RAGE and its ligands in cancer - culprits, biomarkers, or therapeutic targets?

Receptor for advanced glycation end products (RAGE) plays a central role in the regulation of tissue homeostasis, regeneration and resolution of inflammation, but under pathological conditions RAGE-mediated pathways may induce diminished apoptosis, but enhanced autophagy and cell necrosis. These mechanisms may contribute to malignant transformation, cancer progression and metastases. Soluble RAGE may bind natural RAGE ligands and counteract some of the RAGE-mediated effects. Activation of RAGE was demonstrated in different types of cancer (including colon, pancreatic and breast cancer). Expression of RAGE and serum levels of soluble RAGE may serve as cancer biomarkers and strategies aimed at interfering with RAGE signaling might be promising anticancer drugs.

Predictive factors for the presence of tumor cells in bone marrow and peripheral blood in breast cancer patients.

UNLABELLED: Simultaneous detection of disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) was shown to be associated with an especially poor prognosis and increased incidence of disease-related deaths in non-metastatic breast cancer patients. We analyzed the occurance of DTCs and CTCs in patients with primary breast cancer and evaluated the correlation of their presence with other prognostic markers and investigated the changes in DTCs/CTCs number at different time points during treatment.Blood of 50 patients with primary breast cancer were used for immunomagnetic separation and detection of circulating tumor cells using the commercial available system the AdnaTest Breast Cancer™ (AdnaGen GmbH, Langenhagen, Germany). Bone marrow aspirates from 50 patients were analyzed for DTCs by immunocytochemistry using the pan-cytokeratin antibody conjugated with FITC (Monoclonal Anti-Cytokeratin antibody F3418, Sigma Aldrich).DTCs were identified in 30% (15/50) and CTCs in 22% (11/50) of patients. We found that DTC positivity could point to a significantly high risk of larger primary tumor size (p-value 0.011) and significantly higher risk of lymph node involvement (p-value 0.002). For CTC positivity, no such relationship was proven. DTCs have shown significantly higher prevalence in ER/PR-negative females and in HER2-positive cases. CTCs were equally prevalent in patients with the presence and absence of standard prognostic and predictive markers such as ER, PR and HER2. We found no correlation between CTCs and DTCs findings (r = -0.097, p = 0.504). We used DTCs/CTCs analysis for therapy monitoring in a small group of 29 patients, who underwent neoadjuvant chemotherapy (NACT). We find out no significant correlation between DTCs/CTCs detection and the primary tumor response to NACT. A pathologic complete response (pCR) was achieved by 31% (9/29) of the patients in our study, however, no association was observed between pCR and the detection of DTCs after NACT.These results support the use of DTCs/CTCs analysis in early breast cancer to generate clinically useful prognostic information. The study of these cells apart from the impact on refining prognosis, has the exciting potential of individualising treatment for women with breast cancer. KEYWORDS: breast cancer, disseminated tumor cells, circulating tumor cells, bone marrow aspiration, prognostic/predictive markers, therapy monitoring.

Disseminated and circulating tumour cells and their role in breast cancer.

Metastatic spread of the primary tumour is responsible for the vast majority of cancer-related deaths. Detection of disseminated tumour cells in the bone marrow and circulating tumour cells in the peripheral blood is correlated with early metastatic relapse in breast cancer. Positive detection of disseminated tumour cells was associated with poor overall survival of patients. Current research has been focused on integrating minimal residual disease as a prognostic and predictive tool in the management of breast cancer. Detection of disseminated tumour cells/circulating tumour cells is not yet standardized in clinical practice because of using different enrichment and detection methods. Therefore, standardization of the used methods is necessary in the future. Previous achieved findings must be verified in larger prospective multicentre studies. Further characterization of disseminated tumour cells/circulating tumour cells will be essential for developing and monitoring the efficacy of new therapeutic concepts. The aim of this review was to provide a short survey of the metastatic cascade and cancer stem cell theory, and data on the molecular and functional characterization of disseminated tumour cells/circulating tumour cells. Finally, we discuss the potential clinical impact of disseminated tumour cells/circulating tumour cells and results of several recent studies.