According to the concept by Cohen and Varki, cell membrane glycomolecules form a dense network characterized by a high grade of diversity and dynamic variability [1]. It makes these structures like a forest with complex “tree crowns” formed by glycans covalently conjugated to protein or a lipid core. The complex structure and function of the glycome depend on monosaccharide units and the stereospecific formation of glycosidic bonds that determine their combination and the spatial organization of glycans. Indeed, the glycoconjugate landscape is dynamically formed by glycome–metabolic enzyme and glycome–metabolic pathway modifying factors that result in specific glycosylation patterns and their critical role in molecular and cellular biology. As a result of metabolic conversion, the activated monosaccharide units of dietary or molecular carbohydrate recycling origin are assembled into complex sugar chains in the Golgi apparatus and attached to the protein or lipid core via glycosyltransferases ^[2][3][2,3] (Figure 1).

Structural studies on cellular glycomes have revealed the glycan epitopes of defined sequences featured in the wide expression of neuraminic acid derivatives routinely called sialic acids. The attachment of sialic acids to the non-reducing end of sugar chains is the last step of glycosylation and results in enhanced microheterogeneity that influences the physical and biochemical properties of glycoconjugates [4]. The specific location, ubiquity, and varied forms of these molecules make them one of the most versatile molecules participating in many physiological processes. They are of particular importance in the field of cell–cell and cell–extracellular matrix interactions that underlie biological recognition, cellular communication, adhesion, and migration. The high-specific sialoglycans have been shown to modulate the function of cell membrane receptors via alterations in dimerization, activation, and autophosphorylation that result in changes in cellular signaling and thereby regulate cell proliferation and survival [5]. The proper sialylation pattern is balanced via the activities of sialyltransferases and sialidases that play crucial roles in the maintenance of cellular homeostasis. Therefore, the ability to affect cellular processes makes sialylation a key player in human health in the fields of nephrology, hepatology, neurobiology, endocrinology, cardiovascular physiology, reproductive processes, and immune responses [6]. Advances in glycobiology and glycoengineering have revealed that the unbalanced synthesis and metabolism of sialoglycans is a pathological risk factor and predictive factor for cell and tissue dysfunction. Finally, aberrant sialylation has been described as a potential therapeutic target and modulator of conventional therapy efficiency. Molecular and clinical studies have confirmed the participation of sialic acids in human pathology; however, the role of sialoglycans in cancer deserves particular attention. Clinical and molecular investigations have confirmed alterations in the sialylation patterns of tumors of various histological types and origins. As shown, the presence of hypersialylated glycans is crucial for malignant cells’ behavior, particularly their activity in a tumor niche, cross-talk with surrounding normal tissue, and infiltrating immune cells [7]. This variation modulates immunosurveillance, making the cells more resistant to the immune response. Indeed, sialic-acid-related immune evasion is a hallmark of many malignancies closely associated with a poor prognosis [4]. Moreover, there is increasing evidence of the engagement of sialic acids in the drug resistance phenomenon in cancer management [8]. Although the modulatory effects of sialic acids on the drug action have been described, the exact mechanisms by which an altered sialylation pattern contributes to drug resistance in cancer are not yet fully understood. Both a poor therapeutic response and multidrug resistance are serious clinical problems; therefore, understanding the modulatory role of sialome in drug sensitivity seems to be important for the development and/or improvement of therapeutic efficiency.

2. Sialic Acids and the Regulation of Cellular Functions in Cancer

Sialome plays a complex and multifaceted role in the structure of cell membranes and the extracellular matrix; therefore, numerous alterations in this field are known to be critical for cancer progression. Similar to normal cells, the decoration of the cellular glycocalyx via sialic acids can impact cellular recognition, signaling, adhesion, molecular trafficking, and migration. However, cancer cells do not express the molecules on their membrane properly, and altered glycosylation and changes in glycoprotein expression are common features of tumorigenesis [9]. Among molecular variations, increased sialylation is a hallmark of several cancers, including breast, colorectal, lung, and brain tumors ^{[7][10][11][12][13][14]}[7,10,11,12,13,14]. Many functions in cells and tissues are regulated via ionic flows, electric fields, and voltage gradients, so any aberrations that cause changes in charge will affect them [15]. Sialic acids are known to create a negative charge on the cell membrane that influences the hydrophilicity of the cell surface and regulates cellular adhesiveness. It is of particular importance in cell migration and determines the metastatic potential of malignant cells [7]. As shown, the overexpression of sialic-acid-terminated glycans leads to alterations in immune status and antibody functions that facilitate tumor formation and correlate with aggressiveness ^[7][16][7,16]. Among sialylated adhesion modulators, the polymers of alpha 2,8-linked sialic acid (polysialic acid, PSA) affect the adhesive properties of neuronal cell adhesion molecules (NCAMs) and perform a pivotal function in the dynamic neuronal generation in the embryonic and neonatal hippocampus ^{[17][18][19][20]}[17,18,19,20]. The repulsive effects caused by PSA allow cells to migrate, as has been confirmed in various types of cancer ^[17][21][22][17,21,22]. Sialic-acid-dependent cell migration is potentiated via PSA in a hypoxic environment; however, it is still unknown how oxygen deficiency affects glycosylation and sialylation in cancer ^[23][24][23,24]. In addition to polysialylated NCAMs (PSA-NCAMs), the family of selectins is involved in adhesion processes during cancer progression. The interplay between selectins and their ligands, sialyl-Lewis-X (sLeX), promotes interactions between cancer cells and endothelial cells, leukocytes, or platelets and thereby plays an important role in metastasis via facilitating the extravasation of tumor cells from the bloodstream [25]. The meta-analysis by Liang et al. has shown that sialyl-Lewis-X overexpression is associated with cancer metastasis, disease recurrence, and overall survival in cancer patients [26]. The exact reasons for altered sialylation in cancer are still unknown. However, three probable mechanisms that may influence changes in sialome are indicated [14]. The first mechanism underlying hypersialylation may be associated with altered metabolic flux via cancer cells with the ability to modulate their metastatic potential. Metabolic reprogramming is one of the hallmarks of cancer, and the reprogrammed metabolism supports its development. Moreover, there are several reports dealing with the influence of metabolic flux on sialylation. The investigation by Almaraz et al. has indicated that the malignancy status becomes altered due to massive metabolic flux through the sialic acid pathway. As shown, the uptake of sialic acid precursors in tumor cells from the extracellular space results in a significant increase in glycoproteins sialylation [27].

