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  In this article
 »  Abstract
 » Introduction
 »  CTCS Detection M...
 » Discussion
 » Conclusion
 »  References

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  Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 2  |  Page : 232-234
 

Circulating tumor cells in oral squamous cell carcinoma: An insight


Department of Oral and Maxillofacial Pathology, The Oxford Dental College, Hospital and Research Centre, Bommanahalli, Bangalore, Karnataka, India

Date of Web Publication5-Feb-2016

Correspondence Address:
B V Prakruthi
Department of Oral and Maxillofacial Pathology, The Oxford Dental College, Hospital and Research Centre, Bommanahalli, Bangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175844

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 » Abstract 

Circulating tumor cells (CTCs) are those cells present in the blood and have antigenic and/or genetic characteristics of a specific tumor type. CTCs can be detected in the peripheral blood of cancer patients. Various techniques are available for detection of CTCs, which provide evidence for future metastasis. CTCs may provide new insight into the biology of cancer and process of metastasis in oral squamous cell carcinoma (OSCC). The detection of CTCs may represent a new diagnostic tool for predicting the occurrence of metastatic disease in OSCC and endow with the treatment strategies to efficiently treat and prevent cancer metastasis. This review gives an insight into the significance of CTCs and different techniques for detection of CTCs.


Keywords: Circulating tumor cells, metastasis, oral squamous cell carcinoma


How to cite this article:
Prakruthi B V, Babu N C. Circulating tumor cells in oral squamous cell carcinoma: An insight. Indian J Cancer 2015;52:232-4

How to cite this URL:
Prakruthi B V, Babu N C. Circulating tumor cells in oral squamous cell carcinoma: An insight. Indian J Cancer [serial online] 2015 [cited 2021 Aug 5];52:232-4. Available from: https://www.indianjcancer.com/text.asp?2015/52/2/232/175844



 » Introduction Top


Squamous cell carcinoma (SCC) is the most common malignant neoplasm of the oral cavity, accounting for more than 90% of all oral malignancies.[1] Early diagnosis is the key to success in the management of oral squamous cell carcinoma (OSCC). In spite of early detection and adjuvant treatment modalities, many patients die of cancer.[2] Metastatic disease accounts for around 90% of the mortality.[3] The metastasis occurs in different types of cancer, including squamous cell carcinoma of the head and neck (SCCHN).

The development of distant metastasis is the critical issue in the management of malignancies. The tumor cells dissociate from the primary cancer and gain access to circulation either directly through blood vessels or after transit in lymphatic channels. Later these cells get lodge as disseminated metastatic tumor cells in secondary organs such as liver, bone and lungs.[4]

This review gives an insight into the significance of circulating tumor cells (CTCs) and different techniques for detection of CTCs. Thus, further researches can be done to establish specific technique, which aids in the diagnosis, treatment and prognosis of cancer patients.


 » CTCS Detection Methods: A review of Literature Top


Studies have revealed that tumor cells can be detected in the bone marrow and in the peripheral blood of cancer patients, thus detection of disseminated tumor cells in the bone marrow and CTCs in the peripheral blood can be helpful for early diagnosis of a malignant tumor, the therapeutic outcome and prognosis of OSCC patients.[5]

Researches on CTCs evolve since 19th century. In 1869, Ashworth an Australian pathologist first reported the presence of CTCs in peripheral blood of cancer patient during autopsy procedure. In 1889, Paget described the theory of “seed and soil” based on his observation of metastatic breast cancer.[6]

In the early 1990s, molecular methods were first used to spot circulating prostate cancer and melanoma tumor cells using Reverse transcriptasepolymerase chain reaction (RT-PCR) techniques.[2]

CTCs are those cells present in the blood and have antigenic and/or genetic characteristics of a specific tumor type.[7] CTCs can be detected in the peripheral blood of cancer patients. Various techniques are available for detection of CTCs, which provide evidence for future metastasis.[8]

Studies have been carried out in patients with SCCHN and results showed that patients with no detectable CTCs/ml of blood had a significantly higher probability of disease-free survival.[9]

A study showed that detection of CTCs correlates with regional metastasis in inoperable SCCHN and follow-up will help to evaluate the prognostic significance of CTC detection.[10]

Another study was carried out in OSCC patients and the study emphasized the detection of CTCs and their effectiveness in early detection to increase the survival rate and quality-of-life for OSCC patients.[11]

The challenge of CTC detection is related to the high sensitivity and specificity. As invasion can start very early during tumor development, identification and counting of CTCs can alert the oncologist regarding tumor invasion process.[12]

Numerous methods have been developed to detect CTCs in peripheral blood of cancer patients. The initial methods for detection of CTCS have been based on histopathological techniques and were time consuming.[6] The development of newer techniques led to proper identification and quantification of CTCs.

