Abstract
Transforming growth factor-beta (TGF-β) signaling is one of the important cellular pathways that play key roles for tissue maintenance. In particular, it is important in the context of inflammation and tumorigenesis by modulating cell growth, differentiation, apoptosis, and homeostasis. TGF-β receptor type 2 (TGFBR2) mutations affected by a mismatch repair deficiency causes colorectal cancers (CRCs) with microsatellite instability, which is, however, associated with relatively better survival rates. On the other hand, loss of SMAD4, a transcription factor in the TGF-β superfamily signaling, promotes tumor progression. Loss of heterozygosity on chromosome 18 can case SMAD4-deficient CRC, which results in poorer patients’ survival. Such bidirectional phenomenon driven by TGF-β signaling insufficiency reflects the complexity of this signaling pathway in CRC. Moreover, recent understanding of CRC at the molecular level (consensus molecular subtype classification) provides deep insight into the important roles of TGF-β signaling in the tumor microenvironment. Here we focus on the TGF-β signaling in CRC and its interaction with the tumor microenvironment. We summarize the molecular mechanisms of CRC tumorigenesis and progression caused by disruption of TGF-β signaling by cancer epithelial cells and host stromal cells.
Highlights
Transforming growth factor-beta (TGF-β) signaling pathway plays critical roles in controlling tissue development, proliferation, differentiation, apoptosis, and homeostasis [1]
Exposure to TGF-β ligand decreases the ability of activated NK cells to kill cancer cells ex vivo, while inhibition of TGF-β signaling in the tumor microenvironment preserves the function of highly activated, in vitro expanded NK cells in colorectal cancers (CRCs) in vivo [96]
Comprehensive understanding of TGF-β signaling in both tumor cells and the tumor microenvironment is mandatory for the construction of novel therapeutic strategies
Summary
Transforming growth factor-beta (TGF-β) signaling pathway plays critical roles in controlling tissue development, proliferation, differentiation, apoptosis, and homeostasis [1]. TGF-β signaling inhibits epithelial growth in normal tissues, it promotes tumor cell progression in tissues with advanced cancer [3]. This phenomenon is known as TGFβ paradox. Disruption of TGF-β signaling in the colon prompts tumor progression via epithelial cells transformation and via tumor-stromal interactions [7,8,9,10,11]. Most CRC cells with high levels of MSI (MSI-H) accumulate mutations in TGF-β receptor type 2 (TGFBR2) as it carries microsatellite sequences [13,14] As these findings indicated, disruption of TGF-β signaling plays a pivotal role in CRC pathogenesis in several molecular types of CRC. We summarize the proposed mechanisms of TGF-β signaling disruption involved in CRC development, progression, and invasion/metastasis
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