3. Enzymatic Dysregulation of Sialylated Glycocalyx in Cancer

Changes in the sialylation controlling machinery were found in several types of cancers and described as markers of sialome-related tumorigenesis. First, the aberrant sialylation processes in malignancies correspond to the altered expression and activity of endogenous sialidases in diverse cellular compartments. Among the four sialidases (NEU1, NEU2, NEU3, and NEU4), the enhanced expression of NEU3 was observed in malignant tissues, whereas the rest of these enzymes tended to be reduced, which led to the accumulation of sialoconjugates [14]. According to Miyagi et al., the altered sialidases of different subcellular localizations play pivotal roles in controlling transmembrane signaling, lysosomal catabolism, and the modulation of functional molecules involved in many biological processes [28]. Besides the sialidases, the family of glycosyltransferases is part of the complex mechanism underlying changes in glycosylation patterns that are closely related to human pathologies, including the pathology of cancer [29]. The transfer of sialic acid to the appropriate acceptors is catalyzed via the group of 20 sialyltransferases that are observed to be raised in many malignancies [30]. As a result, the overexpression of sialoglycans and their incorrect branching promote tumor migration and invasion through the influence of cancer cell angiogenesis, adhesion, and epithelial–mesenchymal transition (EMT) [31]. These effects are strongly correlated with the advanced stage of malignancy, high metastatic potential, and patients’ reduced overall survival ^[32][33][34][32,33,34] (Figure 2A,B). The dysregulation of sialyltransferases depends on the mechanisms that involve genetic, epigenetic, transcriptional, and post-transcriptional regulations known to be developed in cancer and closely associated with the glycosylation pattern ^[32][35][36][32,35,36]. Finally, the biosynthesis and distribution of glycans in malignant cells are regulated via microenvironmental cues [37]. The tumor microenvironment (TME) is composed of immune system cells, cancer-associated fibroblasts (CAFs), that communicate with cancer cells and each other during tumor progression [38]. This is mentioned because even the extracellular matrix (ECM) consists of proteoglycans and fibrous proteins and is a highly glycosylated (and, thus, also a sialylated) environment [39]. Molecular investigations have confirmed that ECM is a physiologically active component of living tissue that provides biochemical and structural support to cells. The highly dynamic structure constantly undergoes remodeling processes, and moreover, each organ is characterized by a unique ECM composition [40]. The dysregulation of ECM dynamics leads to the development of cancer; however, cancer cells are able to modulate the extracellular matrix ^[40][41][42][40,41,42]. Abnormalities in the ECM also deregulate stromal cell behavior, facilitate angiogenesis, deregulate the activation of immune cells, and promote the formation of a TME [43]. The increased expression of glycoconjugates within the ECM results in worse adhesion to fibronectin and collagen, which influence proliferation, differentiation, and migration, whereas desialylation exerts the opposite effects ^[44][45][44,45]. Furthermore, it has been demonstrated that α-2,6 sialic acid is required for the adhesion of cells to fibronectin, which underlies the adhesion of cancer cells to the ECM ^{[41][45][46][47]}[41,45,46,47]. In line with this, sialic acids affect the integrin-mediated intercellular communication between tumor cells and ECM ^{[48][49][50][51]}[48,49,50,51]. Furthermore, the sialylated podoplanin (PDPN) on CAFs plays a key role in tumor-cell-induced platelet aggregation; however, the deprivation of sialic acid reduces this function within the TME ^{[52][53][54][55]}[52,53,54,55]. The importance of the microenvironment in cancer progression is also based on the interaction of immune cells with tumor cells. Sialic-acid-mediated immunosuppression is known as one of the malignancy-promoting mechanisms (Figure 2C). The upregulation of sialic acid in the tumor microenvironment contributes to the establishment of an immunosuppressive environment through the involvement of immunomodulatory Siglec receptors expressed on tumor-infiltrating immune cells [56] (Figure 3). Given the high specificity of the distribution of CD33-related Siglecs and differences in the structure of intracellular signaling domains, the interplay between receptors and their ligands determines the activating or suppressive signaling pathways responsible for the function of the immune cells. It is of particular importance in the context of immune homeostasis maintenance. The sialic acid–Siglec axis modulates the balance between self-recognition and non-recognition and mediates cell signaling and adhesion ^[57][58][57,58]. However, inhibitory Siglecs containing an immunoglobulin-like inhibitory motif (ITIM) have been shown to play a role in regulating immune and non-immune responses within the TME and can influence various aspects of cancer progression [59]. In a model of hypersialylated cancer cells, it was shown that such cells behave like a “super-me” and reduce the immune response via binding to Siglec-7 on NK cells [60].