Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, De Boelelaan 1117-1118, 1081 HV Amsterdam, The Netherlands.
Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Cancer Treat Rev. 2021 Nov;100:102285. doi: 10.1016/j.ctrv.2021.102285. Epub 2021 Sep 2.
Esophageal and gastric malignancies are associated with poor prognosis, in part due to development of recurrences or metastases after curative treatment. The transforming growth factor β (TGF-β) pathway might play a role in the development of treatment resistance. In this systematic review, we provide an overview of preclinical studies investigating the role of TGF-β in esophageal and gastric malignancies. We systematically searched MEDLINE/PubMed and EMBASE for eligible preclinical studies describing the effect of TGF-β or TGF-β inhibition on hallmarks of cancer, such as proliferation, migration, invasion, angiogenesis and immune evasion. In total, 2107 records were screened and 45 articles were included, using mouse models and 45 different cell lines. TGF-β failed to induce apoptosis in twelve of sixteen tested cell lines. TGF-β could either decrease (five cell lines) or increase proliferation (seven cell lines) in gastric cancer cells, but had no effect in esophageal cancer cells. In all esophageal and all but two gastric cancer cell lines, TGF-β increased migratory, adhesive and invasive capacities. In vivo studies showed increased metastasis in response to TGF-β treatment. Additionally, TGF-β was shown to induce vascular endothelial growth factor production and differentiation of cancer-associated fibroblasts and regulatory T-cells. In conclusion, we found that TGF-β enhances hallmarks of cancer in most gastric and esophageal cancer cell lines, but not in all. Therefore, targeting the TGF-β pathway could be an attractive strategy in patients with gastric or esophageal cancer, but additional clinical trials are needed to define patient groups who would benefit most.
食管和胃恶性肿瘤的预后较差，部分原因是在根治性治疗后复发或转移。转化生长因子β（TGF-β）通路可能在治疗耐药的发展中起作用。在本系统评价中，我们概述了研究 TGF-β在食管和胃恶性肿瘤中作用的临床前研究。我们系统地检索了 MEDLINE/PubMed 和 EMBASE，以寻找描述 TGF-β或 TGF-β抑制对癌症特征（如增殖、迁移、侵袭、血管生成和免疫逃逸）影响的临床前研究。共筛选了 2107 条记录，纳入了 45 篇文章，这些研究使用了小鼠模型和 45 种不同的细胞系。在 16 种测试的细胞系中，有 12 种细胞系的 TGF-β未能诱导细胞凋亡。TGF-β可降低（5 种细胞系）或增加（7 种细胞系）胃癌细胞的增殖，但对食管癌细胞无影响。在所有食管癌细胞系和除 2 种以外的所有胃癌细胞系中，TGF-β均增加了迁移、黏附和侵袭能力。体内研究表明，TGF-β 治疗可增加转移。此外，TGF-β 可诱导血管内皮生长因子的产生，并促进癌症相关成纤维细胞和调节性 T 细胞的分化。总之，我们发现 TGF-β增强了大多数胃和食管癌细胞系的癌症特征，但并非所有细胞系都如此。因此，靶向 TGF-β通路可能是胃或食管癌患者有吸引力的策略，但需要更多的临床试验来确定最受益的患者群体。
