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Review
. 2024 Jul 5;25(13):7400.
doi: 10.3390/ijms25137400.

TGF-β Modulated Pathways in Colorectal Cancer: New Potential Therapeutic Opportunities

Morena Fasano  1 , Mario Pirozzi  1 , Chiara Carmen Miceli  1 , Mariateresa Cocule  1 , Michele Caraglia  2   3 , Mariarosaria Boccellino  2 , Pasquale Vitale  4 , Vincenzo De Falco  4 , Stefano Farese  1 , Alessia Zotta  1 , Fortunato Ciardiello  1 , Raffaele Addeo  4
Affiliations
Review

TGF-β Modulated Pathways in Colorectal Cancer: New Potential Therapeutic Opportunities

Morena Fasano et al. Int J Mol Sci. .

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with 20% of patients presenting with metastatic disease at diagnosis. TGF-β signaling plays a crucial role in various cellular processes, including growth, differentiation, apoptosis, epithelial-mesenchymal transition (EMT), regulation of the extracellular matrix, angiogenesis, and immune responses. TGF-β signals through SMAD proteins, which are intracellular molecules that transmit TGF-β signals from the cell membrane to the nucleus. Alterations in the TGF-β pathway and mutations in SMAD proteins are common in metastatic CRC (mCRC), making them critical factors in CRC tumorigenesis. This review first analyzes normal TGF-β signaling and then investigates its role in CRC pathogenesis, highlighting the mechanisms through which TGF-β influences metastasis development. TGF-β promotes neoangiogenesis via VEGF overexpression, pericyte differentiation, and other mechanisms. Additionally, TGF-β affects various elements of the tumor microenvironment, including T cells, fibroblasts, and macrophages, promoting immunosuppression and metastasis. Given its strategic role in multiple processes, we explored different strategies to target TGF-β in mCRC patients, aiming to identify new therapeutic options.

Keywords: EMT; TGF-β; angiogenesis; colorectal cancer; microenvironment.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A schematic representation of the TGF-β signaling pathway illustrates its key components and interactions in both canonical and non-canonical pathways.
Figure 2
Figure 2
The role of TGF-β in EMT: SMAD-dependent and SMAD-independent pathways.
Figure 3
Figure 3
The role of TGF-β in angiogenesis: pericyte differentiation, and regulation of key angiogenic factors including VEGF, PDGF-D, and TSP-1.
Figure 4
Figure 4
Interactions of TGF-β with the tumor microenvironment: insights into TGF-β signaling, EMT, metastasis, and tumor progression.
Figure 5
Figure 5
Additional roles of TGF-β: EMT regulation by TGF-β and PODXL, peritoneal metastasis through TSIP formation via ROCK and Smad, TGFβR2 mutations in vascularization enhancement, and concomitant KRAS-TGFβR2 mutation in EMT.
Figure 6
Figure 6
TGF-β mediated mechanisms of resistance: Oxaliplatin resistance, Cetuximab resistance, 5-FU resistance, BRAFi resistance.
See this image and copyright information in PMC

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