Several markers have been used for the detection of CTCs, based on their expression on epithelial cells (epithelial-specific markers) or their specific expression on certain tissues (tissue-specific markers). As cytokeratins are intermediate filament keratins in the cytoskeleton of epithelial cells these have been commonly used.[13]

Tumor cell enrichment techniques including density gradient centrifugation, immunomagnetic or size filtration procedures are usually used to enrich tumor cells before their detection as CTCs are found at very low frequencies among the normal peripheral blood mononuclear cells.[14],[15]

A potentially more sensitive molecular approach for detection of CTCs is the reverse-transcriptase polymerase chain reaction (RT-PCR)[16] It has been proven to be highly specific method for detection of CTCs.[17]

Adna test cancer select/detection is another method, which works by using proprietary mixture of immunomagnetic beads coated with one of three antibodies to the epithelial surface antigen.[2]

Membrane micro filter assay is relatively, simple, efficient and inexpensive technique for CTC detection. Polycarbonate filters are used to separate CTCs from circulating leukocytes and platelets, which helps pathologists for microscopic identification.[12]

Microfluidic CTC chip most recently deliberated to improve CTC capture efficiency. It consists of the array of micro posts coated with anti-epithelial cell adhesion molecule antibodies. A laminar flow system passes whole blood from the patient through the coated posts. Then, captured CTCs are visualized through fluorescence microscopy.[18]

Epithelial immunospot (EPISPOT) assay detects CTCs by their secreted proteins after a 48-h cell culture and CD45 is employed to negatively select leukocytes. However, disadvantage of this method is dead CTCs that do not produce or secrete epithelial associated proteins are not identified.[19],[20]

There is no standardized method for CTC detection and no studies are done on comparison of different techniques to achieve definite technique with good sensitivity and specificity.

The present gold standard method is the CellSearch system. It is currently the only Food and Drug Administrated (FDA)-approved device for CTC detection.[18],[21] This technology combines the positive selection of cells with epithelial markers and negative selection of leukocytes. This standardized method has been associated with high intraobserver, interobserver and inter-instrument accordance.[3]


 » Discussion Top


The study of CTCs may provide new insight into the biology of cancer and process of metastasis in OSCC. CTCs may act as a reservoir for metachronous metastasis in various neoplasms and seem to be able to re-seed into the initial tumor tissues. Thus, it only contributes to distant but also to locoregional recurrence.[10]

Various methods are available for CTCs detection such as epithelial markers, immunocytochemistry, CellSearch system, RT-PCR, CTC chip, microfluidic platform, EPISPOT assay etc., The present gold standard is CellSearch system, which is FDA approved and RT-PCR.

The process of metastasis occurs by initial detachment of tumor cells from the primary tumor and then extravasates a new organ either through blood or lymphatics circulation. It has been reported by experimental studies that tumors shed a number of cells into circulation, but only a very minute amount of them, ~0.01%, can survive.

It is uncertain at which steps in the process cells are lost, but it has generally been thought that most cancer cells are rapidly destroyed in the circulation, either by the immune system or hemodynamic forces. In addition, the ability of cells to extravasate into the surrounding tissue, by degrading basement membrane and extracellular matrix, has been considered another major rate-limiting step in metastasis.[4]

From model systems, it has been estimated that around 1 × 106 tumor cells/g of tumor tissue can be introduced daily into the bloodstream. Epithelial cancer cells have very low survival rates in circulation. The fate of CTC includes a rapid phase of intravascular cancer cell disappearance, which is completed in less than 5 min and accounts for 85% of the circulating cancer cells. This process has been related to “anoikis” (apoptosis induced by disruption of cell attachment and cell-matrix interactions). Many cancer cell types with increased metastatic potential are resistant to anoikis compared with the parental cells.[12] Finally, it has been suggested that any factor that tips the balance between proliferation and apoptosis may result in tumor progression or regression.

In addition, tumor cells lack the typical morphological signs of malignant transformation, but show obvious molecular characteristics of malignancy.[11] A study in the literature suggests that the detection of CTCs might represent a novel non-invasive diagnostic tool for predicting the occurrence of metastatic disease in OSCC.[4]

The ability to detect CTCs still remains a technical challenge. Advancements in CTC detection methods that possess the requisite sensitivity and reproducibility will revolutionize the field.


 » Conclusion Top


The knowledge of CTCs is still need to be highly developed as little is known about these cells. The detection of CTCs may represent a new diagnostic tool for predicting the occurrence of metastatic disease in OSCC and endow with the treatment strategies to efficiently treat and prevent cancer metastasis. Further scientific advances may offer new prospect with enhanced sensitive method for early diagnosis of OSCC to increase the survival rate and quality-of-life for OSCC patients.

