Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer

Abstract

Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, and proteins known to be associated with the TGF-β pathway have been reported as constituents in the cargo of extracellular vesicles (EVs). EVs are secreted vesicles delimited by a lipid bilayer and play critical functions in intercellular communication, including regulation of the tumor microenvironment and cancer development. Thus, this review aims at summarizing the impact of EVs on TGF-β signaling by focusing on mechanisms by which EV cargo can influence tumorigenesis, metastatic spread, immune evasion and response to anti-cancer treatment. Moreover, we emphasize the potential of TGF-β-related molecules present in circulating EVs as useful biomarkers of prognosis, diagnosis, and prediction of response to treatment in cancer patients.

A Novel Localization in Human Large Extracellular Vesicles for the EGF-CFC Founder Member CRIPTO and Its Biological and Therapeutic Implications

“…The pleiotropic pathway is modulated by the cellular context and its integration with other signaling pathways [ 79 ]. In addition, TGFβ itself, other ligands of the TGFβ superfamily, as well as key components of the TGFβ signaling machinery, including GRP78, have been found associated to EVs [ 81 , 82 ]. The use of alternative routes might serve the purpose of finely regulating the role of these factors in cancer development and progression.…”

Proteomic profiling of cell line-derived extracellular vesicles to identify candidate circulatory markers for detection of gallbladder cancer

“…The functional role of EV-derived TGFB1 and ILK in cancer has been reported earlier. TGFB1 is also reported to be present in EV in multiple cancers ( 30 ). TGFB1 containing EVs has been reported to bind to the receptors present on the recipient cells and activating SMAD dependent or SMAD independent signaling regulating the expression of oncogenes (PI3K, AKT, N-cadherin, vitronectin, MMPs) ( 30 ) and promoting tumor cell proliferation, invasion.…”

“…TGFB1 is also reported to be present in EV in multiple cancers ( 30 ). TGFB1 containing EVs has been reported to bind to the receptors present on the recipient cells and activating SMAD dependent or SMAD independent signaling regulating the expression of oncogenes (PI3K, AKT, N-cadherin, vitronectin, MMPs) ( 30 ) and promoting tumor cell proliferation, invasion. ILK-expressing EVs derived from primary tumor are reported to promote EV uptake in the recipient cells which may further promote activation of cancer-associated signaling in the cells ( 30 ).…”

“…TGFB1 containing EVs has been reported to bind to the receptors present on the recipient cells and activating SMAD dependent or SMAD independent signaling regulating the expression of oncogenes (PI3K, AKT, N-cadherin, vitronectin, MMPs) ( 30 ) and promoting tumor cell proliferation, invasion. ILK-expressing EVs derived from primary tumor are reported to promote EV uptake in the recipient cells which may further promote activation of cancer-associated signaling in the cells ( 30 ). Overall, we found TGF beta signaling associated proteins in GBC-derived EVs, however, their functional role in tumor progression and development needs to be established in GBC.…”

TMEM16A as a potential treatment target for head and neck cancer

“…TGF-β is found to be a potent secreted cytokine that drives cancer progression, not only through its immunosuppressive and proangiogenic roles, but also more importantly as a potent inducer of EMT by regulating E-cadherin expression [ 56 ]. The activation of TGF-β receptor complex recruit and induce many signaling proteins such as protein and lipid kinases, scaffolding proteins and small GTPases, whereas some of these proteins become directly phosphorylated by the TGF-β receptors [ 57 ]. It is now generally accepted that TGF-β and other members of its family control many fundamental aspects of cellular behaviour, including migration, adhesion, differentiation, and modification of the microenvironment [ 58 ].…”