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REVIEW ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 3  |  Page : 401-404

Relevance of serum and salivary sialic acid in oral cancer diagnostics


Department of Oral Medicine Diagnosis and Radiology, Sree Balaji Dental College and Hospital, BIHER, Chennai, Tamil Nadu, India

Date of Submission22-Jul-2019
Date of Decision08-Oct-2019
Date of Acceptance19-Dec-2019
Date of Web Publication18-Jul-2020

Correspondence Address:
Dr. T Sarumathi
Department of Oral Medicine Diagnosis and Radiology, Sree Balaji Dental College and Hospital, BIHER, Chennai - 600 100, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_512_19

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 > Abstract 


To review the relevance of sialic acid as a tumour marker in oral cancer. Tumour marker are useful in the screening for early malignancy. Sialic acids are important in determining the surface properties of cells and has been implicated in cellular invasiveness, adhesiveness, and immunogenicity. Sialic acids are commonly found at the outermost end of glycan chains of all cell types. Increase in the levels of sialic acid in oral cancer indicates its importance as a tumour marker.Both serum and salivary sialic acid levels can be used as a screening tool and a diagnostic aid for oral cancer. Salivary sialic acid can be used as a non-invasive, cost effective and reliable diagnostic methods for screening and monitoring of oral cancer. In patients with oral cancer, glycoprotein metabolism is altered. Increase in the levels of sialic acid in oral cancer indicate its importance as a tumour marker. Changes in the serum is reflected in saliva. Salivary sialic acid can be used as non-invasive, cost effective and reliable diagnostic methods for screening and monitoring of oral cancer. Early the diagnosis, better the prognosis.

Keywords: Oral cancer, sialic acid, tumor marker


How to cite this article:
Guruaribam VD, Sarumathi T. Relevance of serum and salivary sialic acid in oral cancer diagnostics. J Can Res Ther 2020;16:401-4

How to cite this URL:
Guruaribam VD, Sarumathi T. Relevance of serum and salivary sialic acid in oral cancer diagnostics. J Can Res Ther [serial online] 2020 [cited 2020 Aug 11];16:401-4. Available from: http://www.cancerjournal.net/text.asp?2020/16/3/401/289974




 > Introduction Top


Oral cancer is highly widespread in many parts of the world. Oral squamous cell carcinoma accounts for more than 90% of oral cancer cases.

Smoking, alcohol, and betel quid chewing are some of the risk factors associated with oral potentially malignant disorders and oral cancer.[1]

The WHO stated that cancer burden would increase to 20 million by 2020, with 70% in the developing world.[2]

Oral cancer, with its widely variable rate of occurrence, has one of the highest incidences in India, constituting around 12% of all cancers in men and 8% of all cancers among women. It has been estimated that 83,000 new oral cancer cases occur here each year.[3]

Berenblum and Schubik first suggested the theory of multistage carcinogenesis in 1948. Initiation, promotion, and progression are the three main phases which are recognized.[4] Cancer diagnosis is based on the analysis of tissue, and cytology specimens obtained through different procedures. When a cell becomes cancerous, new antigens foreign to the immune system appear on the cell's surface. A tumor marker can be defined as a molecule that indicates the likely presence of cancer or can also be defined as one that provides information about the likely future behavior of an existing cancer (e.g., ability to metastasize or to respond to therapy). They are useful in the screening for early malignancy, as a diagnostic aid for malignancy, determining prognosis in malignancy, predicting therapeutic efficacy, maintaining surveillance following surgical of the primary tumor, and removal and monitoring therapy in advanced malignancy.[5]

Glycoproteins and glycolipids are major constituents of cell membrane, which is why cell surface glycoconjugates are important in malignancy. Various characteristics of mammalian cells are exhibited through the surface of the cell. Altered surface characteristics are essential for the abnormal growth and behavior of malignant cells as neoplastic changes are expressed at the cell surface.[6] Tumor markers are biochemical substances expressed by tumor cells either due to the cause or effect of malignant process. These substances that are expressed by cancer cells can be used as diagnostic and prognostic markers in cancer patients.[7] During malignant transformation, the enlargement of oligosaccharides resulting in branching sites for incorporation of sialic acid (SA) is one of the most common changes in glycoconjugates.[8]


 > Sialic Acid Top


SAs are commonly found at the outermost end of glycan chains of all cell types. They have a nine-carbon backbone which decorates all surfaces of cell, and they are the most secreted proteins of vertebrates and “higher” invertebrates, mediating or modulating a variety of normal and pathological processes. They are principal factors influencing the half-life of glycoproteins in circulation.[9]

Two forms of SA are present:

  1. Lipid-bound SA (LSA) consists of glycolipid-bound SA
  2. Total SA (TSA) consists of glycoprotein and glycolipid-bound SA.


