Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA.
Brain Tumor Center of Excellence, Wake Forest Baptist Medical Center Comprehensive Cancer Center, Winston Salem, NC 27157, USA.
Cells. 2021 Sep 20;10(9):2485. doi: 10.3390/cells10092485.
Glioblastoma (GBM) is the most aggressive malignant glioma. Therapeutic targeting of GBM is made more difficult due to its heterogeneity, resistance to treatment, and diffuse infiltration into the brain parenchyma. Better understanding of the tumor microenvironment should aid in finding more effective management of GBM. GBM-associated macrophages (GAM) comprise up to 30% of the GBM microenvironment. Therefore, exploration of GAM activity/function and their specific markers are important for developing new therapeutic agents. In this study, we identified and evaluated the expression of ALDH1A2 in the GBM microenvironment, and especially in M2 GAM, though it is also expressed in reactive astrocytes and multinucleated tumor cells. We demonstrated that M2 GAM highly express ALDH1A2 when compared to other ALDH1 family proteins. Additionally, GBM samples showed higher expression of ALDH1A2 when compared to low-grade gliomas (LGG), and this expression was increased upon tumor recurrence both at the gene and protein levels. We demonstrated that the enzymatic product of ALDH1A2, retinoic acid (RA), modulated the expression and activity of MMP-2 and MMP-9 in macrophages, but not in GBM tumor cells. Thus, the expression of ALDH1A2 may promote the progressive phenotype of GBM.
胶质母细胞瘤（GBM）是最具侵袭性的恶性神经胶质瘤。由于其异质性、治疗耐药性和向脑实质弥漫性浸润，治疗靶向 GBM 变得更加困难。更好地了解肿瘤微环境应有助于找到更有效的 GBM 管理方法。GBM 相关巨噬细胞（GAM）占 GBM 微环境的 30%。因此，探索 GAM 的活性/功能及其特定标志物对于开发新的治疗药物非常重要。在这项研究中，我们鉴定并评估了 ALDH1A2 在 GBM 微环境中的表达，尤其是在 M2 GAM 中，尽管它也在反应性星形胶质细胞和多核肿瘤细胞中表达。我们证明 M2 GAM 比其他 ALDH1 家族蛋白高表达 ALDH1A2。此外，与低级别胶质瘤（LGG）相比，GBM 样本中 ALDH1A2 的表达更高，并且在肿瘤复发时，无论是在基因水平还是在蛋白水平上，这种表达都增加了。我们证明 ALDH1A2 的酶产物视黄酸（RA）调节了巨噬细胞中 MMP-2 和 MMP-9 的表达和活性，但对 GBM 肿瘤细胞没有影响。因此，ALDH1A2 的表达可能促进 GBM 的进行性表型。
