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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 33-39

Biomarkers of oral cancer: A current views and directions


1 Department of Oral Pathology and Microbiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
2 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
3 Department of Oral and Maxillofacial Surgery, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
4 Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India

Date of Submission29-Aug-2021
Date of Acceptance26-Oct-2021
Date of Web Publication11-Mar-2022

Correspondence Address:
Gurupadayya Bannimath
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru - 570 015, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_204_21

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  Abstract 


Tumor biomarkers are the chemical substances that the human body or cancer cells produce in response to the presence of cancer. These markers are mostly proteins that cancer cells produce more quickly. Patients with certain types of cancer have higher levels of these protein substances in their urine, blood, or body tissue and help differentiate between primary and secondary tumors. Oral carcinomas, especially of the head-and-neck region, represent a critical diagnostic challenge not only for the histopathologist but also for the clinician when planning an appropriate treatment protocol. For these reasons, the practice and understanding of these biomarkers have improved tremendously. This review not only sheds light on the different types of tumor markers but also shows their role in some diseases.

Keywords: Head-and-neck cancer, malignancy, oral cancer, tumor markers


How to cite this article:
Doddawad VG, Bannimath G, Shivakumar S, Bannimath N. Biomarkers of oral cancer: A current views and directions. Biomed Biotechnol Res J 2022;6:33-9

How to cite this URL:
Doddawad VG, Bannimath G, Shivakumar S, Bannimath N. Biomarkers of oral cancer: A current views and directions. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 May 19];6:33-9. Available from: https://www.bmbtrj.org/text.asp?2022/6/1/33/339366




  Introduction Top


Tumor markers are substances produced by the tumor or the body in response to the presence of cancer or certain benign (noncancerous) diseases that can aid in cancer diagnosis and assessment.[1],[2],[3] Tumor markers have been used to predict the recurrence and prognosis of a lesion/disease. A specific marker is different from a single tumor, so it is considered a tumor-specific marker that is unique, and the majority of tumor markers are found in multiple tumors known as tumor-associated markers.[4] The specific biomarkers are an excessive concentration in the tissue or body fluids of cancer patients compared to a healthy person.[5]

Rapid diagnosis is essential to prevent the oral premalignant disease from progressing to cancer and to improve patient prognosis and survival.[6] According to the literature, for premalignant lesions or oral cancer, a biopsy is the gold standard technique/method of diagnosis, but it is an invasive procedure and requires some tissue processing time.[7] Exfoliative cytology is a process that scrapes cells from the surface of the lesion and requires the application of these markers to it, which aids in early detection.[8] Autofluorescence is another new noninvasive method for identifying early changes in the oral mucosa.[9] Hence, it helps the clinician to identify changes in the oral mucosa and pinpoint the specific location of the lesion.[10],[11]

Benefits of oral premalignant and malignant biomarkers:[12]

Biomarkers for oral premalignant and malignant lesions can be used as a screen to detect early asymptomatic changes in the mucosa. There are few advantages are given below:[13]

  1. Body fluids such as saliva nd urine (non-invasive) can be used to diagnose cancer through biomarkers.
  2. At a lesser time, a large number of samples can be automated assay using many markers
  3. Markers will provide qualitative and quantitative results with measurable values
  4. Marker assays are less expensive compared to other investigation procedures such as radiography, computed tomography scan, and endoscopic procedure
  5. Biomarkers' results are precise, reproducible, and reliable.


The exploration and utilization of biomarkers are the boons in the field of health science. It not only helps in the early identification of cancer but also indicates the prognostic values and survival rate of patients. These markers are the guidelines for the pathologists and surgeons to make a cancer grading as well as plan the treatment.[14] Several biomarkers have emerged in the field of oral cancer that is of considerable interest in terms of diagnosis, early detection, and prognosis.[15]


  Classification Top


The classification of biomarkers according to Spieght and Morgan [Figure 1] and Schliephake [Figure 2] mentioned below.
Figure 1: Classification of biomarkers according to Spieght and Morgan

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Figure 2: Classification of biomarkers according to Schliephake

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According to Spieght and Morgan (1993)[16]

  1. Proliferative markers: PCNA, Ki67, BrU, histones, and AgNORs
  2. Genetic markers: Ploidy
  3. Oncogene: C-myc
  4. Tumor suppressor markers: P53 mutations
  5. Cytokines
  6. Blood group antigens
  7. Integrins ECM ligands.


According to Schliephake H[16],[17]

Tumor growth markers

  1. Epithelial growth
  2. Cyclin
  3. Nuclear cell proliferation antigens
  4. AgNORs (Agryophilic nucleolar organizer region)
  5. Skp2 (S-phase kinase-interacting protein 2)
  6. HSP 27 and 70 (Heat shock protein)
  7. Telomerase.