In serum/plasma, the normal range of TSA level is 1.58–2.22 mmol/L, the free form of SA only amount to 0.5–3 mmol/L, and the LSA forms 10–50 mmol/L.[10]

The dwelling of SA at the terminal or near to terminal position underlies its vital role in determining surface characteristics of cells and secreted glycoproteins. SA, being nonreducible termini, has gained tremendous importance in cancer research.[11]

Functions of sialic acid

Schauer et al.[12] proposed the following functions of SA:

  1. Stabilizing the conformation of glycoproteins and cellular membranes which is due to the negatively charged, outer SA units of the membrane glycoproteins repelling one another
  2. Assisting in cell-to-cell recognition and interaction and helping as chemical messengers in body fluids and tissues
  3. Impacting transmembrane transportation mechanisms
  4. Affecting the function of membrane receptor molecules by developing binding sites for ligands, antibodies, enzymes, and microbes
  5. Affecting the functioning, stability, and survival of glycoproteins in blood circulation
  6. Regulating the permeability of basement membrane of glomeruli.


Sialic acid estimation

Some of the techniques used to detect SA are.[10]

  1. Orcinol method – based on orcinol reacting with SA in the presence of iron ions and hydrochloric acid
  2. Resorcinol method – SA is first dissociated with acid hydrolysis, then resorcinol and Cu2+ are used to obtain chromogen
  3. Thiobarbiturate assay method – the SA is first dissociated with acid hydrolysis, followed by periodic acid which is used to oxidize free SA to form formyl pyruvic acid, which is allowed to react with thiobarbiturate to obtain chromophore
  4. Acetylneuraminate pyruvate lyase assay – SA is released with neuraminidase and converted to pyruvate and acylmannosamines.



 > Serum Sialic Acid Top


SAs are important in determining the surface properties of cells and have been implicated in cellular invasiveness, adhesiveness, and immunogenicity. Through increased turnover, secretion, and/or shedding from malignant cells, these glycoconjugates are released into the circulation[6] Joshi and Patil,[13] Shashikant and Rao,[14] Rajpura et al.,[8] and Vallikanthan et al.[15] have found a statistically significant rise in serum SA levels as compared to healthy individuals with reference to oral squamous cell carcinoma. They also noticed the increased levels of SA when correlated with the clinical staging of oral squamous cell carcinoma. Elevations in the levels of SA appeared to reflect tumor burden and correlated well with the stage of the primary lesion and presence of distant metastasis.[8],[16],[17]

Early detection of cancer is of utmost importance to decrease the morbidity and mortality of the disease. Saliva can provide a cost-effective approach for screening a large population since it is a noninvasive method. Saliva is composed of a wide variety of organic and inorganic constituents that wholly act to modulate the oral environment. Salivary glycoproteins play an important role in the properties and functions of saliva. CA-125, CA-15-3, kallikrein, epidermal growth factor, and p53 are some of the salivary parameters which were estimated as tumor markers in different types of malignancies.[18]

Since a growing number of physiological conditions and systemic diseases were shown to be accurately reflected by the composition of saliva, salivary diagnostics have received the utmost attention. There is much attention and concentration on technological advancement and development in techniques focusing on salivary diagnostics in order to identify disease-signaling biomarkers.[19]

Advantages of saliva as a diagnostic fluid:[20]

  1. Potentially attractive for clinical diagnostics
  2. Different molecules reach the saliva through extracellular and intracellular routes, providing information about the function of several organs in the body
  3. Collection is noninvasive, low levels of anxiety and stress
  4. Low risk of exposure of laboratory workers to hazardous samples
  5. Some of the most abundant proteins in plasma are also found in saliva at moderately high concentrations.


Disadvantages of saliva as a diagnostic fluid:[20]

  1. In most cases, biomarkers are not yet fully validated for diagnosis and monitoring of diseases
  2. Methods of collection are not fully standardized
  3. Variation in the concentration of molecules more affected by circadian rhythm, stimulus, age, and among others
  4. Lower concentration of biomolecules.



 > Salivary Sialic Acid Top


Saliva being a biofluid, which is a filtrate of serum from the vasculature, any change that occurs in the serum as a result of disease process will be reflected in saliva.[21],[22] Achalli et al.[23] suggested that the mean serum and salivary SA levels were increased significantly in patients with oral potentially malignant disorders and oral cancer when compared to healthy control. Dadhich et al.[22] stated a significant and gradual increase in serum and salivary SA from control to oral potentially malignant disorders to oral cancer. Chaudhari et al.[7] stated that salivary SA was elevated in oral squamous cell carcinoma compared to oral premalignancy and control group where they observed a statistically significant correlation between the grades of squamous cell carcinoma, grades of dysplasia in premalignancy, and SA level. Sanjay et al.[18] found that the salivary-free SA levels were found to be significantly higher in well-differentiated squamous cell carcinoma than in moderately differentiated carcinoma. Shivashankara and Prabhu.[24] found that oral squamous cell carcinoma patients had higher salivary levels of free SA, protein-bound SA when compared to healthy controls. Salivary SA can be used as a noninvasive, reliable, and cost-effective tool in the diagnosis and management of oral potentially malignant disorders and oral cancer.

