Abstract
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.
Highlights
Esophageal and gastric malignancies are the sixth and third leading causes of cancer-related deaths worldwide respectively, [1] with 5-year survival rates below 30% [2,3]
It has been suggested that the transforming growth factor β (TGF-β) pathway might play a role in treatment resistance through a process called epithelial-to-mesenchymal transition [7,8] and that targeting this pathway may lead to treatment sensitization [9]
TGF-β has often been implicated in carcinogenesis, but has been shown to have antitumor properties
Summary
Esophageal and gastric malignancies are the sixth and third leading causes of cancer-related deaths worldwide respectively, [1] with 5-year survival rates below 30% [2,3]. TGF-β is expressed by a variety of cells, including tumor cells and stromal cells, and its signaling pathway is responsible for regulation of a wide variety of physiological processes such as cellular differentiation, apoptosis, and migration [10]. As a result, this pathway and disruptions thereof play a pivotal role in cancer suppression or promotion [11]. Binding of TGF-β to TβRII, which is facilitated by TβRIII, results in recruitment and phosphorylation of TβRI [12] This activated receptor complex phosphorylates the intracellular SMAD-1, 2 and 3 proteins. In addition to this pathway, TGF-β affects cell processes through non-canonical pathways, including regu lation of p21 and c-Myc [14,15]
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