Clinica Chimica Acta 445 (2015) 7–11
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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Cervical cancer: Biomarkers for diagnosis and treatment Subramanyam Dasari a, Rajendra Wudayagiri b, Lokanatha Valluru a,⁎ a b
Department of Biotechnology, Dravidian University, Kuppam, 517426 AP, India Department of Zoology, Sri Venkateswara University, Tirupati, 517502 AP, India
a r t i c l e
i n f o
Article history: Received 12 December 2014 Received in revised form 2 March 2015 Accepted 5 March 2015 Available online 12 March 2015 Keywords: Cervical cancer Biomarkers Diagnosis Prognosis Cancer antigen Magnetic resonance imaging
a b s t r a c t Cervical cancer is a major gynecological cancer which involves uncontrolled cell division and tissue invasiveness of the female uterine cervix. With the availability of new technologies researchers have increased their efforts to develop novel biomarkers for early diagnosis, and evaluation and monitoring of therapeutic treatments. This approach will help in the development of early diagnosis and in increasing treatment efficacy with decreased recurrence. The present review explains the currently available biomarkers for cervical cancer diagnosis and prognosis. Apart from the currently available biomarkers the review also explains strategies for the development of biomarkers based on cellular and molecular approaches such as DNA, protein and other metabolic markers with suitable clinical examples. The investigations of specific proteins, enzymes and metabolites will establish more useful biomarkers for accurate detection and management of gynecological cancers especially cervical cancer. © 2015 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . The importance of biomarkers in cervical cancer . . . . . Biomarkers . . . . . . . . . . . . . . . . . . . . . . Cervical cancer biomarkers based on biomolecules . . . . 4.1. Molecular biomarkers . . . . . . . . . . . . . . 4.1.1. HPV-DNA . . . . . . . . . . . . . . . 4.2. Protein based biomarkers . . . . . . . . . . . . 4.2.1. Squamous cell carcinoma antigen (SCC-Ag) 4.2.2. Serum fragments of cytokeratin (CYFRA) . 4.2.3. Carcinoma embryonic antigen (CEA) . . . 4.2.4. Soluble CD44 (sCD44) . . . . . . . . . . 4.3. Other protein markers . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . Authors' contributions . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Cancer is characterized by abnormal, uncontrolled cell proliferation due to genetic and epigenetic changes that regulate cell growth, differentiation and cell death. Cancer of the uterine cervix is the major cause
⁎ Corresponding author. Tel.: +91 9652840923; fax: +91 08570278230. E-mail address: [email protected] (L. Valluru).
http://dx.doi.org/10.1016/j.cca.2015.03.005 0009-8981/© 2015 Elsevier B.V. All rights reserved.
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of death from gynecological cancers in developing countries like India. Cervical cancers (80–90%) are caused by infection with high risk human papilloma virus (HR-HPV). They are mainly involved in the integration of viral DNA into the chromosomal DNA activating the proto-oncogenes to oncogenes, or in deactivation of tumor suppressor genes; this enhances the rate of cell proliferation, leasing to cervical intraepithelial neoplasia (CIN) [1]. The disparities in the evolution of diseases with similar clinical and pathological characteristics are probably related to macromolecular variations which have become the main
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feature in clinical diagnosis. The development of biomarkers by genomic and proteomic means holds the promise of individualized medicine, bringing a new dimension to disease analysis, classification and therapeutics [2]. The most common cancers among females are cancers of the breast, cervix, ovary, esophagus and mouth. Of these, cervical cancer is the second most common cancer among women worldwide, after breast cancer between 15 and 44 years of age [3]. The World Health Organization (WHO) reported that, cervical cancer comprises 12% of all cancers globally and it is the most common gynecological malignancy in the world [4]. The burden of cervical cancer in India is enormous, accounting for about 20% of all cancer-related deaths in women and it is the main cause of death in middle aged Indian women. It is estimated that there will be 16 million new cases by the year of 2020 [5].
