Svalina Matthew N, Kikuchi Ken, Abraham Jinu, Lal Sangeet, Davare Monika A, Settelmeyer Teagan P, Young Michael C, Peckham Jennifer L, Cho Yoon-Jae, Michalek Joel E, Hernandez Brian S, Berlow Noah E, Jackson Melanie, Guillaume Daniel J, Selden Nathan R, Bigner Darell D, Nazemi Kellie J, Green Sarah C, Corless Christopher L, Gultekin Sakir, Mansoor Atiya, Rubin Brian P, Woltjer Randall, Keller Charles
Children's Cancer Therapy Development Institute, Beaverton, OR USA.
Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
Sci Rep. 2016 Jun 3;6:27012. doi: 10.1038/srep27012.
Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.
髓母细胞瘤转移的风险或存在会导致大量与治疗相关的发病率和总体死亡率。通过比较转移性髓母细胞瘤患者脑脊液（CSF）中的细胞因子和生长因子与MYC扩增的转移性髓母细胞瘤或软脑膜细胞条件培养基中的因子，我们受脑脊液中IGF1水平升高、IGF隔离蛋白IGFBP3、IGFBP3裂解蛋白酶（MMP和tPA）以及蛋白酶调节剂（TIMP1和PAI-1）的引导，探索IGF1在髓母细胞瘤中的生物活性。IGF1不仅导致受体磷酸化，还在适当的基质或脑膜内皮细胞环境中加速了MYC扩增的髓母细胞瘤细胞的迁移/黏附。临床相关性表明，IGF释放蛋白酶的来源是软脑膜周围/软脑膜下，这可能促进软脑膜转移。同时，对MYC扩增的髓母细胞瘤中负责细胞自主生长的关键因子的研究优先考虑了IGF1R抑制剂。总之，我们的研究确定IGF1R是高危髓母细胞瘤临床试验的高价值靶点。
