Molecular alterations in fibroblasts exposed to Helicobacter pylori: a missing link in bacterial inflammation progressing into gastric carcinogenesis?

Major human pathogen Helicobacter pylori (Hp) can colonize the gastric mucosa causing inflammation and being of potential risk for gastric cancer development but the contribution of fibroblasts to the pathogenesis of Hp in the stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts, but their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue. We determined the effect of coincubation of cultured rat gastric fibroblasts with alive Hp on the transdifferentiation of fibroblasts into myofibroblasts associated with Hp-induced inflammation and neoplasia. Gastric mucosal samples were harvested from 8-week-old Spraque-Dowley rats and cultured to obtain the sub-confluent fibroblasts. The isolated fibroblasts were infected with 1 x 10(9) of live Hp (ATCC 700824, cagA+, vacA+) per dish and incubated in humidified atmosphere for 3, 24 and 48 hours. At respective times, fibroblasts were harvested and the expression of mRNA for α-smooth muscle actin (SMA), hypoxia inducible factor (HIF)-1α, collagen I, heat shock protein (HSP)-70, heme oxygenase (HO)-1, Bax and Ki67 transcripts was determined by RT-PCR with specific primers. Hp increased the transdifferentiation of fibroblasts into myofibroblasts as reflected by the time-dependent overexpression of mRNA for α-SMA. The increased expression of HIF-1α and collagen I was observed in fibroblasts co-cultured with Hp. The expression of HSP70 which was negligible in isolated fibroblasts incubated with vehicle (saline) showed time-dependent 2-3 fold increase in those incubated with Hp. The HO-1 mRNA was strongly expressed in rat gastric fibroblasts without or with the co-incubation with Hp. The mRNA for Bax was progressively downregulated within the time of incubation while no significant changes in expression of proliferation marker Ki67 were recorded. We conclude that Hp-induced transdifferentiation of fibroblasts into myofibroblasts involves an increased expression of the early carcinogenic marker HIF-1α, and inhibition of proapoptotic Bax expression, and 2) the overexpression of HSP70 and the unchanged expression HO-1 and Ki67 probably represent the enhanced protective activity of Hp-infected fibroblasts to maintain their own integrity under inflammatory action of this bacteria and its cytotoxins.

Mechanisms promoting physiological cells progression into tumorigenesis.

Cancer as the most frequent cause of death worldwide requires detailed investigation of its biology. This knowledge may open a new possibilities of generating novel targets, help to overcome issues of drug resistance, improve therapeutic efficacy, and make disease treatment more successful. The major advance in recent years was the discovery of the cancer stem cells (CSCs) population responsible for tumor maintenance. Numerous signalling pathways and genes connected with stem cell biology, such as an alternation in multiple malignancies resulting from the WNT/ß-catenin signalling pathway, have been identified. Crucial is knowledge concerning CSCs dependence and interactions with adjacent stromal cells that comprise a specialized microenvironment or niche. The niche shelters cells from diverse genotoxic factors thereby strengthening antitumor therapy resistance, and supports the growth of primary tumors converting non-tumorigenic cells into CSCs by processes related to the epithelial-to-mesenchymal transition (EMT). Moreover, numerous experiments confirmed that target genes of WNT signalling are implicated in cell-adhesion, which in consequence has an impact on EMT. This suggests a model that integrates a number of fundamental processes that underlie disease development and it should be put forward as an important target for novel therapies. Hence, linking the potency of silanols moiety, as innovative inhibitors of EMT resistant with the anticancergenic properties of selenium agents that targeting genetic basis of cancer stem cells development, requires a need for a design, synthesis and evaluation of novel compounds as a prospective direction of cancer research.