2. The importance of biomarkers in cervical cancer For many decades, the microscopic observation of biopsied samples has been the mainstay of screening/diagnostic processes, even though this technique suffers from intra-observational subjectivity. Therefore, despite numerous technical innovations that have been developed to detect cancer in their earliest stages of formation, unfortunately the detection of many cancers at the microscopic level is often too late for successful intervention [6]. Unlike many genitourinary infections, cervical cancer is not usually associated with immediate symptoms such as itching, burning or vaginal discharge [7]. The initial changes that may occur in some cervical cells are not cancerous. However, these precancerous cells form dysplasia or squamous intraepithelial lesions (SIL) within the epithelial or outer layer of cells. Fig. 1 shows that the majority of all mild dysplasias regress spontaneously within less than a year. A proportion of the high-risk HPV infections will however become persistent and, if left untreated, proceed to high-grade lesions and invasive cervical cancer. A number of signs and symptoms of cervical cancer are associated mainly with the later stages of the infection (CIN 1, 2 and 3). Cervical cancer seems to be the most appropriate disease for the application of screening principles. The long transit time from early cervical atypia to invasive cancer provides an opportunity to identify pre-cancerous at a stage where safe and affordable treatment is available. In summary, the diagnosis and prognosis of asymptomatic, invasive disease is very poor but treatment of pre-invasive lesions is highly effective [8]. It is well established that no single screening method exists that is highly sensitive, highly specific, affordable and practical [9]. Historically, some screening tools (Pap smears and colonoscopy) have successfully reduced mortality through detection at early stages. Despite these successes, the field of detection has been plagued by problems of over diagnosis, inadequate specificity of individual markers (Cancer antigen-125, Carcino embryonic antigen), low compliance (colonoscopy) and a lack of analytical tools for discovering new detection methods. Hence there is an obvious interest in identifying markers that could complement standard cyto/histopathologic evaluation to determine the presence of cancer cells in tissues [10].
3. Biomarkers According to the US National Institute of Health's (NIH) working group and the biomarkers consortium, “a biomarker is a characteristic that can objectively be measured as an indicator of normal pathogenic processes or a pharmacological response to a therapeutic intervention” [12]. The primary goal of biomarker development is not only focused on upgraded therapeutics but also focused on improved methods to determine an individual's risk assessment in cancer development, and to detect cancers at early stages, when they can be more effectively treated [11]. Biomarkers are generally found in the blood or tissues or other body fluids providing a sign of normal or abnormal processes or conditions. A biomarker may be measured by genetics, proteomics, cellular or molecular substances found in higher than normal amounts in the body fluids (blood, urine) of cancer patients [13]. An ideal biomarker test would have 100% sensitivity and specificity but none of the currently available biomarkers achieve this [14]. The clinical significance of tumor markers has been demonstrated in several studies which are listed in Table 1 (from the guidelines of the National Academy of Clinical Biochemistry (NACB)). 4. Cervical cancer biomarkers based on biomolecules 4.1. Molecular biomarkers The major pathological event involved in cervical carcinogenesis is the integration of HR-HPV viral DNA into the host chromosomal DNA which initiates the formation of pre-neoplastic cells by the emergence of cell clones with deregulated expression of viral oncogenes in basal and parabasal cell layers finally leading to invasive carcinoma of the cervix. Hence, DNA based assays can be designed and applied to demonstrate the presence of the DNA responsible for cervical cancer [15]. HPV DNA is the only molecular marker developed for the diagnosis of cervical cancer. Molecular abnormalities such as chromosomal anomalies, DNA mutations, cell cycle check points, expression of oncogenes and tumor suppressor genes, apoptotic markers, epigenetic regulation (hypermethylation) have to be evaluated as markers based on their clinical utility [16]. 4.1.1. HPV-DNA Cervical cancer is a rare complication of a common cervical infection with a HR-HPV type. Persistent HR-HPV infection is necessary for the development, maintenance and progression of CIN 3 [17]. The detection of HPV DNA test alone is employed as a primary screening method to exhibit it as more sensitive than cytology among abundant clinical studies. Since HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, women with concurrent negative test results (Pap and HPV test) can be reassured that they have no risk of unidentified CIN 2, CIN 3 or cervical cancer [18,19]. Widschwendter et al. (2003) suggest that the serum HPV DNA might be a useful additional marker for early detection of recurrence in cervical cancer [20]. Recently, Campitelli et al. (2012) reported that mutation in HPV (insertion) constitutes a highly specific molecular marker of circulating DNA (ctDNA) in HPV-associated cervical cancer patients. Using this approach, ctDNA was detected in most of cervical cancer patients over stage I and the ctDNA concentration was found to reveal the tumor burden [21].
Fig. 1. From HPV infection to cancer: developmental stages of cervical cancer, in which the mild dysplasia regresses spontaneously within less than a year. A proportion of the high-risk HPV infections will however become persistent and may, left untreated, proceed to high-grade lesions and invasive cervical cancer.