 
 » References Top

1.
Massano J, Regateiro FS, Januário G, Ferreira A. Oral squamous cell carcinoma: Review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:67-76.  Back to cited text no. 1
    
2.
Ross JS, Slodkowska EA. Circulating and disseminated tumor cells in the management of breast cancer. Am J Clin Pathol 2009;132:237-45.  Back to cited text no. 2
    
3.
Zhe X, Cher ML, Bonfil RD. Circulating tumor cells: Finding the needle in the haystack. Am J Cancer Res 2011;1:740-51.  Back to cited text no. 3
[PUBMED]    
4.
Balasubramanian P, Yang L, Lang JC, Jatana KR, Schuller D, Agrawal A, et al. Confocal images of circulating tumor cells obtained using a methodology and technology that removes normal cells. Mol Pharm 2009;6:1402-8.  Back to cited text no. 4
    
5.
Tanaka F, Yoneda K, Hasegawa S. Circulating tumor cells (CTCs) in lung cancer: Current status and future perspectives. Lung Cancer Targets Ther 2010;1:77-84.  Back to cited text no. 5
    
6.
Loberg RD, Fridman Y, Pienta BA, Keller ET, McCauley LK, Taichman RS, et al. Detection and isolation of circulating tumor cells in urologic cancers: A review. Neoplasia 2004;6:302-9.  Back to cited text no. 6
    
7.
Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007;25:5287-312.  Back to cited text no. 7
    
8.
Mavroudis D. Circulating cancer cells. Ann Oncol 2010;21 Suppl 7:vii95-100.  Back to cited text no. 8
    
9.
Jatana KR, Balasubramanian P, Lang JC, Yang L, Jatana CA, White E, et al. Significance of circulating tumor cells in patients with squamous cell carcinoma of the head and neck: Initial results. Arch Otolaryngol Head Neck Surg 2010;136:1274-9.  Back to cited text no. 9
    
10.
Hristozova T, Konschak R, Stromberger C, Fusi A, Liu Z, Weichert W, et al. The presence of circulating tumor cells (CTCs) correlates with lymph node metastasis in nonresectable squamous cell carcinoma of the head and neck region (SCCHN). Ann Oncol 2011;22:1878-85.  Back to cited text no. 10
    
11.
Mollaoglu N, Vairaktaris E, Nkenke E, Neukam FW, Ries J. Single disseminated tumor cell detection in peripheral blood sample of patients with oral squamous cell carcinoma using MAGE-A4. LabMedicine 2009;40:665-8.  Back to cited text no. 11
    
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Paterlini-Brechot P, Benali NL. Circulating tumor cells (CTC) detection: Clinical impact and future directions. Cancer Lett 2007;253:180-204.  Back to cited text no. 12
    
13.
Pantel K, Cote RJ, Fodstad O. Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 1999;91:1113-24.  Back to cited text no. 13
    
14.
Pinzani P, Salvadori B, Simi L, Bianchi S, Distante V, Cataliotti L, et al. Isolation by size of epithelial tumor cells in peripheral blood of patients with breast cancer: Correlation with real-time reverse transcriptase-polymerase chain reaction results and feasibility of molecular analysis by laser microdissection. Hum Pathol 2006;37:711-8.  Back to cited text no. 14
    
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Wong NS, Kahn HJ, Zhang L, Oldfield S, Yang LY, Marks A, et al. Prognostic significance of circulating tumour cells enumerated after filtration enrichment in early and metastatic breast cancer patients. Breast Cancer Res Treat 2006;99:63-9.  Back to cited text no. 15
    
16.
Lin H, Balic M, Zheng S, Datar R, Cote RJ. Disseminated and circulating tumor cells: Role in effective cancer management. Crit Rev Oncol Hematol 2011;77:1-11.  Back to cited text no. 16
    
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Hughes AD, King MR. Nanobiotechnology for the capture and manipulation of circulating tumor cells. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2012;4:291-309.  Back to cited text no. 17
    
18.
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 2007;450:1235-9.  Back to cited text no. 18
    
19.
Pantel K, Alix-Panabières C. The clinical significance of circulating tumor cells. Nat Clin Pract Oncol 2007;4:62-3.  Back to cited text no. 19
    
20.
Alix-Panabières C, Riethdorf S, Pantel K. Circulating tumor cells and bone marrow micrometastasis. Clin Cancer Res 2008;14:5013-21.  Back to cited text no. 20
    
21.
Hou JM, Krebs M, Ward T, Morris K, Sloane R, Blackhall F, et al. Circulating tumor cells, enumeration and beyond. Cancers 2010;2:1236-50.  Back to cited text no. 21
    



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