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Formerly with School of Dentistry, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA; currently with Department of Diagnostic Sciences, Dental Branch, University of Texas Health Science Center at Houston, 6516 M.S. Anderson Blvd., Houston, TX 77030, USA
Correspondence: * corresponding author, bolide5{at}aol.com
KEY WORDS: Breast cancer • saliva • c-erbB-2
A surge of new technological developments, coupled with the limitations of existing disease-detection methodologies, is propelling the field of medical diagnostics forward at unprecedented rates. Advancements in proteomics and nanotechnology are paving the way for diagnostic tests that will be capable of rapid multi-analyte detection in both laboratory and non-laboratory settings. Technological advancements have also benefited biomarker research to the point where saliva is now recognized as an excellent diagnostic medium that can be collected simply and non-invasively. Salivary biomarkers have been identified that may provide diagnostic information about a variety of cancers and other diseases. In particular, proof-of-principle has been demonstrated for salivary c-erbB-2, whose elevation has been shown to correlate strongly with breast malignancy in women. The purpose of this manuscript is to review the past literature and present the current research focused on the use of saliva as a diagnostic medium for the detection of malignancies that are remote from the oral cavity.
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Introduction |
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 TOP Introduction Current Research: Salivary c...SummaryReferences |
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It has been shown that screening for breast cancer can reduce breast cancer mortality (Zapka et al., 1989; Kelsey and Horn-Ross, 1993; Morrison, 1993; Kerlikowske et al., 1995; Kosary et al., 1995; Lenhard, 1996; NIH, 1997). Among women aged 50 and older, studies have demonstrated a 20–40% reduction in breast cancer mortality for women screened by mammography and clinical breast examination (Zapka et al., 1989; Kelsey and Horn-Ross, 1993; Kerlikowske et al., 1995). Among women 40–49 years of age, the mortality rate is reduced by 13–23%. Additionally, studies using mathematical modeling suggest that more frequent screening would further increase patient survival (Michaelson et al., 1999). Analysis of these data suggests a 96% survival rate if patients could receive a mammogram every 3 months (Michaelson et al., 1999). However, due to the costs associated with mammography, coupled with the invasiveness of the procedure, i.e., radiation exposure, this increase in the frequency of mammography is currently not feasible.
Despite efforts to provide accurate mammography diagnoses, screening procedures can produce a substantial percentage of false-positive and false-negative results, especially in women with dense parenchyma breast tissue (Kelsey and Horn-Ross, 1993; Kerlikowske et al., 1995). For example, the probability of having a false-negative mammography examination is 20–25% among women 40–49 years of age and 10% among women 50–69 years of age (NIH, 1997). Consequently, screening will result in several negative biopsy results, yielding a high percentage of false-positives (Kelsey and Horn-Ross, 1993; Kerlikowske et al., 1995; NIH, 1997). Conversely, screening detects a large percentage of malignant lesions and is effective in diagnosing breast cancer in women aged 50 years and older; however, there is a demonstrated lack of sensitivity in detecting cancerous lesions in younger women, yielding a significant percentage of false-negatives.
Technological advancements in mammography have yielded more reliable detection of small lesions, although interpretation remains highly subjective and can vary among radiologists by as much as 11% (Kerlikowske et al., 1995). Because the study of breast biology remains incomplete, some breast abnormalities detected by mammography may not be aggressive malignancies, but rather pre-malignant or benign lesions that will not progress to life-threatening disease. However, clinicians are cautious and tend to treat suspicious lesions as cancer, leading to some women having unnecessary treatment and undue psychological distress associated with a cancer diagnosis (Kelsey and Horn-Ross, 1993). Because of the shortcomings of current imaging techniques, researchers in the field of breast cancer continue to seek additional adjunct diagnostic procedures to further enhance cancer screening and, thereby, reduce mortality rates (Zapka et al., 1989; Kelsey and Horn-Ross, 1993; Morrison, 1993; Kerlikowske et al., 1995; Kosary et al., 1995; Lenhard, 1996; NIH, 1997).
The presence of cancer-related proteins in saliva: the oral connection
Increasing interest has developed in the use of saliva as an adjunct test medium to aid in conventional medical assessment of serious systemic diseases (Mandel, 1993; NIDCR, 1999; Tabak, 2001; Kaufman and Lamster, 2002; Lawrence, 2002; Streckfus and Bigler, 2002). Due to its simplicity in collection, saliva may be collected repeatedly with minimal discomfort to the patient, thereby rendering saliva as a very desirable diagnostic medium (Kaufman and Lamster, 2002; Lawrence, 2002; Streckfus and Bigler, 2002). More importantly, saliva contains constituents that are frequently altered in the presence of systemic diseases (Kaufman and Lamster, 2002; Lawrence, 2002; Streckfus and Bigler, 2002). Because of these significant characteristics, finding biomarkers in saliva for the detection of serious systemic illnesses, such as cancer, is on the national health care agenda (NIDCR, 1999) and is of great interest for most salivary researchers (Mandel, 1993).