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Table 1 Recently available and potentially useful serum markers for cervical cancer. Cancer marker
Proposed use
LOE
References
SSC-Ag
Identification of high risk groups with lymph node metastases in squamous cell cervical Pre-treatment prediction of prognosis in squamous cell cervical cancer Prediction of response to treatment in squamous cell cervical cancer Pre-treatment prediction of prognosis, in particular in cervical adenocarcinoma Preoperative prediction of the presence of lymph node metastases, in particular in cervical adenocarcinoma Monitoring disease, in particular in cervical adenocarcinoma Pre-treatment prediction of prognosis Preoperative prediction of the presence of lymph node metastases, in particular in cervical adenocarcinoma Pre-treatment prediction of clinical response to neoadjuvant chemotherapy Pre-treatment prediction of prognosis Monitoring disease after primary treatment
III–IV III–IV III–IV III–IV III–IV III–IV III–IV III–IV IV III–IV III–IV
[26] [29] [29] [26] [26] [37] [26] [26] [37] [26] [17]
CA-125 CEA
Cytokeratins (TPA, TPS, Cyfra21-1)
Note: extracted from NACB: Practice guidelines and recommendations for use of tumor markers in the clinic. LOE: level of evidence.
4.2. Protein based biomarkers Protein based biomarkers are important in the fast growing area of the application of proteomic techniques to diagnostic and prognostic medicine. Protein biomarkers could facilitate the early detection of the on-set of disease at a curable stage, and help to distinguish subgroups of patients who respond well to certain types of treatments from those who do not respond to the treatment [22]. The only FDAapproved biomarkers currently available for clinical use are protein based biomarkers with effective diagnostic and prognostic importance.
4.2.1. Squamous cell carcinoma antigen (SCC-Ag) The squamous cell carcinoma antigen (SCC-Ag) was first described by Kato and Tarigoe (1997) [23] in a neutral and acidic sub-fractions of tumor antigen 4 (TA-4). Squamous cell cervical carcinomas constitute 85–90% of all cervical carcinomas [24]. Elevated serum SCC levels have been detected in 28–88% of cervical squamous cell carcinomas [25]. During the early treatment of cervical cancer, the levels of SCC have been shown to be related to the stage of the disease, size of the tumor and depth of the stromal invasion [26]. Earlier studies have shown that elevated levels of SCC have predictive value for prognosis [27] and they indicated that this SCC-Ag may also be used to show the response of therapy [28] and also used in the follow-up examination of cervical cancer patients. Increased serum SCC was shown to precede the clinical detection of recurrence of the disease [29].
4.2.2. Serum fragments of cytokeratin (CYFRA) Cytokeratins are the major constituents of the cytoskeleton in epithelial cells and belongs to the group of intermediate filament proteins. CYFRA is a measure of serum concentrations of fragments of cytokeratin 19, an acidic subunit of cytokeratin that is expressed in normal epithelium and in carcinomas of the uterine cervix. Pujol et al. (1993) [30] reported that cytokeratin fragment proteins acts as a tumor marker for lung cancer, and Bonfrer et al. (1994) [31] used this as a prognostic indicator in cervical cancers. Elevated levels of cytokeratin fragments have been detected in 42–52% of patients with squamous cell carcinoma of the uterine cervix [32]. As with SCC, the levels of cytokeratin fragments can also be used to evaluate the disease stage, size of the tumor, depth of the stromal invasion, the lymph–vascular space involvement and lymph node metastasis in cervical cancer [33]. However, Gaarenstroom et al. (2000) reported that raised cytokeratin fragments levels were not demonstrated to be of predictive value for prognosis [27]. Tissue polypeptide antigen (TPA) and tissue polypeptide specific antigen (TPS) are the type of cytokeratins used for the prediction of prognosis during treatment and also used in monitoring the disease after primary treatment, but it requires further evaluation [27].
