The role of transforming growth factor β in upper gastrointestinal cancers: A systematic review

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 beta (TGF-beta) 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-beta in esophageal and gastric malignancies. We systematically searched MEDLINE/PubMed and EMBASE for eligible preclinical studies describing the effect of TGF-beta or TGF-beta 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-beta failed to induce apoptosis in twelve of sixteen tested cell lines. TGF-beta 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-beta increased migratory, adhesive and invasive capacities. In vivo studies showed increased metastasis in response to TGF-beta treatment. Additionally, TGF-beta 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-beta enhances hallmarks of cancer in most gastric and esophageal cancer cell lines, but not in all. Therefore, targeting the TGF-beta 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.