Markers of tumor suppression and antitumor response

  1. Retinoblastoma protein
  2. Cyclin-dependent kinase inhibitors
  3. p53
  4. bax
  5. Fas/FasL.


Angiogenesis markers

  1. Vascular endothelial growth factor/receptor
  2. Platelet-derived endothelial cell growth factor
  3. Fibroblast growth factor.


Markers of tumor invasion and metastatic potential

  1. matrix metalloproteases
  2. Cathepsins
  3. Cadherins and catenins
  4. Desmoplakin.


Cell surface markers

  1. Carbohydrates
  2. Histocompatibility antigen
  3. CD57 antigen.


Intracellular markers

  1. Cytokeratins.


Markers of anomalous keratinization

  1. Filagrins
  2. Invoulcrin
  3. Desmosomal proteins
  4. Intercellular substances antigen
  5. Nuclear analysis.


Arachidonic acid products

  1. Prostaglandin E2
  2. Hydroxyeicosatetraenoic acid
  3. Leukotriene B4.


Enzymes

  1. Glutathione S-transferase.


Based on site[18]

Epithelial marker

  • Cytokeratins
  • Desmoplakin
  • Epithelial membrane antigen
  • Oncofetal antigens
  • Alpha-fetoprotein (AFP)
  • Carcinoembryonic antigen (CEA).


Mesenchymal marker

  1. Muscle antigen:


    • Desmin
    • Actin
    • Myoglobin
    • Myosin.


  2. Neural antigen


    • S 100
    • Neuron-specific enolase (NSE)
    • Glial fibrillary acidic protein
    • Synaptophysin
    • Nerve growth factor receptor.


  3. Vascular antigen


    • CD 34
    • CD 31.


Other biomarkers

Prognostic markers

  1. Cell adhesion molecule


    • Cadherins
    • Integrins
    • Selectins.


  2. Proliferation marker


    • PCNA
    • P53 and Ki67
    • AgNORs.


Biochemical marker

  1. Enzyme and isoenzyme:


    • Prostatic acid phosphatase
    • Prostate-specific antigen
    • Placental alkaline phosphatase
    • Lysozyme.


  2. Protein:


    • Ferritin
    • Glycoprotein
    • Beta protein
    • Immuno globulins.


  3. Hormone receptors:


    • Estrogen receptor
    • Progesterone receptor.


Epithelial marker

Biomarkers of oral cancer are location specific and are represented in [Figure 3] (i.e., few can be traced in epithelial cells and others in mesenchymal cell part of a typical cell).
Figure 3: Location-specific biomarkers for oral cancer

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Cytokeratins

Cytokeratins are the water-insoluble intermediate filament proteins that are present in the cytoplasm of epithelial cells or hair.[19] Oral epithelium cytokeratins are either acidic or basic which are in the family of 20 numbers.[20] The cytokeratins have a molecular weight of 40−68 kDa and an isoelectric pH of 5−8.

Based on their isoelectric point, the cytokeratins are divided into two types:[21]

  • Type I: The acidic group includes keratins from CK10 to CK19 and their molecular weight in the range of 40 − 56.5 kD
  • Type II: The basic group contains keratins from CK1 to CK8 and their molecular weight is in the range of 52 − 67 kD.


Cytokeratin expression in healthy oral mucosa

Keratins are usually found in two types: Type I (920) and Type II (18), both of which are encoded by their genes.[22] The basal cells of the keratinized oral mucosa express K5 and K14, while K19 is usually found in nonkeratinized areas.[23] Suprabasal cells in nonkeratinizing areas, such as lining mucosa, express K4 and K13. K1 and K10 are predominant in keratinizing areas, such as the masticatory mucosa. K6 and K16 are found in the highly proliferative epithelium. The simple epithelial keratins like K8 and K18 are normally found in individual cells, such as glandular tissue, rather than in the stratified squamous epithelium (e.g., salivary glands).[20]

Cytokeratin expression in pathology

Low-molecular weight keratins are observed in simpler, non-stratified epithelia and tumors derived therefrom (i.e., breast carcinomas or gastrointestinal carcinomas derived from cuboid or simple columnar epithelia). The higher molecular weight keratins are observed in more ortho-keratinized stratified squamous cells and their corresponding tumors (i.e., squamous cell carcinomas).[20],[21] Hence, pathologists will use the pan-cytokeratin which is different from cytokeratin and more sensitive to it.

Desmoplakins

Desmoplakins are the proteins that are present in the desmosomes of epithelial attachments and consist of 2871 amino acid proteins. This protein is expressed by a DSP gene.[24] Desmoplakin can be expressed by epithelial cells, meningeal cells, myocardial cells, and the mesothelium. Desmoplakins exist in two isoforms, i.e., DP2 (molecular weight 260 kDa) and DP1 (molecular weight 332 kDa).