4.2.3. Carcinoma embryonic antigen (CEA) Carcinoma embryonic antigen (CEA) is a glycoprotein and was first defined by Gold and Freedman [34]. CEA has been extensively studied in relation to its potential role as a marker for early cancer and as a prognostic indicator. Interestingly it was first used as marker for colon cancer and subsequent studies indicated that elevated levels of CEA occur in many other cancers [35]. Lo Gerfo et al. (1971) first reported elevated levels of serum CEA in patients with gynecological malignancies [36]. Estimation of CEA levels cannot be a screening procedure, because it was also reported that the levels of CEA were elevated in noncancerous conditions. The most significant application of CEA to gynecological cancer would be in the management of patients with ovarian/ cervical cancer. Di Saia et al. (1977) reported that there was a progressive increase in the percentage of CEA values in advanced stages from stage I to stage II (26%–88%) in patients with invasive squamous cell carcinoma of the cervix, indicating the prognostic value of the CEA marker in cervical cancer [37]. Borras et al. (1995) also reported that the levels of CEA act as a prognostic indicator in adenocarcinoma of cervical cancer to plan disease management [38]. Another novel marker (target for new drug development) is immunosuppressive acidic protein (IAP), which is raised in 43–51% of cervical carcinomas [39]. Battaglia et al. (1994) also found elevated levels of serum IAP in 53% of squamous cell carcinoma cases and in 40% of adenocarcinoma pre-treatment cases. The levels of IAP were associated with disease stage and lymph node metastasis, hence it may also have a use in prediction, prognosis and evaluation of treatment efficacy [39]. Cyclooxygenase [COX]-2, is a key enzyme involved in the conversion of arachidonic acid to prostaglandins and in modulation of several cellular processes in cell cycle regulation, apoptosis, extracellular matrix deposition and angiogenesis [40]. Over expression of COX-2 has been considered an indicator of metastatic invasiveness in different malignancies including cervical carcinoma [41]. However, COX-2 is a strong predictor of poor response to radiotherapy or chemoradiation, irrespective of the histologic type [40,42].
4.2.4. Soluble CD44 (sCD44) CD44 is one of the integral membrane proteins that have been implicated in tumorigenesis. They act as both cell adhesion molecules and as a lymphocyte homing mechanism (both cell–cell and cell–matrix), as well as being involved with tumor growth, spread and invasion [43]. The standard CD44 protein, as well as the variant proteins, CD44v1-9, can be found in both tissue and serum of cervical cancer patients since they are shed from the cellular surface [44]. A significant increase in the levels of CD44 was observed in sixty-one cases of cervical intraepithelial neoplasia (CIN), and microinvasive carcinoma (MIC), and it was also observed that the sCD44 staining showed a progressive decrease as the lesions increased from CIN 1 to CIN 3 and then to MIC [45]. Recently, Subramanyam et al. (2014) reported that the soluble
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CD44 protein marker could be used to distinguish premalignant cancer cases from malignant carcinoma cases in cervical cancer [46]. 4.3. Other protein markers Another family of proteins with potential usefulness as molecular markers or prognostic indicators is the family of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). MMPs belong to the family of endogenous proteases that degrade the extracellular matrix (including collagen, elastin and gelatin) and are considered to be critical for the development and invasion of tumors. Both MMP-2 and MMP-9 are important matrix metalloproteinase known to be involved in the breakdown of the basement membrane, a pre-requisite for invasion of cancer [47]. Recently, Li et al. (2012) also confirmed that the expression of MMP-9 was an independent prognostic factor in cervical cancer patients, which might be a potential diagnostic and even therapeutic target for cervical cancer [48]. Human cartilage glycoprotein-39 was shown to be a potential biomarker for the detection and management of cervical cancer [49]. Elevated levels of serum cartilage glycoprotein-39 were found in 75% of squamous cell carcinoma patients and 78% of adenocarcinoma patients. Significantly elevated serum levels of circulating soluble Fas (sFas) were demonstrated in squamous cell carcinomas when compared to that of healthy women [50]. 5. Conclusion In light of the above appraisal, tumor markers are important tools that can aid clinicians regarding early diagnosis, prediction of therapy response and disease monitoring. Discovery and appreciation of the clinical relevance of novel biomarkers, are predicted to play a significant role in reshaping cancer research, thereby profoundly influencing the detection and treatment of many cancers including cervical cancer. Genomic and proteomic technologies are quite promising in identifying new biomarkers, which can significantly enhance the efficacy of cancer treatment management. A comprehensive understanding of each biomarker will be important to efficiently diagnose the disease and to provide direction in selecting the appropriate therapeutic alternatives. Competing interests All the authors declared that there is no competing interest for the present review. Authors' contributions The first author was involved in the acquisition of data and drafting the manuscript; the second author reviewed critically for important intellectual content and interpretation of the data. The third and corresponding author has made substantial contributions to the conception and design. References [1] Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. [2] Franco EL. Cancer causes revisited: human papillomavirus and cervical neoplasia. J Natl Cancer Inst 1995;87:779–80. [3] Brayand F, Moller B. Predicting the future burden of cancer. Nat Rev Cancer 2006;6: 63–74. [4] Senapathy JG, Umadevi P, Kannika PS. The present scenario of cervical cancer control and HPV epidemiology in India: an outline. Asian Pac J Cancer Prev 2011;12:1107–15. [5] Anant NB, Rohit M, Abdullah F, Amit V, Dwarakanath BS. Cancer biomarkers — current perspectives. Indian J Med Res 2010;132:129–49. [6] Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–18.