There are only a few studies in the literature concerning the use of saliva for the detection of malignancies remote from the oral cavity. These reports deal primarily with the identification and quantification of cancer-related proteins, in saliva, that were previously discovered to be present in cancer tissue supernatants or elevated in the serum of diagnosed cancer patients. The importance of these studies demonstrates the feasibility of salivary cancer diagnostics and establishes the basis for continued biomarker research (Kaufman and Lamster, 2002; Lawrence, 2002; Streckfus and Bigler, 2002).
A group of these studies that serves to establish the basis for salivary cancer biomarker research methodology comes from reports of kallikrein used as a diagnostic marker (Jenzano et al., 1986a,b, 1987, 1988). These investigations report the use of saliva to detect variations in the concentrations of kallikrein, a regulatory protease, among healthy individuals and patients with malignant breast and gastro-intestinal tumors. The results of their investigation revealed higher concentrations of salivary kallikrein among patients diagnosed with malignant tumors in comparison with those individuals diagnosed with benign tumors or those from a cohort of healthy subjects, as measured by chromogenic tripeptide assay (Jenzano et al., 1986a,b, 1987, 1988).
Saliva has also been assayed for the presence of serum cancer antigens such as Cancer Antigen-125 (CA125). These investigations found that saliva contained CA125, a glycoprotein complex that is an often-used serum marker for the detection and post-operative follow-up of ovarian cancer. In comparisons of salivary CA125 concentrations among healthy women, women with benign lesions, and those with ovarian cancer, a significant elevation was found among the ovarian cancer subjects when measured by radioimmunoassay. The results also suggested that CA125, when assayed in saliva, had a better diagnostic value than when assayed in serum with the same kit (Chen et al., 1988, 1990).
In addition to Chen’s findings, a subsequent study (Cornelissen et al., 1992) reported the utility of salivary CA125 for the optimization of taxol-based chemotherapy. Using salivary CA125 as a putative marker, these investigators were able to optimize the administration of taxol (a CA125 inhibitor) chemotherapy by monitoring the patient’s circadian tumor rhythm using salivary CA125 concentrations. When the salivary CA125 concentrations were at their circadian peak value, indicating when the tumor is most active, the taxol was administered for maximum drug effectiveness. The study suggests that, by using salivary CA125 as an indicator for the timing of taxol administration, the physician can optimize the efficacy of the chemotherapeutic agent (Cornelissen et al., 1992).
Epidermal growth factor (EGF) is a regulatory growth factor protein responsible for tissue growth and repair in the oral cavity (Hirata and Orth, 1979; Thesleff et al., 1988; Navarro et al., 1997). Since EGF overexpression is thought to be implicated in tumorigenesis, it may therefore be useful as a tumor marker. Based on this thinking, an additional study (Navarro et al., 1997) demonstrated that EGF concentrations were higher in the saliva of women with primary or recurrent breast cancer in comparison with women lacking a malignancy (Navarro et al., 1997). The highest concentrations of EGF were found in the local recurrence subgroup, suggesting a potential use for this marker in the post-operative follow-up of diagnosed cancer patients (Navarro et al., 1997).
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Current Research: Salivary c-erbB-2 for the Detection of Cancer |
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TOPIntroductionCurrent Research: Salivary c...SummaryReferences |
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To summarize the materials presented in the previous sections, the authors of this manuscript have presented (1) the need for an adjunct test for cancer detection, (2) the logistical utility of a salivary test, and (3) a discussion of previous investigations establishing the feasibility of using salivary proteins for detecting malignant tumors remote from the oral cavity. Collectively, this information establishes the basis for the ensuing research, which addresses the public health issue presented in Healthy People 2010, which is to reduce overall morbidity and mortality rates for carcinoma of the breast (HHS, 2000b).
The initial pilot study: the selection of a suitable salivary biomarker
An exploratory study (Streckfus et al., 2000a) was conducted to determine if cancer-related proteins are present in saliva. To ascertain their presence, we examined a panel of cancer markers in the saliva of a cohort of healthy women, women with benign breast lesions, and women with diagnosed breast cancer. Using ELISA kits, with each kit possessing a monoclonal capture antibody, we found the presence of the following tumor markers: c-erbB-2 (Triton Co., Alameda, CA, USA), CA 15-3 (Cis Bio-International, Paris, France), cathepsin-D (Triton Co., Alameda, CA, USA), EGFR (Triton Co., Alameda, CA, USA), and pantropic p53 (Oncogene Research Products, Boston, MA, USA) in the saliva of all three groups of women. The levels of c-erbB-2 and CA 15-3 in the cancer patients evaluated were significantly higher than those in the healthy controls and the benign tumor patients. Conversely, pantropic p53 levels were higher in control subjects compared with those in women with breast cancer and those with benign tumors. Although cathepsin-D and EGFR were detected and elevated in patients with carcinoma of the breast, they did not demonstrate a clear correlation with disease status. The results of the pilot study suggest that cancer-related biomarkers are present in saliva, and are modulated in the presence of carcinoma (Streckfus et al., 2000a).
