[Show abstract][Hide abstract] ABSTRACT: High grade serous ovarian cancer (HGSC), the most lethal and frequent type of epithelial ovarian cancer (EOC), has poor long term prognosis due to a combination of factors: late detection, great metastatic potential and the capacity to develop resistance to available therapeutic drugs. Furthermore, there has been considerable controversy concerning the etiology of this malignancy. New studies, both clinical and molecular, strongly suggest that HGSC originates not from the surface of the ovary, but from the epithelial layer of the neighboring fallopian tube fimbriae. In this paper we summarize data supporting the central role of fallopian tube epithelium in the development of HGSC. Specifically, we address cellular pathways and regulatory mechanisms which are modulated in the process of transformation, but also genetic changes which accumulate during disease progression. Similarities between fallopian tube mucosa and the malignant tissue of HGSC warrant a closer analysis of homeostatic mechanisms in healthy epithelium in order to elucidate key steps in disease development. Finally, we highlight the importance of the cancer stem cell (CSC) identification and understanding of its niche regulation for improvement of therapeutic strategies.
International Journal of Molecular Sciences 01/2013; 14(4):6571-96. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Antimicrobial peptides are key players of initial innate immune responses to human pathogens. Two major representatives, the human beta defensin 2 and 3 (hBD2 and hBD3), are both known to be regulated by, and to affect viability of, Helicobacter pylori. Previously, it was demonstrated in vitro that H. pylori actively abrogates hBD3 expression during prolonged infections. Here, we comprehensively assessed hBD2 and hBD3 expression ex vivo in the gastric mucosa of healthy individuals. MATERIALS AND METHODS: Twenty volunteers (H. pylori positive and H. pylori negative: n = 10) were enrolled. Helicobacter pylori-positive subjects underwent eradication therapy and repeated the protocol. Expression of both defensins was assessed by quantitative RT-PCR and ELISA, and correlated with histopathologic degree of gastritis. RESULTS: hBD2 and hBD3 were found to be ubiquitously expressed in all three groups. In general, hBD2 levels were elevated in relation to H. pylori infection (up to 40-fold). This upregulation correlated with degree of gastritis in corpus and antrum. In contrast, hBD3 protein levels were significantly decreased, while corresponding mRNA amounts remained unchanged. Eradication therapy led to normalization of mucosal hBD2 expression, while hBD3 expression demonstrated high interindividual variations among individuals. CONCLUSIONS: Both defensins are ubiquitously but differentially expressed in gastric mucosa in relation to H. pylori infection. Ex vivo data support the notion that H. pylori infection is associated with reduced hBD3 expression in chronic active gastritis.