Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2021 Jul 22;16(7):e0241766. doi: 10.1371/journal.pone.0241766. eCollection 2021.
Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.
对膀胱癌 (BCa) 的全面特征分析已经确定了具有不同改变和生存趋势的分子表型类别。在酪氨酸激酶 (TK) 家族中扩展这些研究以确定疾病驱动因素，可以提高我们使用 TK 抑制剂来治疗特定患者群体或个体的效果。我们检查了 TKs 作为一类 (n = 89) 在癌症基因组图谱 (TCGA) 肌肉浸润性 BCa 数据集中的表达分布 (n >400)。具有潜在致癌改变 (过表达和/或扩增) 的患者谱将 TKs 聚类为 3 组；与没有改变的患者相比，第 1 组和第 3 组 TKs 的改变与患者生存显著恶化相关。许多 TK 途径诱导上皮-间充质转化 (EMT)，促进肿瘤侵袭和转移。在 TCGA 病例中，有 9 个 EMT 转录激活因子发生过表达和/或扩增。在 TCGA 病例中，43%发生了 9 个 EMT 转录激活因子的共表达和/或扩增改变。第 1 组 TKs 的共表达和/或扩增改变涉及大多数组 1 TKs；其中 24%的事件与患者生存显著恶化相关。受体 TKs 及其配体的共表达和/或扩增改变发生在 TCGA 病例的 16%和几种 BCa 衍生细胞系中。在 BCa 细胞系中抑制 GAS6、MST1 或 CSF1 或它们各自的受体 (AXL、MST1R 和 CSF1R) 与受体激活、细胞迁移、细胞增殖和非锚定依赖性细胞生长减少相关。这些研究揭示了 BCa 中潜在致癌 TK 途径相关改变的模式和普遍性，并确定了与 BCa 患者生存减少相关的特定改变。在 BCa 患者中检测到这些特征可以更好地指导 TK 抑制剂的使用并改善临床结果。