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Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Cervical cancer: Biomarkers for diagnosis and treatment Subramanyam Dasari a, Rajendra Wudayagiri b, Lokanatha Valluru a,⁎ a b
Department of Biotechnology, Dravidian University, Kuppam, 517426 AP, India Department of Zoology, Sri Venkateswara University, Tirupati, 517502 AP, India
a r t i c l e
i n f o
Article history: Received 12 December 2014 Received in revised form 2 March 2015 Accepted 5 March 2015 Available online 12 March 2015 Keywords: Cervical cancer Biomarkers Diagnosis Prognosis Cancer antigen Magnetic resonance imaging
a b s t r a c t Cervical cancer is a major gynecological cancer which involves uncontrolled cell division and tissue invasiveness of the female uterine cervix. With the availability of new technologies researchers have increased their efforts to develop novel biomarkers for early diagnosis, and evaluation and monitoring of therapeutic treatments. This approach will help in the development of early diagnosis and in increasing treatment efficacy with decreased recurrence. The present review explains the currently available biomarkers for cervical cancer diagnosis and prognosis. Apart from the currently available biomarkers the review also explains strategies for the development of biomarkers based on cellular and molecular approaches such as DNA, protein and other metabolic markers with suitable clinical examples. The investigations of specific proteins, enzymes and metabolites will establish more useful biomarkers for accurate detection and management of gynecological cancers especially cervical cancer. © 2015 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . The importance of biomarkers in cervical cancer . . . . . Biomarkers . . . . . . . . . . . . . . . . . . . . . . Cervical cancer biomarkers based on biomolecules . . . . 4.1. Molecular biomarkers . . . . . . . . . . . . . . 4.1.1. HPV-DNA . . . . . . . . . . . . . . . 4.2. Protein based biomarkers . . . . . . . . . . . . 4.2.1. Squamous cell carcinoma antigen (SCC-Ag) 4.2.2. Serum fragments of cytokeratin (CYFRA) . 4.2.3. Carcinoma embryonic antigen (CEA) . . . 4.2.4. Soluble CD44 (sCD44) . . . . . . . . . . 4.3. Other protein markers . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . Authors' contributions . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Cancer is characterized by abnormal, uncontrolled cell proliferation due to genetic and epigenetic changes that regulate cell growth, differentiation and cell death. Cancer of the uterine cervix is the major cause
⁎ Corresponding author. Tel.: +91 9652840923; fax: +91 08570278230. E-mail address: [email protected] (L. Valluru).
http://dx.doi.org/10.1016/j.cca.2015.03.005 0009-8981/© 2015 Elsevier B.V. All rights reserved.
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of death from gynecological cancers in developing countries like India. Cervical cancers (80–90%) are caused by infection with high risk human papilloma virus (HR-HPV). They are mainly involved in the integration of viral DNA into the chromosomal DNA activating the proto-oncogenes to oncogenes, or in deactivation of tumor suppressor genes; this enhances the rate of cell proliferation, leasing to cervical intraepithelial neoplasia (CIN) [1]. The disparities in the evolution of diseases with similar clinical and pathological characteristics are probably related to macromolecular variations which have become the main
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feature in clinical diagnosis. The development of biomarkers by genomic and proteomic means holds the promise of individualized medicine, bringing a new dimension to disease analysis, classification and therapeutics [2]. The most common cancers among females are cancers of the breast, cervix, ovary, esophagus and mouth. Of these, cervical cancer is the second most common cancer among women worldwide, after breast cancer between 15 and 44 years of age [3]. The World Health Organization (WHO) reported that, cervical cancer comprises 12% of all cancers globally and it is the most common gynecological malignancy in the world [4]. The burden of cervical cancer in India is enormous, accounting for about 20% of all cancer-related deaths in women and it is the main cause of death in middle aged Indian women. It is estimated that there will be 16 million new cases by the year of 2020 [5].
