TGF-β Signaling in Metastatic Colorectal Cancer (mCRC): From Underlying Mechanism to Potential Applications in Clinical Development

Abstract

Colorectal cancer (CRC) is a serious public health issue, and it has the leading incidence and mortality among malignant tumors worldwide. CRC patients with metastasis in the liver, lung or other distant sites always have poor prognosis. Thus, there is an urgent need to discover the underlying mechanisms of metastatic colorectal cancer (mCRC) and to develop optimal therapy for mCRC. Transforming growth factor-β (TGF-β) signaling plays a significant role in various physiologic and pathologic processes, and aberrant TGF-β signal transduction contributes to mCRC progression. In this review, we summarize the alterations of the TGF-β signaling pathway in mCRC patients, the functional mechanisms of TGF-β signaling, its promotion of epithelial–mesenchymal transition, its facilitation of angiogenesis, its suppression of anti-tumor activity of immune cells in the microenvironment and its contribution to stemness of CRC cells. We also discuss the possible applications of TGF-β signaling in mCRC diagnosis, prognosis and targeted therapies in clinical trials. Hopefully, these research advances in TGF-β signaling in mCRC will improve the development of new strategies that can be combined with molecular targeted therapy, immunotherapy and traditional therapies to achieve better efficacy and benefit mCRC patients in the near future.

Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila

“…These differences might reflect the more nuanced and paradoxical role of TGF-β signaling in cancer, where it can be tumor suppressive and tumor promoting in the same tumor type at different stages of tumorigenesis. 57 …”

Effect of CHRDL1 on angiogenesis and metastasis of colorectal cancer cells via TGF‐β/VEGF pathway

“…Several reports have shown that TGF‐β is highly expressed in CRC, increasing the production of several mitotic growth factors, including TGF‐α, FGF, and EGF. Thus it acts as a tumor promoter in the final stages of CRC 50,51 . Angiogenesis is the development of new blood vessels that are involved in the genesis, growth, and metastasis of tumors and involves a variety of factors, including VEGF 52 .…”

“…49 The initiation of TGF-β signaling occurs through the binding of the a tumor promoter in the final stages of CRC. 50,51 Angiogenesis is the development of new blood vessels that are involved in the genesis, growth, and metastasis of tumors and involves a variety of factors, including VEGF. 52 VEGF levels and VEGFR activity are enhanced and associated with poor prognosis in CRC.…”

Interplay between Signaling Pathways and Tumor Microenvironment Components: A Paradoxical Role in Colorectal Cancer

“…The TGF-β signaling pathway is critical in many biological processes. It regulates cell growth, differentiation, apoptosis, cell motility, extracellular matrix production, epithelial–mesenchymal transition (EMT), angiogenesis, and cellular immunity [ 97 , 98 , 99 ]. There are three receptors in the TGF-β signaling pathway: Transforming growth factor-β receptor (TGFBR)-1, TGFBR2, and TGFBR3, and three ligand isoforms: TGF-β1, TGF-β2, and TGF-β3 [ 100 , 101 ].…”

“…The deregulation of this pathway is associated with many diseases, such as cancer [ 103 ]. Indeed, the aberrant activation of this signaling pathway promotes a variety of tumors, including hepatocellular carcinoma, pancreatic cancer, esophageal cancer, gastric cancer and CRC [ 99 , 104 ]. In tumor, the TGF-β signaling pathway exhibits a paradoxical role that is known as the “TGF-β paradox” [ 97 ] ( Figure 6 ).…”