Osaka Iseikai Clinic for Cancer Therapy, Iseikai Holonics Group, Osaka, Japan.
Laboratory of Molecular Target Therapy for Cancer, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
PLoS One. 2021 Jun 24;16(6):e0251272. doi: 10.1371/journal.pone.0251272. eCollection 2021.
Dysregulation of cell morphology and cell-cell interaction results in cancer cell growth, migration, invasion, and metastasis. Besides, a balance between the extracellular matrix (ECM) and matrix metalloprotease (MMP) is required for cancer cell morphology and angiogenesis. Here, we determined gene signatures associated with the morphology and microenvironment of primary central nervous system lymphoma (PCNSL) to enable prognosis prediction. Next-generation sequencing (NGS) on 31 PCNSL samples revealed gene signatures as follows: ACTA2, ACTR10, CAPG, CORO1C, KRT17, and PALLD in cytoskeleton, CDH5, CLSTN1, ITGA10, ITGAX, ITGB7, ITGA8, FAT4, ITGAE, CDH10, ITGAM, ITGB6, and CDH18 in adhesion, COL8A2, FBN1, LAMB3, and LAMA2 in ECM, ADAM22, ADAM28, MMP11, and MMP24 in MMP. Prognosis prediction formulas with the gene expression values and the Cox regression model clearly divided survival curves of the subgroups in each status. Furthermore, collagen genes contributed to gene network formation in glasso, suggesting that the ECM balance controls the PCNSL microenvironment. Finally, the comprehensive balance of morphology and microenvironment enabled prognosis prediction by a combinatorial expression of 8 representative genes, including KRT17, CDH10, CDH18, COL8A2, ADAM22, ADAM28, MMP11, and MMP24. Besides, these genes could also diagnose PCNSL cell types with MTX resistances in vitro. These results would not only facilitate the understanding of biology of PCNSL but also consider targeting pathways for anti-cancer treatment in personalized precision medicine in PCNSL.
细胞形态和细胞间相互作用的失调导致癌细胞生长、迁移、侵袭和转移。此外，癌症细胞形态和血管生成需要细胞外基质 (ECM) 和基质金属蛋白酶 (MMP) 之间的平衡。在这里，我们确定了与原发性中枢神经系统淋巴瘤 (PCNSL) 的形态和微环境相关的基因特征，以实现预后预测。对 31 个 PCNSL 样本进行下一代测序 (NGS) 显示了以下基因特征：细胞骨架中的 ACTA2、ACTR10、CAPG、CORO1C、KRT17 和 PALLD，粘附中的 CDH5、CLSTN1、ITGA10、ITGAX、ITGB7、ITGA8、FAT4、ITGAE、CDH10、ITGAM、ITGB6 和 CDH18，ECM 中的 COL8A2、FBN1、LAMB3 和 LAMA2，MMP 中的 ADAM22、ADAM28、MMP11 和 MMP24。基因表达值和 Cox 回归模型的预后预测公式清楚地划分了每个状态亚组的生存曲线。此外，玻璃体内胶原基因有助于基因网络的形成，表明 ECM 平衡控制着 PCNSL 微环境。最后，通过 8 个代表性基因（包括 KRT17、CDH10、CDH18、COL8A2、ADAM22、ADAM28、MMP11 和 MMP24）的组合表达，实现了对形态和微环境的综合平衡预测。此外，这些基因还可以诊断体外 MTX 耐药的 PCNSL 细胞类型。这些结果不仅有助于理解 PCNSL 的生物学，还可以考虑在 PCNSL 的个性化精准医学中针对抗癌治疗的靶向途径。