Desmoplakins can also be identified only in the glandular component of synovial sarcomas but not in other mesenchymal sarcomas.[25],[26] Mutations in the gene that codes for these proteins lead to several cardiomyopathies and keratoderma as well as to autoimmune diseases like paraneoplastic pemphigus. The expression of desmoplakin is lesser in oropharyngeal cancer and breast cancer.[26]

Alpha-fetoprotein

Human AFP is a fetal glycoprotein associated with tumors that play a role in oncogenic growth. AFP is also called alpha-1fetoprotein or alpha-fetoglobulin. It is encoded by an AFP gene. It is produced in the fetal liver and yolk sac during the intrauterine life of the embryo. It consists of a glycoprotein with 591 amino acids and a molecular weight of 69 kDa.[27] During pregnancy, AFP levels can be used as tool biomarkers to identify a variety of diseases such as congenital malformations/sarcomas/carcinomas in the embryo and fetal stage.[28] This biomarker is determined in the serum, blood, amniotic fluid, and urine.

Abnormal AFP values indicate neural tube defects/brain/spinal cord malformations and gastrointestinal malignancies. Primary hepatocellular carcinoma, hepatoblastoma, nonseminomatous testicular germ cell tumors, embryonic carcinoma, teratomas, chorionic carcinoma, and yolk sac carcinoma are all diagnosed using serum AFP levels. The AFP tumor marker helps to distinguish benign and malignant tumors of the liver, i.e., AFP is elevated in malignant liver tumor-like hepatocellular carcinomas.

Carcinoembryonic antigen

CEA is a glycosylated protein with a molecular weight of 180 kDa that is produced in gastrointestinal tissue during fetal development and terminates before birth.[29] The normal level of CEA in human blood is 2 − 4 ng/ml. The CEA is encoded by the gene called the CEA-related cell adhesion gene. The CEA levels are high in colorectal, stomach, pancreatic, nonsmall cell lung, and breast cancers as well as in some nonneoplastic diseases such as ulcerative colitis, pancreatitis, cirrhosis, COPD, Crohn's disease, and in smokers.[30],[31] The CEA level is primarily used to detect relapses after surgical resection by using biological fluids.[32] The CEA blood test is not an effective marker for diagnosing early cancer detection tests as well as a cancer screening test.

Mesenchymal markers

Desmin

Desmin is an intermediate filament protein that is encoded by the DES gene. It is a 53.5 kDa that consists of 470 amino acids.[31] Desmin is mainly used as a diagnostic marker in few cases such as rhabdomyosarcoma, leiomyosarcoma, and other spindle cell lesions such as fibromatosis, malignant fibrous histiocytoma, and breast myofibroblastoma. Desmin positivity can also occur in malignant peripheral nerve sheath tumors, epithelial sarcoma, liposarcoma, and angiomatoid fibrous histiocytoma.[20]

Vimentin

Vimentin is an intermediate filament structural protein that is encoded by the VIM gene. This protein is expressed by mesenchymal cells of humans. Vimentin markers are strongly expressed in malignant lesions such as colon cancer, gastrointestinal cancer, and breast cancers.[33]

Actin

Actins are a contractile multifunctional protein family with a molecular weight of about 42 kD. Actin has two types of filaments in cells, namely G-actin (globular) and F-actin (filamentous). It is also classified based on electrophoretic mobility into alpha, beta, and gamma subtypes.[34] This protein is found in the heart, skeletal, and smooth muscle cells of mammals. It also recognizes pericytes, myoepithelial cells, and myofibroblasts. This can be used to identify the myofibroblastic cells by immunostaining in granulation tissue, scar tissue, nodular fasciitis, and fibromatosis. It is positive for rhabdomyosarcoma and considered a diagnostic marker but negative for other round cell sarcomas such as neuroblastoma and Ewing's sarcoma.[35]

Myoglobin

Myoglobin is the iron and oxygen-binding protein and occurs in the skeletal and heart muscles of humans. It is encoded by the MB gene. It has a molecular weight of 17,800 Daltons. It serves as a diagnostic marker for rhabdomyosarcomas and acute myocardial infarction.[17]

Neural antigen

S100 protein

S100 is a low-molecular weight acidic protein encoded by S100 gene. Its function is unknown, but its relationship with calcium and potassium has led to the hypothesis that it plays a role in the regulation of ions in the brain.[36] It is present in glia, Schwann cells, melanocytes, Langerhans cells of the epidermis, histiocytes, chondrocytes, lipocytes, skeletal and cardiac muscle cells, macrophages, myoepithelial cells, and some epithelial cells of the breast, salivary, and sweat gland. It is used in diagnosing soft tissue lesions such as benign nerve sheath tumors (neurilemmoma and neurofibroma) and melanoma as well as autoimmune diseases such as psoriasis. It helps to separate malignant tumors of the peripheral nerve sheath from other similar sarcomas (e.g., clear cell sarcoma and fibrosarcoma).[37]