The second study: targeting salivary c-erbB-2 as a marker
We selected c-erbB-2 as the salivary biomarker of choice, because this protein has been shown to be immunohistologically present on the membrane of the ductal epithelium of salivary gland tissues (Wick et al., 1998; Nagler et al., 2002, 2003). In the event of c-erbB-2 over-expression, these receptors can be identified through immunohistological staining (Wick et al., 1998), similar to ductal carcinoma of the breast. Additionally, c-erbB-2 is found in serum (Breuer et al., 1998) and, therefore, could provide the investigators with a basis for analytical comparison. Collectively, these points aided us in the selection of c-erbB-2 as the salivary biomarker. With these facts in mind, we performed a second, larger, study (Streckfus et al., 2000b), using a c-erbB-2 ELISA kit from Oncogene Research Products (Boston, MA, USA), which replaced the Triton Co. (Alameda, CA, USA) assay, which was no longer available on the market.
Patient saliva samples were collected and assayed for differential levels of c-erbB-2 protein. In addition, to compare the relative diagnostic utility of the c-erbB-2 protein, we also measured CA 15-3 (Cis Bio-International, Paris, France). The CA 15-3 measurements served as a ‘gold standard’ against which to compare the c-erbB-2 protein’s diagnostic effectiveness.
Again, we found the c-erbB-2 and CA 15-3 proteins in the saliva and serum of all three groups of women. The salivary and serological levels of c-erbB-2 among the cancer patients were significantly higher (p < 0.001) than the salivary and serum levels of healthy controls and benign tumor patients. Additionally, the c-erbB-2 protein was found to be equal to or to surpass the ability of CA 15-3 to detect cancer patients. The results of the study suggest that the c-erbB-2 protein may have potential diagnostic utility.
To summarize these findings: Women with malignant breast lesions were found to have significantly higher salivary c-erbB-2 levels than healthy women and women with benign breast lesions (Fig. 1
). These results were comparable with the c-erbB-2 levels assayed in serum (Fig. 2).
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). These results were comparable with the serum levels of c-erbB-2 protein and were better than those for the PSA test, which has been approved by the US Food and Drug Administration and is clinically being used for the detection of carcinoma of the prostate.
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Longitudinal study: salivary c-erbB-2 utility for post-operative monitoring
This study (Bigler et al., 2002) was undertaken to establish further the possible usefulness of the salivary protein product of the oncogene c-erbB-2 in monitoring patients diagnosed with carcinoma of the breast. Included in this study were 25 patients with various histological diagnoses and stages of carcinoma of the breast. ELISA assays for c-erbB-2 and CA 15-3 were performed on serum and stimulated whole-saliva samples collected from all patients prior to any adjunct therapy or surgery and sequentially during therapy. As noted in Fig. 4, the results of the study demonstrated that c-erbB-2 concentrations respond to treatment and can detect recurrence over time. Salivary c-erbB-2 may have the potential to track treatment success and guide therapy. The salivary c-erbB-2 determinations also mirrored those for serum c-erbB-2 and CA 15-3 (Bigler et al., 2002).
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). We performed a second Western blot to ascertain which salivary gland(s) were producing the salivary c-erbB-2. Salivary collections from the parotid and submandibular glands, and from total whole saliva, were collected from two healthy individuals. The results suggest that the submandibular gland (Fig. 6) is the primary contributor of c-erbB-2 salivary secretions (Streckfus et al., 2004). A third Western blot compared c-erbB-2 salivary secretions between three individuals diagnosed with carcinoma of the breast and two healthy controls. The results of the blot demonstrate denser 170- to 185-kDa bands among the cancer subjects as compared with healthy controls (Fig. 7). The results of this investigation suggest that this protein is increased in saliva in the presence of carcinoma of the breast (Streckfus et al., 2004).
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Prior to using the SELDI technique, however, we used the service offered by BD Biosciences Pharmingen (Bigler and Streckfus, 2004). This comprehensive protein-screening service is a powerful tool to aid researchers needing to elucidate the proteins and signaling pathways involved in a variety of normal and aberrant cellular processes. To initiate a more complete characterization of proteins present in saliva, the investigators selected a subset of antibodies from this unique protein-screening analysis to be performed on stimulated whole saliva from normal and breast cancer patients. The results demonstrated the presence of over 100 proteins in saliva (Fig. 8). The presence of these salivary proteins was unique and was not previously described in the salivary gland literature (Bigler and Streckfus, 2004).
