Sialylated glycoproteins and sialyltransferases in digestive cancers: Mechanisms, diagnostic biomarkers, and therapeutic targets

Blockade of Sialylation with Decrease in Polysialic Acid Levels Counteracts Transforming Growth Factor β1-Induced Skin Fibroblast-to-Myofibroblast Transition

“…Even considering the important biological roles played by polySia and other sialosides in the regulation of the immune response [ 28 , 35 , 59 ], such an experimental system will allow to dissect the role of sialylation in cell signaling interactions of skin fibroblasts with the surrounding microenvironment bearing inflammatory/immune cells that release TGFβ1 along with multiple other profibrotic stimuli. Although in our in vitro study we employed the 3-Fax sialic acid analog that inhibits virtually all sialyltransferases [ 37 , 41 ], we should consider that the use of this compound in vivo may have some limitations, at least if systemically administered, because of deleterious effects on liver and kidney function [ 40 ]. Therefore, exploiting more selective sialyltransferase inhibitors such as 8-keto-Neu5Ac, which was found to be nontoxic at effective concentrations and to block polySia synthesis in cancer cell lines with minimal effects on other sialyl glycoforms [ 37 , 60 ], is advisable for future in vivo experimentation.…”

“…Although in our in vitro study we employed the 3-Fax sialic acid analog that inhibits virtually all sialyltransferases [ 37 , 41 ], we should consider that the use of this compound in vivo may have some limitations, at least if systemically administered, because of deleterious effects on liver and kidney function [ 40 ]. Therefore, exploiting more selective sialyltransferase inhibitors such as 8-keto-Neu5Ac, which was found to be nontoxic at effective concentrations and to block polySia synthesis in cancer cell lines with minimal effects on other sialyl glycoforms [ 37 , 60 ], is advisable for future in vivo experimentation. Finally, we acknowledge that, following the herein demonstration of the ability of sialylation blockade to prevent fibroblast-to-myofibroblast transition, further work is necessary to demonstrate whether the same approach might also be effective in inducing myofibroblast dedifferentiation and skin fibrosis regression.…”

“…Moreover, aberrant sialylation is increasingly recognized as a hallmark of numerous challenging chronic diseases other than cancers, such as autoimmune diseases [ 34 , 35 ]. Of note, potential therapeutic effects of modulating sialyltransferase activity with different compounds were demonstrated both in vitro and in vivo [ 31 , 36 , 37 , 38 ]. As far as the implication of sialylation in skin fibrosis is concerned, a recent study reported that polySia is dysregulated in systemic sclerosis, a multisystem autoimmune disease characterized by fibrosis not only of the skin but also of various internal organs [ 39 ].…”

“…On these premises, we herein investigated whether inhibition of sialylation could interfere with the transition from skin fibroblasts to myofibroblasts induced by the master profibrotic mediator TGFβ1. To this aim, we employed the 3-Fax-peracetyl-Neu5Ac (3-Fax) compound that results in production of CMP-3-Fax-Neu5Ac, which is a competitive inhibitor of virtually all sialyltransferases and also causes negative feedback inhibition for the synthesis of CMP-Neu5Ac, thus resulting in the global blockade of sialylation [ 37 , 40 , 41 ].…”