Limitations of sialic acid

The limitations of using SA are:

  1. The serum SA levels are increased in inflammatory conditions, cardiovascular diseases, and diabetes
  2. Inherited disorders of SA – highly increased SA levels (10–30 fold) have also been observed in several inborn errors of metabolic diseases such as sialidosis, Salla disease, infantile SA storage disease, and neuraminidase deficiency[25]
  3. TSA concentration was found to be significantly increased in patients with chronic glomerulonephritis and chronic renal failure.



 > Conclusion Top


Early detection is the key in reducing the mortality and morbidity of oral squamous cell carcinoma in which screening plays a vital role. Salivary diagnostics has gained great attention in the recent years. Due to the intimate contact of the saliva with the lesion tissue, the diagnostic capacity of saliva in oral and oropharyngeal lesions may be enhanced. Increase in the levels of SA in oral cancer indicates its importance as a tumor marker. The methods used to detect SA in saliva are comparatively easy and cost-effective. For large populations, such noninvasive, cost-effective, and reliable diagnostic methods can be used for screening and monitoring of oral cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Yu JS, Chen YT, Chiang WF, Hsiao YC, Chu LJ, See LC, et al. Saliva protein biomarkers to detect oral squamous cell carcinoma in a high-risk population in Taiwan. Proc Natl Acad Sci U S A 2016;113:11549-54.  Back to cited text no. 1
    
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Pavani PM, Srinivas P, Kothia NR, Chandu VC. Awareness on oral cancer: An overriding track toward its prevention – A cross sectional survey. Int J Prev Clin Dent Res 2018;5:35-40.  Back to cited text no. 2
    
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Baxi BR, Patel PS, Adhvaryu SG, Dayal PK. Usefulness of serum glycoconjugates in precancerous and cancerous diseases of the oral cavity. Cancer 1991;67:135-40.  Back to cited text no. 6
    
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8.
Rajpura KB, Patel PS, Chawda JG, Shah RM. Clinical significance of total and lipid bound sialic acid levels in oral pre-cancerous conditions and oral cancer. J Oral Pathol Med 2005;34:263-7.  Back to cited text no. 8
    
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12.
Schauer R, Kelm S, Reuter G, Roggentin P, Shaw L. Biochemistry and role of sialic acids. In: Biology of the Sialic Acids. Boston, MA: Springer; 1995. p. 7-67.  Back to cited text no. 12
    
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Joshi M, Patil R. Estimation and comparative study of serum total sialic acid levels as tumor markers in oral cancer and precancer. J Cancer Res Ther 2010;6:263-6.  Back to cited text no. 13
    
14.
Shashikanth MC, Rao BB. Study of serum fucose and serum sialic acid levels in oral squamous cell carcinomia. Indian J Dent Res 1994;5:119-24.  Back to cited text no. 14
    
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Vallikanthan N, Vijay Raghavan MR, Aroor AR, Keshava Murthy KR. Estimation of serum sialic acid in oral cancer. J Indian Dent Assoc 1992;63:121-3.  Back to cited text no. 15
    
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Plucinsky MC, Riley WM, Prorok JJ, Alhadeff JA. Total and lipid-associated serum sialic acid levels in cancer patients with different primary sites and differing degrees of metastatic involvement. Cancer 1986;58:2680-5.  Back to cited text no. 16
    
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Xing RD, Wang ZS, Li CQ, Tang QY, Jiang CB, Zhang YZ. Total sialic acid as a tumor marker for oral cancer. Int J Biol Markers 1994;9:239-42.  Back to cited text no. 17
    
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Sanjay PR, Hallikeri K, Shivashankara AR. Evaluation of salivary sialic acid, total protein, and total sugar in oral cancer: A preliminary report. Indian J Dent Res 2008;19:288-91.  Back to cited text no. 18
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Cuevas-Córdoba B, Santiago-García J. Saliva: A fluid of study for OMICS. OMICS 2014;18:87-97.  Back to cited text no. 20
    
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Dadhich M, Prabhu V, Pai VR, D'Souza J, Harish S, Jose M. Serum and salivary sialic acid as a biomarker in oral potentially malignant disorders and oral cancer. Indian J Cancer 2014;51:214-8.  Back to cited text no. 22
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Achalli S, Madi M, Babu SG, Shetty SR, Kumari S, Bhat S. Sialic acid as a biomarker of oral potentially malignant disorders and oral cancer. Indian J Dent Res 2017;28:395-9.  Back to cited text no. 23
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Shivashankara AR, Prabhu MK. Salivary total protein, sialic acid, lipid peroxidation and glutathione in oral squamous cell carcinoma. Biomed Res 2011;22:355-9.  Back to cited text no. 24
    
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