2. The importance of biomarkers in cervical cancer For many decades, the microscopic observation of biopsied samples has been the mainstay of screening/diagnostic processes, even though this technique suffers from intra-observational subjectivity. Therefore, despite numerous technical innovations that have been developed to detect cancer in their earliest stages of formation, unfortunately the detection of many cancers at the microscopic level is often too late for successful intervention [6]. Unlike many genitourinary infections, cervical cancer is not usually associated with immediate symptoms such as itching, burning or vaginal discharge [7]. The initial changes that may occur in some cervical cells are not cancerous. However, these precancerous cells form dysplasia or squamous intraepithelial lesions (SIL) within the epithelial or outer layer of cells. Fig. 1 shows that the majority of all mild dysplasias regress spontaneously within less than a year. A proportion of the high-risk HPV infections will however become persistent and, if left untreated, proceed to high-grade lesions and invasive cervical cancer. A number of signs and symptoms of cervical cancer are associated mainly with the later stages of the infection (CIN 1, 2 and 3). Cervical cancer seems to be the most appropriate disease for the application of screening principles. The long transit time from early cervical atypia to invasive cancer provides an opportunity to identify pre-cancerous at a stage where safe and affordable treatment is available. In summary, the diagnosis and prognosis of asymptomatic, invasive disease is very poor but treatment of pre-invasive lesions is highly effective [8]. It is well established that no single screening method exists that is highly sensitive, highly specific, affordable and practical [9]. Historically, some screening tools (Pap smears and colonoscopy) have successfully reduced mortality through detection at early stages. Despite these successes, the field of detection has been plagued by problems of over diagnosis, inadequate specificity of individual markers (Cancer antigen-125, Carcino embryonic antigen), low compliance (colonoscopy) and a lack of analytical tools for discovering new detection methods. Hence there is an obvious interest in identifying markers that could complement standard cyto/histopathologic evaluation to determine the presence of cancer cells in tissues [10].
3. Biomarkers According to the US National Institute of Health's (NIH) working group and the biomarkers consortium, “a biomarker is a characteristic that can objectively be measured as an indicator of normal pathogenic processes or a pharmacological response to a therapeutic intervention” [12]. The primary goal of biomarker development is not only focused on upgraded therapeutics but also focused on improved methods to determine an individual's risk assessment in cancer development, and to detect cancers at early stages, when they can be more effectively treated [11]. Biomarkers are generally found in the blood or tissues or other body fluids providing a sign of normal or abnormal processes or conditions. A biomarker may be measured by genetics, proteomics, cellular or molecular substances found in higher than normal amounts in the body fluids (blood, urine) of cancer patients [13]. An ideal biomarker test would have 100% sensitivity and specificity but none of the currently available biomarkers achieve this [14]. The clinical significance of tumor markers has been demonstrated in several studies which are listed in Table 1 (from the guidelines of the National Academy of Clinical Biochemistry (NACB)). 4. Cervical cancer biomarkers based on biomolecules 4.1. Molecular biomarkers The major pathological event involved in cervical carcinogenesis is the integration of HR-HPV viral DNA into the host chromosomal DNA which initiates the formation of pre-neoplastic cells by the emergence of cell clones with deregulated expression of viral oncogenes in basal and parabasal cell layers finally leading to invasive carcinoma of the cervix. Hence, DNA based assays can be designed and applied to demonstrate the presence of the DNA responsible for cervical cancer [15]. HPV DNA is the only molecular marker developed for the diagnosis of cervical cancer. Molecular abnormalities such as chromosomal anomalies, DNA mutations, cell cycle check points, expression of oncogenes and tumor suppressor genes, apoptotic markers, epigenetic regulation (hypermethylation) have to be evaluated as markers based on their clinical utility [16]. 4.1.1. HPV-DNA Cervical cancer is a rare complication of a common cervical infection with a HR-HPV type. Persistent HR-HPV infection is necessary for the development, maintenance and progression of CIN 3 [17]. The detection of HPV DNA test alone is employed as a primary screening method to exhibit it as more sensitive than cytology among abundant clinical studies. Since HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, women with concurrent negative test results (Pap and HPV test) can be reassured that they have no risk of unidentified CIN 2, CIN 3 or cervical cancer [18,19]. Widschwendter et al. (2003) suggest that the serum HPV DNA might be a useful additional marker for early detection of recurrence in cervical cancer [20]. Recently, Campitelli et al. (2012) reported that mutation in HPV (insertion) constitutes a highly specific molecular marker of circulating DNA (ctDNA) in HPV-associated cervical cancer patients. Using this approach, ctDNA was detected in most of cervical cancer patients over stage I and the ctDNA concentration was found to reveal the tumor burden [21].
Fig. 1. From HPV infection to cancer: developmental stages of cervical cancer, in which the mild dysplasia regresses spontaneously within less than a year. A proportion of the high-risk HPV infections will however become persistent and may, left untreated, proceed to high-grade lesions and invasive cervical cancer.