Neuron-specific enolase

NSE belongs to the enolase family of dimeric isoenzymes which is encoded by the ENO2 gene. It consists of three types of subunits of the enolase enzyme: alpha, beta, and gamma. It occurs mainly in neurons and neuroendocrine cells. NSE has been demonstrated in patients with neuroblastoma, small cell lung cancer, Wilms tumor, melanoma, and cancer of the thyroid, kidney, testicle, and pancreas.[38]

Synaptophysin

It is a membrane protein that is encoded by the SYP gene and found in the presynaptic vesicles of nerve cells. It can be identified within the nerve cells of the peripheral, central nervous system, and neuroendocrine cells. It is used to identify tumors originating from nerves (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) and small cell carcinoma.[38]

Vascular antigen

CD 34 and CD 31

Angiogenesis is a critical process in the development of malignant growth and is induced by a complex set of proteins that involve growth factors and extracellular enzymes. Higher CD34 and CD31 were observed during tumor angiogenesis.[39] Understanding of the angiogenic process in malignant tumors strongly depends on finding the CD34 and CD31 marker in the blood vessel endothelium. The immune-histochemical expression of the angiogenic marker CD34/CD31 can be of immense importance as a prognostic factor in the routine diagnosis of OSCC. These markers are considered prognostic biomarkers (CD31 and CD34), with the behavior and prognosis of oral squamous cell carcinomas being recommended.[40],[41]

Oral biomarkers

Major classes of biomarkers of oral cancer are represented in [Figure 4].
Figure 4: Major classes of biomarkers of oral cancer

Click here to view


Proliferation marker

AgNOR

NORs are found on the short arms of acrocentric chromosomes 13, 14, 15, 21, and 22.[42] The silver nitrate stain can be used to identify NORs and the resulting structures are called AgNORs. These argyrophilic associated proteins can be identified using a simple silver staining technique. After silver staining, they appear as black spots in nucleolar and extranucleolar regions. Twenty black AgNOR dots can be seen in a normal cell (2 per chromosome arm, i.e., 2 × 10 = 20), but only one or two dots are tightly packed.

In the dysplastic cells and malignant cells, the number of AgNOR points (AgNOR count) also increases as the number of DNA increases.[20] The AgNOR values are proportional to the rate of the cell cycle. Due to this reason, cell proliferation is considered a prognostic value since the high proliferative activity is associated with a poor prognosis.[43]

P53 mutation

p53 (the product of the human TP53 and mouse TRP53 genes) is best known and most extensively studied as a central signaling node that converts various upstream stress signals into downstream responses, including cell cycle arrest, senescence, DNA repair, and apoptosis.[38] In recent years, the role of p53 in regulating cell differentiation, self-renewal, and plasticity has attracted the interest of many scientists, especially cancer researchers. P53 mutation is almost always associated with poorly differentiated carcinomas. P53 mutations are found in the most common of all malignant lesions in breast cancer as well as in squamous cell carcinoma.[44]

Implications of tumor markers in clinical practice

Routine histopathological HE staining is the primary diagnostic investigative procedure, but tumor markers are the adjunct diagnostic tool to confirm cancer and aid in the classification of malignant tumors based on their origin.[45] These markers will guide us in the early detection and screening of cancer, the extent of the lesion, the grading of the lesion, the extent of disease progression, diagnostic confirmation, the prognostic values of the lesion, postoperative surveillance therapy, and prediction and monitoring response to systemic therapy.[46],[47] Therefore, it is considered to be a primary application in diagnostic tools in the laboratory as well as in clinical medicine.[48]

The ideal properties of tumor markers are highly specific and sensitive to the specific tumor, easy to use, less cost-effective, good half-life, and obtain the prognostic values of the lesion.[49] New cellular and molecular examination techniques show promise in identifying potentially malignant lesions, but more perspective, in-depth research is needed to determine their practical utility.[50],[51],[52]


  Conclusion Top


Tumor markers are chemical substance released by the cancer cells which helps to differentiate the benign and malignant lesions and also differentiate the grades of malignancy. The production of tumor markers, such as type and amount of tumor markers, depends on the growth rate and type of tissue involved. Tumor markers not only identify the type of malignancy but also guide the line of treatment, recurrence, and prognosis of cancer. There are many tumor markers are available in the literature, but only a few markers are specific for prognosis factors. Therefore, we need to explore and identify the new specific markers to categorize the prognostic value of the oral premalignant and malignant lesions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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