Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea.
Gastric Cancer. 2021 May;24(3):577-588. doi: 10.1007/s10120-020-01139-4. Epub 2020 Nov 9.
Despite the promising preclinical antitumor activity of MET-targeting therapies, most clinical trials have failed. We introduced a new concept of quantitation of stroma-induced hepatocyte growth factor (HGF) to assess the actual MET signalling activity in gastric cancer (GC).
We treated serially diluted HGF and conditioned media (CM) from cancer-associated fibroblasts (CAFs) on low MET-expressing cancer cells and investigated the phenotypical and signalling changes. Stromal proportion and MET expression in GC samples were assessed, and gene set enrichment analysis (GSEA) from the public database was performed. The antitumor effect of anti-MET treatment was examined, especially when cancer cells were activated in a ligand-dependent manner.
Relatively high doses of HGF or high-concentrated CM fully activated MET signalling cascades and promoted cell proliferation/invasion. High stromal proportion denoted worse patient survival in MET-positive GCs than in MET-negative ones. GSEA showed that the gene sets regarding proliferation, migration, and CAF as well as MET pathway signature were enriched in simultaneously MET- and HGF-positive samples. Sufficient ligand-dependent MET signalling activation increased the sensitivity to crizotinib.
We conclude that patients whose tumours have a high stromal proportion and at least low MET expression may benefit more from MET-targeted therapies.
尽管针对 MET 的靶向治疗具有很有前景的抗肿瘤活性，但大多数临床试验都失败了。我们提出了一种新的概念，即定量评估间质诱导的肝细胞生长因子（HGF），以评估胃癌（GC）中实际的 MET 信号活性。
我们用低表达 MET 的癌细胞上的 HGF 和癌症相关成纤维细胞（CAF）的条件培养基（CM）进行连续稀释处理，并研究了表型和信号变化。评估 GC 样本中的基质比例和 MET 表达，并从公共数据库中进行基因集富集分析（GSEA）。检查了抗-MET 治疗的抗肿瘤作用，尤其是当癌细胞以配体依赖性方式被激活时。
相对较高剂量的 HGF 或高浓度的 CM 可完全激活 MET 信号级联反应，并促进细胞增殖/侵袭。高基质比例表示在 MET 阳性 GC 中患者的生存情况比 MET 阴性的更差。GSEA 显示，与增殖、迁移和 CAF 以及 MET 通路特征相关的基因集在同时具有 MET 和 HGF 的样本中富集。足够的配体依赖性 MET 信号激活增加了对克唑替尼的敏感性。
我们的结论是，肿瘤基质比例高且至少 MET 表达低的患者可能会从 MET 靶向治疗中获益更多。
