Lenora Bigler

Salivary biomarkers for the detection of malignant tumors that are remote from the oral cavity.

Proteomic analyses by mass spectrometry are propelling the field of medical diagnostics forward at unprecedented rates because of its ability reliably to identify proteins that are at the femtomole level in concentration. These advancements have also benefited biomarker research to the point where saliva is now recognized as an excellent diagnostic medium for the detection of malignant tumors that are remote from the oral cavity. Saliva is easy to collect and may provide diagnostic information about a variety of cancers. In particular, proof-of-principle has been demonstrated for salivary biomarker research. This article reviews the literature, discusses the theories associated with saliva-based tumor diagnostics, and presents the current research focused on the use of saliva as a diagnostic medium for the detection of cancer.

CA 15–3 and c-erbB-2 presence in the saliva of women

Abstract Two markers used to aid in the diagnosis and treatment of breast cancer were examined in the saliva of a cohort of 135 healthy women. The investigators detected the presence of cancer antigen 15–3 (CA 15–3) and c-erbB-2 in the saliva sampled from the 135 women. The marker concentrations for CA 15–3 and c-erbB-2 were also evaluated and compared in terms of tobacco usage, menopausal status, estrogen usage, systemic diseases, prescription medications, race, and age. The results of the study showed no association between the aforementioned variables and salivary marker concentrations. The results of this study establish a baseline for measuring the biomarkers in the saliva of women with no evidence of malignant disease and add further support to the notion that salivary concentrations of CA 15–3 and c-erbB-2 may be useful in the detection of breast cancer and/or the post operative follow-up of patients being treated for carcinoma of the breast.

Progesterone inhibits glucocorticoid-induced murine thymocyte apoptosis

Sex and sex hormones modulate immune development and responses. A primary target of their effects is the structure and cellularity of the thymus; therefore, we examined the effects of sex and sex steroids on thymocyte apoptosis. We demonstrate initially that male DBA mice have a significantly higher percentage of glucocorticoid-induced apoptotic thymocytes (46.1+/-3.8%) than their female counterparts (31.6+/-3.1%; P=0.012). We postulated that this gender difference was due to differential modulation of glucocorticoid-induced apoptosis by sex hormones such as estrogen, testosterone or progesterone. Both estrogen and testosterone increased in vitro thymocyte apoptosis. In contrast, progesterone not only inhibited spontaneous in vitro thymocyte apoptosis, but also prevented in vitro glucocorticoid-induced apoptosis. Progesterone administration also suppressed glucocorticoid-induced in vivo thymocyte apoptosis. These results suggest that anti-apoptotic effects of progesterone may influence T cell development and subsequent immune responses.

Cytokine concentrations in stimulated whole saliva among patients with primary Sjögren's syndrome, secondary Sjögren's syndrome, and patients with primary Sjögren's syndrome receiving varying doses of interferon for symptomatic treatment of the condition: a preliminary study

Abstract. Sjögren’s syndrome is an autoimmune disorder which causes diminished salivary flow due to autoimmune sialoadenitis. This decrease in saliva flow is the result of inflammation and atrophy of the salivary glands. Most treatment regimens are palliative in nature, but treatment with interferon (IFN) holds promise for Sjögren’s syndrome sufferers. Several studies have investigated cytokine concentrations in the salivary glandular tissues from Sjögren’s syndrome patients; however, there is little information concerning cytokine expression in saliva. This is especially true with respect to treatment modalities and their effects on local cytokines. A clinical study was conducted to determine salivary interleukin (IL)-6, IFN , and IL-2, concentrations among subjects diagnosed with primary and secondary Sjögren’s syndrome and a healthy control group. The primary Sjögren’s syndrome showed significantly higher salivary IL-2 and salivary IL-6 than the control and secondary Sjögren’s groups. There were no between group differences for salivary IFN concentrations. In addition, the study assessed salivary IL-6, IFN, and IL-2 concentrations among 18 Sjögren’s syndrome patients before and after administration of IFN via the oral mucosal route. The results of the study showed that the mean values for the pre- and post-treatment groups for stimulated whole saliva flow rates were 3.15 and 3.74 ml/5 min, respectively. The post-treatment group exhibited a 16.8% increase in stimulated whole saliva flow rates. The salivary IL-6 concentration was 53.3% lower for the post-treatment group (17.79) as compared to the baseline value (33.35). The values for salivary IFN and salivary total protein were virtually unchanged from their baseline values. Salivary IL-2 values, however, were 50% lower in the post-treatment group (3.07) when compared to their respective baseline values(6.10). The results of this study suggest that healthy individuals exhibit lower salivary IL-2 and IL-6 as compared to individuals suffering from primary and secondary Sjögren’s syndrome. The results also suggest that administration of IFN via the oral mucosal route may increase salivary flow rates and depress certain cytokines (IL-2, IL-6) associated with inflammatory destruction of salivary glandular tissues in Sjögren’s syndrome patients.

Salivary Protein Profiles among HER2/neu-Receptor-Positive and -Negative Breast Cancer Patients: Support for Using Salivary Protein Profiles for Modeling Breast Cancer Progression

Purpose. The objective of this study was to compare the salivary protein profiles from individuals diagnosed with breast cancer that were either HER2/neu receptor positive or negative. Methods. Two pooled saliva specimens underwent proteomic analysis. One pooled specimen was from women diagnosed with stage IIa HER2/neu-receptor-positive breast cancer patients (n = 10) and the other was from women diagnosed with stage IIa HER2/neu-receptor-negative cancer patients (n = 10). The pooled samples were trypsinized and the peptides labeled with iTRAQ reagent. Specimens were analyzed using an LC-MS/MS mass spectrometer. Results. The results yielded approximately 71 differentially expressed proteins in the saliva specimens. There were 34 upregulated proteins and 37 downregulated proteins.

Using Saliva Secretions to Model Disease Progression

To date, because of the complexity and heterogeneity of cancer, no individual model recapitulates all aspects of this disease. The authors of this chapter developed a molecular model that utilizes one of the most easily obtained body fluids for tumor marker analysis. The in vivo model can fill in the current gaps in our understanding of cancer pathogenesis, signaling pathways, the efficacy of varying chemotherapeutics, identifying novel therapies, and, most importantly, shed new light on metastatic progression that is the principal cause of mortality. We propose that, secondary to cancer, the malignancy’s rapid growth alters the proteomic content of the tissue microenvironment. These changes may manifest in up- or downregulation of salivary protein concentrations, which can be used as a sentinel for cancer modeling.

A Catalogue of Altered Salivary Proteins Secondary to Invasive Ductal Carcinoma: A Novel In Vivo Paradigm to Assess Breast Cancer Progression

The objective of this manuscript is to introduce a catalogue of salivary proteins that are altered secondary to carcinoma of the breast. The catalogue of salivary proteins is a compilation of twenty years of research by the authors and consists of 233 high and low abundant proteins which have been identified by LC-MS/MS mass spectrometry, 2D-gel analysis and by enzyme-linked immunosorbent assay. The body of research suggests that saliva is a fluid suffused with solubilized by-products of oncogenic expression and that these proteins may be useful in the study of breast cancer progress, treatment efficacy and the tailoring of individualized patient care.