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Table 1 Recently available and potentially useful serum markers for cervical cancer. Cancer marker
Proposed use
LOE
References
SSC-Ag
Identification of high risk groups with lymph node metastases in squamous cell cervical Pre-treatment prediction of prognosis in squamous cell cervical cancer Prediction of response to treatment in squamous cell cervical cancer Pre-treatment prediction of prognosis, in particular in cervical adenocarcinoma Preoperative prediction of the presence of lymph node metastases, in particular in cervical adenocarcinoma Monitoring disease, in particular in cervical adenocarcinoma Pre-treatment prediction of prognosis Preoperative prediction of the presence of lymph node metastases, in particular in cervical adenocarcinoma Pre-treatment prediction of clinical response to neoadjuvant chemotherapy Pre-treatment prediction of prognosis Monitoring disease after primary treatment
III–IV III–IV III–IV III–IV III–IV III–IV III–IV III–IV IV III–IV III–IV
[26] [29] [29] [26] [26] [37] [26] [26] [37] [26] [17]
CA-125 CEA
Cytokeratins (TPA, TPS, Cyfra21-1)
Note: extracted from NACB: Practice guidelines and recommendations for use of tumor markers in the clinic. LOE: level of evidence.
4.2. Protein based biomarkers Protein based biomarkers are important in the fast growing area of the application of proteomic techniques to diagnostic and prognostic medicine. Protein biomarkers could facilitate the early detection of the on-set of disease at a curable stage, and help to distinguish subgroups of patients who respond well to certain types of treatments from those who do not respond to the treatment [22]. The only FDAapproved biomarkers currently available for clinical use are protein based biomarkers with effective diagnostic and prognostic importance.
4.2.1. Squamous cell carcinoma antigen (SCC-Ag) The squamous cell carcinoma antigen (SCC-Ag) was first described by Kato and Tarigoe (1997) [23] in a neutral and acidic sub-fractions of tumor antigen 4 (TA-4). Squamous cell cervical carcinomas constitute 85–90% of all cervical carcinomas [24]. Elevated serum SCC levels have been detected in 28–88% of cervical squamous cell carcinomas [25]. During the early treatment of cervical cancer, the levels of SCC have been shown to be related to the stage of the disease, size of the tumor and depth of the stromal invasion [26]. Earlier studies have shown that elevated levels of SCC have predictive value for prognosis [27] and they indicated that this SCC-Ag may also be used to show the response of therapy [28] and also used in the follow-up examination of cervical cancer patients. Increased serum SCC was shown to precede the clinical detection of recurrence of the disease [29].
4.2.2. Serum fragments of cytokeratin (CYFRA) Cytokeratins are the major constituents of the cytoskeleton in epithelial cells and belongs to the group of intermediate filament proteins. CYFRA is a measure of serum concentrations of fragments of cytokeratin 19, an acidic subunit of cytokeratin that is expressed in normal epithelium and in carcinomas of the uterine cervix. Pujol et al. (1993) [30] reported that cytokeratin fragment proteins acts as a tumor marker for lung cancer, and Bonfrer et al. (1994) [31] used this as a prognostic indicator in cervical cancers. Elevated levels of cytokeratin fragments have been detected in 42–52% of patients with squamous cell carcinoma of the uterine cervix [32]. As with SCC, the levels of cytokeratin fragments can also be used to evaluate the disease stage, size of the tumor, depth of the stromal invasion, the lymph–vascular space involvement and lymph node metastasis in cervical cancer [33]. However, Gaarenstroom et al. (2000) reported that raised cytokeratin fragments levels were not demonstrated to be of predictive value for prognosis [27]. Tissue polypeptide antigen (TPA) and tissue polypeptide specific antigen (TPS) are the type of cytokeratins used for the prediction of prognosis during treatment and also used in monitoring the disease after primary treatment, but it requires further evaluation [27].
