Altered Glycosylation in Progression and Management of Bladder Cancer

Abstract

Bladder cancer (BC) is the 10th most common malignancy worldwide, with an estimated 573,000 new cases and 213,000 deaths in 2020. Available therapeutic approaches are still unable to reduce the incidence of BC metastasis and the high mortality rates of BC patients. Therefore, there is a need to deepen our understanding of the molecular mechanisms underlying BC progression to develop new diagnostic and therapeutic tools. One such mechanism is protein glycosylation. Numerous studies reported changes in glycan biosynthesis during neoplastic transformation, resulting in the appearance of the so-called tumor-associated carbohydrate antigens (TACAs) on the cell surface. TACAs affect a wide range of key biological processes, including tumor cell survival and proliferation, invasion and metastasis, induction of chronic inflammation, angiogenesis, immune evasion, and insensitivity to apoptosis. The purpose of this review is to summarize the current information on how altered glycosylation of bladder cancer cells promotes disease progression and to present the potential use of glycans for diagnostic and therapeutic purposes.

RPN1 promotes the proliferation and invasion of breast cancer cells by activating the PI3K/AKT/mTOR signaling pathway

“…RPN1 is a protein involved in the process of protein synthesis within cells and is responsible for N-glycosylation in the ER of cells [25]. Abnormal or altered N-glycosylation have been suggested to influence the signaling pathways involved in cell proliferation, migration, and angiogenesis in cancer progression [26,27]. Accumulating studies have reported that RPN2 is implicated in multiple cancers, such as breast cancer [28], small-cell lung cancer [29], bladder cancer [30], and colon carcinoma [31].…”

CD44 in Bladder Cancer

“…The role of general glycosylation levels in the cellular proteome of bladder cancer cells specifically is becoming clearer with recent studies. It is evident that alterations to a number of glycan synthesis pathways are associated with bladder cancer occurrence, more advanced disease, and poor prognosis [ 30 ]. Another hallmark of abnormal glycan synthesis and protein modification in bladder cancer is the increased appearance of Tumor-Associated Carbohydrate Antigens (TACAs) [ 31 , 32 ].…”

“…Additional TACAs occur as a result of different saccharide molecules being added in an O-glycosylation-deficient environment, such as STn, T, and Lewis antigens. All of these abnormal antigens are considered significant biomarkers in bladder cancer, along with a host of other altered glycosylation events [ 30 ]. A very intriguing, recent development in assisting clinicians with choosing the best treatment for bladder cancer patients is the development of a glycosylation risk score [ 34 ].…”

Aberrantly Glycosylated GLUT1 as a Poor Prognosis Marker in Aggressive Bladder Cancer

“…Recently, immune checkpoint inhibitors (ICI) for BLCA patients were approved, showing modest 20–25% success rates in providing improved overall survival and progression free survival [ 1 , 3 , 4 ], urging novel therapeutic strategies. Advanced BLCA is characterized by alterations in glycosylation pathways, mainly oversialylation of terminal glycans and consequent arrest in proteins O -glycosylation [ 5 ]. This event is translated by the overexpression of sialylated short-chain O -GalNAc glycans, such as sialyl-Tn (STn) and mono/di sialylated T (ST) antigens [ 6 , 7 , 8 , 9 ].…”