Presence of stromal cells in a bioengineered tumor microenvironment alters glioblastoma migration and response to STAT3 inhibition.
Presence of stromal cells in a bioengineered tumor microenvironment alters glioblastoma migration and response to STAT3 inhibition.
复制标题
DOI：
10.1371/journal.pone.0194183
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Rickus JL
中科院分区：
文献类型：
--
作者：
Herrera-Perez RM;Voytik-Harbin SL;Sarkaria JN;Pollok KE;Fishel ML;Rickus JL
尽管肿瘤微环境（TME）作为肿瘤进展的调节剂的重要性日益被认识到，但只有少数体外模型被开发用于以受控方式系统地研究TME对肿瘤行为的影响。在这里，我们开发了一个三维（3D）体外模型，概括了胶质母细胞瘤（GBM）细胞外基质（ECM）的物理和组成特征，并纳入脑基质细胞，如星形胶质细胞和内皮细胞前体。该模型用于评估在STAT3抑制的情况下TME组分对各种患者来源的GBM细胞系（GBM10、GBM43和GBAM 1）的迁移和存活的影响。GBM在3D体外模型中的迁移分析表明，星形胶质细胞的存在显著增加了GBM的迁移，而内皮前体的存在对不同GBM细胞系的迁移具有不同的影响。鉴于肿瘤微环境作为STAT3活性调节剂的作用，我们测试了STAT3抑制剂SH-4 - 54对GBM迁移和存活的影响。SH-4 - 54抑制STAT3活性并减少GBM43的3D迁移和存活，但对GBM10没有影响。SH-4 - 54处理显著降低了液体培养物中干细胞样系GBAM 1的活力，但其作用在3D ECM和基质细胞存在下减弱。我们的研究结果强调了ECM和基质细胞在微环境中与癌细胞之间的相互作用，并表明这些关系的影响可能会因不同遗传和临床历史的GBM细胞而异。
Despite the increasingly recognized importance of the tumor microenvironment (TME) as a regulator of tumor progression, only few in vitro models have been developed to systematically study the effects of TME on tumor behavior in a controlled manner. Here we developed a three-dimensional (3D) in vitro model that recapitulates the physical and compositional characteristics of Glioblastoma (GBM) extracellular matrix (ECM) and incorporates brain stromal cells such as astrocytes and endothelial cell precursors. The model was used to evaluate the effect of TME components on migration and survival of various patient-derived GBM cell lines (GBM10, GBM43 and GBAM1) in the context of STAT3 inhibition. Migration analysis of GBM within the 3D in vitro model demonstrated that the presence of astrocytes significantly increases the migration of GBM, while presence of endothelial precursors has varied effects on the migration of different GBM cell lines. Given the role of the tumor microenvironment as a regulator of STAT3 activity, we tested the effect of the STAT3 inhibitor SH-4-54 on GBM migration and survival. SH-4-54 inhibited STAT3 activity and reduced 3D migration and survival of GBM43 but had no effect on GBM10. SH-4-54 treatment drastically reduced the viability of the stem-like line GBAM1 in liquid culture, but its effect lessened in presence of a 3D ECM and stromal cells. Our results highlight the interplay between the ECM and stromal cells in the microenvironment with the cancer cells and indicate that the impact of these relationships may differ for GBM cells of varying genetic and clinical histories.
登录
查看更多内容
影响因子：
5.7
作者：
Arpin CC;Mac S;Jiang Y;Cheng H;Grimard M;Page BD;Kamocka MM;Haftchenary S;Su H;Ball DP;Rosa DA;Lai PS;Gómez-Biagi RF;Ali AM;Rana R;Hanenberg H;Kerman K;McElyea KC;Sandusky GE;Gunning PT;Fishel ML
通讯作者：
Fishel ML
影响因子：
11.2
作者：
Bonavia R;Inda MM;Cavenee WK;Furnari FB
通讯作者：
Furnari FB
影响因子：
8
作者：
Kesanakurti, D.;Chetty, C.;Maddirela, D. Rajasekhar;Gujrati, M.;Rao, J. S.
通讯作者：
Rao, J. S.
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
15.9
作者：
Dolecek, Therese A.;Propp, Jennifer M.;Kruchko, Carol
通讯作者：
Kruchko, Carol