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The SELDI Process may be described as follows: (1) Capture or "dock" one or more proteins of interest on the ProteinChip Array (Fig. 9), directly from the original source material, without sample preparation or "labeling"; (2) enhance the "signal-to-noise" ratio by reducing chemical and biomolecular "noise" (i.e., achieve selective retention of target on the chip by washing away undesired materials); (3) read one or more of the target protein(s) retained by a rapid, sensitive, laser-induced process (Fig. 10) that provides direct information about the target (molecular weight); and (4) process (characterize) the target protein(s) at any one or more locations within the addressable array directly in situ by engaging in one or more on-the-chip binding or modification reactions to characterize protein structure and function (Hutchens and Yip, 1993; Merchant and Weinberger, 2000; Madoz-Gurpide et al., 2001; Li et al., 2002).
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shows the profile of proteins in the 125,000- to 250,000-molecular-weight range bound to the WCX biochip. One can also see an increase of the proteins in this range from cancer patient saliva. Full-length c-erbB-2 (based on gel analysis) is estimated to be 185 kDa, with almost 47 kDa contributed by glycosylation (Zabrecky et al., 1991; Breuer et al., 1998). Interestingly, a protein cluster in the range of 170 kDa was more prevalent in cancer patient saliva samples (pool #1, old pool, 5IN, 5IS, and 5IT) than in samples from normal subjects (5FY, MMK, and XD). Also of note, one of the donors in the normal group (XD) is known by ELISA to have quite high c-erbB-2 levels (Streckfus and Bigler, unpublished data) and stands out from the other two normal donors in this analysis. These similar results were also demonstrated by serum and the extract from the SKBR-3 breast cancer cell lines with SELDI analyses.
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shows the analysis of proteins in the molecular weight range of 100 to 150 kDa on the WCX chip. Also, an increase of the proteins in this range from cancer patient saliva, especially in the range of approximately 113 kDa, can be seen. One possible cancer-related biomarker is the extracellular domain (ECD) of c-erbB-2 receptor (Visco et al., 2000), which is approximately 110 kDa (deglycosylated), based on two-dimensional and Western blot gel analyses. Without further biochemical analyses, it would be premature to say that these proteins are the ECD of the c-erbB-2 receptor; however, if further analysis does reveal that it is the ECD of the c-erbB-2 receptor, this finding would be supported by previous findings which ascertained the same results using ELISA assays (Streckfus et al., 2000a,b; Bigler et al., 2002).
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It is conceivable that the presence of c-erbB-2 in saliva is due to ‘leakage’ resulting from hydrostatic pressure, which widens the space between the tight junctions of the acinar epithelium, allowing the molecule to enter the saliva. However, an animal study using a sustained c-erbB-2 delivery system implanted into the peritoneum in rats exhibited classic ‘dose-response’ curves when c-erbB-2 was assayed in saliva over time (Brinkley et al., 2003). This evidence, taken with the repeatable clinical presence (Streckfus et al., 2001) of this protein in saliva, suggests that the mechanism by which c-erbB-2 enters the saliva is probably not leakage.
The other possible explanation is active transport. It is plausible that c-erbB-2 may be secreted into saliva as a consequence of localized regulatory function in the oral cavity via signal transduction, similar to the proposed explanation of c-erbB-2 protein in nipple aspirates (Kuerer et al., 2003). These ‘loop’ mechanisms, in health, appear to be in equilibrium, both intercellularly and extracellularly, with each pathway fulfilling the resultant phenotypic processes of growth, proliferation, and differentiation.
We postulate that, in the presence of carcinoma of the breast, there is an over-abundance of protein resulting from the rapid growth of the malignancy, which, in turn, produces a humoral response in the salivary glands (Fig. 13). This response results in elevated salivary c-erbB-2 concentrations. Similar phenomena have been reported in the literature concerning nipple aspirates (Kuerer et al., 2003). This literature reports elevated levels of c-erbB-2 in nipple aspirates (Fig. 14) from breasts diagnosed with ductal carcinoma. Interestingly, concentrations of c-erbB-2 in nipple aspirates from the opposite healthy breast were also elevated, suggesting intercellular signaling of this receptor among exocrine tissues in both health and disease (Kuerer et al., 2003). To date, little is known about the purpose of c-erbB-2 concentrations in saliva and nipple aspirates. Likewise, little is known about the ligands which initiate c-erbB-2 activation. Until these and other questions are answered, we can only postulate as to how this large 185-kDa protein is secreted into the oral cavity.
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Summary |
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Acknowledgments |
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References |
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TOPIntroductionCurrent Research: Salivary c...SummaryReferences |
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