4.2.3. Carcinoma embryonic antigen (CEA) Carcinoma embryonic antigen (CEA) is a glycoprotein and was first defined by Gold and Freedman [34]. CEA has been extensively studied in relation to its potential role as a marker for early cancer and as a prognostic indicator. Interestingly it was first used as marker for colon cancer and subsequent studies indicated that elevated levels of CEA occur in many other cancers [35]. Lo Gerfo et al. (1971) first reported elevated levels of serum CEA in patients with gynecological malignancies [36]. Estimation of CEA levels cannot be a screening procedure, because it was also reported that the levels of CEA were elevated in noncancerous conditions. The most significant application of CEA to gynecological cancer would be in the management of patients with ovarian/ cervical cancer. Di Saia et al. (1977) reported that there was a progressive increase in the percentage of CEA values in advanced stages from stage I to stage II (26%–88%) in patients with invasive squamous cell carcinoma of the cervix, indicating the prognostic value of the CEA marker in cervical cancer [37]. Borras et al. (1995) also reported that the levels of CEA act as a prognostic indicator in adenocarcinoma of cervical cancer to plan disease management [38]. Another novel marker (target for new drug development) is immunosuppressive acidic protein (IAP), which is raised in 43–51% of cervical carcinomas [39]. Battaglia et al. (1994) also found elevated levels of serum IAP in 53% of squamous cell carcinoma cases and in 40% of adenocarcinoma pre-treatment cases. The levels of IAP were associated with disease stage and lymph node metastasis, hence it may also have a use in prediction, prognosis and evaluation of treatment efficacy [39]. Cyclooxygenase [COX]-2, is a key enzyme involved in the conversion of arachidonic acid to prostaglandins and in modulation of several cellular processes in cell cycle regulation, apoptosis, extracellular matrix deposition and angiogenesis [40]. Over expression of COX-2 has been considered an indicator of metastatic invasiveness in different malignancies including cervical carcinoma [41]. However, COX-2 is a strong predictor of poor response to radiotherapy or chemoradiation, irrespective of the histologic type [40,42].
4.2.4. Soluble CD44 (sCD44) CD44 is one of the integral membrane proteins that have been implicated in tumorigenesis. They act as both cell adhesion molecules and as a lymphocyte homing mechanism (both cell–cell and cell–matrix), as well as being involved with tumor growth, spread and invasion [43]. The standard CD44 protein, as well as the variant proteins, CD44v1-9, can be found in both tissue and serum of cervical cancer patients since they are shed from the cellular surface [44]. A significant increase in the levels of CD44 was observed in sixty-one cases of cervical intraepithelial neoplasia (CIN), and microinvasive carcinoma (MIC), and it was also observed that the sCD44 staining showed a progressive decrease as the lesions increased from CIN 1 to CIN 3 and then to MIC [45]. Recently, Subramanyam et al. (2014) reported that the soluble
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CD44 protein marker could be used to distinguish premalignant cancer cases from malignant carcinoma cases in cervical cancer [46]. 4.3. Other protein markers Another family of proteins with potential usefulness as molecular markers or prognostic indicators is the family of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). MMPs belong to the family of endogenous proteases that degrade the extracellular matrix (including collagen, elastin and gelatin) and are considered to be critical for the development and invasion of tumors. Both MMP-2 and MMP-9 are important matrix metalloproteinase known to be involved in the breakdown of the basement membrane, a pre-requisite for invasion of cancer [47]. Recently, Li et al. (2012) also confirmed that the expression of MMP-9 was an independent prognostic factor in cervical cancer patients, which might be a potential diagnostic and even therapeutic target for cervical cancer [48]. Human cartilage glycoprotein-39 was shown to be a potential biomarker for the detection and management of cervical cancer [49]. Elevated levels of serum cartilage glycoprotein-39 were found in 75% of squamous cell carcinoma patients and 78% of adenocarcinoma patients. Significantly elevated serum levels of circulating soluble Fas (sFas) were demonstrated in squamous cell carcinomas when compared to that of healthy women [50]. 5. Conclusion In light of the above appraisal, tumor markers are important tools that can aid clinicians regarding early diagnosis, prediction of therapy response and disease monitoring. Discovery and appreciation of the clinical relevance of novel biomarkers, are predicted to play a significant role in reshaping cancer research, thereby profoundly influencing the detection and treatment of many cancers including cervical cancer. Genomic and proteomic technologies are quite promising in identifying new biomarkers, which can significantly enhance the efficacy of cancer treatment management. A comprehensive understanding of each biomarker will be important to efficiently diagnose the disease and to provide direction in selecting the appropriate therapeutic alternatives. Competing interests All the authors declared that there is no competing interest for the present review. Authors' contributions The first author was involved in the acquisition of data and drafting the manuscript; the second author reviewed critically for important intellectual content and interpretation of the data. The third and corresponding author has made substantial contributions to the conception and design. References [1] Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. [2] Franco EL. Cancer causes revisited: human papillomavirus and cervical neoplasia. J Natl Cancer Inst 1995;87:779–80. [3] Brayand F, Moller B. Predicting the future burden of cancer. Nat Rev Cancer 2006;6: 63–74. [4] Senapathy JG, Umadevi P, Kannika PS. The present scenario of cervical cancer control and HPV epidemiology in India: an outline. Asian Pac J Cancer Prev 2011;12:1107–15. [5] Anant NB, Rohit M, Abdullah F, Amit V, Dwarakanath BS. Cancer biomarkers — current perspectives. Indian J Med Res 2010;132:129–49. [6] Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–18.
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