术切除。GBM 肿瘤起始细胞（TICs）是负责肿瘤发展、生长、侵袭和化疗后复发的罕见细胞亚群。可以在体外用人 GBM TIC 选择相同的条件下，允许正常神经细胞生长，其中一些特征包括标志物表达、自我更新能力、长期增殖能力和分化为神经元和神经胶质细胞的能力。EGFR 过表达及其组成性激活是 GBM 中最重要的信号改变之一，其药物靶向是一个有吸引力的治疗目标。我们之前证明，人 GBM TIC 对 EGFR 激酶抑制剂厄洛替尼和吉非替尼的敏感性不同，这取决于下游信号级联的差异调节。在这项工作中，我们研究了两种人 GBM TIC 培养物对厄洛替尼耐药的机制，分析了 EGF 和 bFGF 对增殖、集落形成和迁移的单独贡献。我们证明了一小部分细胞亚群的存在，其增殖受到 EGF 的支持，而更大的细胞亚群主要依赖于 bFGF。因此，TIC 增殖对 EGFR 激酶抑制剂不敏感是由于 FGFR 激活占主导地位，掩盖了对 EGFR 信号的抑制作用。相反，EGF 和 bFGF 以相似的效力诱导细胞迁移。此外，与神经干细胞/祖细胞不同，从细胞表面去除硫酸软骨素蛋白聚糖不能区分 GBM TIC 中的 EGF 和 bFGF 依赖性亚群。
