Helicobacter pylori-activated fibroblasts as a silent partner in gastric cancer development

Abstract

The discovery of Helicobacter pylori (Hp) infection of gastric mucosa leading to active chronic gastritis, gastroduodenal ulcers, and MALT lymphoma laid the groundwork for understanding of the general relationship between chronic infection, inflammation, and cancer. Nevertheless, this sequence of events is still far from full understanding with new players and mediators being constantly identified. Originally, the Hp virulence factors affecting mainly gastric epithelium were proposed to contribute considerably to gastric inflammation, ulceration, and cancer. Furthermore, it has been shown that Hp possesses the ability to penetrate the mucus layer and directly interact with stroma components including fibroblasts and myofibroblasts. These cells, which are the source of biophysical and biochemical signals providing the proper balance between cell proliferation and differentiation within gastric epithelial stem cell compartment, when exposed to Hp, can convert into cancer-associated fibroblast (CAF) phenotype. The crosstalk between fibroblasts and myofibroblasts with gastric epithelial cells including stem/progenitor cell niche involves several pathways mediated by non-coding RNAs, Wnt, BMP, TGF-β, and Notch signaling ligands. The current review concentrates on the consequences of Hp-induced increase in gastric fibroblast and myofibroblast number, and their activation towards CAFs with the emphasis to the altered communication between mesenchymal and epithelial cell compartment, which may lead to inflammation, epithelial stem cell overproliferation, disturbed differentiation, and gradual gastric cancer development. Thus, Hp-activated fibroblasts may constitute the target for anti-cancer treatment and, importantly, for the pharmacotherapies diminishing their activation particularly at the early stages of Hp infection.

Keywords: Cancer-associated fibroblasts; Cell reprogramming; Cell signaling; Gastric cancer; Helicobacter pylori–induced fibroblast activation; Stemness.

Fig. 1

Schematic view on the stem and progenitor cell compartment within the oxyntic (corpus) and antral glands

Fig. 2

The participation of canonical and non-canonical Wnt/β-catenin signaling pathway in stem/progenitor cell maintenance and GC development. The canonical pathway is activated by increased release of Wnt canonical ligands and sustained by RSPO-induced ZNRF3/RNF43 ubiquitin ligases inactivation. This pathway is essential for determining the cell fate, proliferation, and self-renewal of both stem and progenitor cells by, e.g., regulation of the transcription of Wnt target genes including CD44, cyclin D1, and c-Myc, promoting regeneration of epithelial cells. Non-canonical pathway is activated by increased release of non-canonical Wnt ligands. It leads to planar cell polarity (PCP) signaling responsible for cell cytoskeleton regulation and Wnt/calcium signaling responsible for the regulation of intracellular calcium concentration, as well as CREB and NFκB transcription factors involved in the regulation of inflammatory response. Another non-canonical pathway that might be triggered is Wnt/STOP pathway serving for cellular divisions. Green asterisk denotes the factors that are upregulated during Hp-positive GC. Red asterisk denotes the factors released by activated fibroblasts/CAFs during Hp infection. ROS, reactive oxygen species

Fig. 3

The influence of Hp-infected fibroblasts on downregulation of canonical and non-canonical BMP signaling. BMPs are regulatory peptides which through the canonical, SMAD-dependent, and non-canonical, SMAD-independent signaling induce mesenchymal, gastric epithelial, and cancer stem cell differentiation. BMPs have also been reported to evoke anti-inflammatory response by inhibition of IL-8 gene expression. Hp infection leads to decreased expression of BMP1 to 7 and increased expression of BMP inhibitors such as CRIM1, CHRDL1, GREM1, and BAMBI, thus diminishing differentiation of stem and progenitor cells leading to hyperproliferation and hyperplasia accompanied with inflammatory reaction. Red asterisk denotes the factors released by activated fibroblasts/CAFs during Hp infection

Fig. 4

The participation of Hp-AGFs in TGF-β canonical and non-canonical signaling. Hp-AGFs release increased amounts of TGF-β and stimulate its bioavailability and activation, leading to pathological events including EMT type 3, cell transformation, pluripotency, and overproliferation evoking CSC and CAF phenotypes. In most of the context, active TGF-β signals through a canonical, SMAD-dependent pathway. The retention of R-SMAD and co-SMAD complexes is mediated by transcriptional co-factors such as transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP), which can also be activated by stiff ECM produced by Hp-activated fibroblasts. The stable binding of SMAD complexes to DNA requires interaction and cooperation with the cell type–specific co-factors FOXH1, EOMES, OCT4, and NANOG, particularly involved in the induction and maintenance of stem cell properties. R-SMADs can regulate miRNA processing by associating with the p68/Drosha/DGCR8 miRNA processing complex. Inhibitory SMADs (I SMAD) such as SMAD6 and 7 bind to activated receptors competing with R-SMAD and recruit the SMURF ubiquitin ligases leading to receptor degradation. Activated R-SMAD proteins could also be degraded by ubiquitination via HECT E3 ligases; thus, the duration of TGF-β family signaling integrates with other pathways such as IGF, FGF, and WNT in dictating stem cell homeostasis. The non-canonical, SMAD-independent TGF-β pathways are important effectors for tyrosine kinase receptors. TGF-β activates non-SMAD pathways either directly or through the adaptor proteins. TGF-β can directly activate the Ras/Raf/MEK/ERK/MAPK participating in the regulation of cell cycle progression, cell differentiation, and proliferation. TGF-β receptor complex is also able to activate TAK1, resulting in p38 and JNK and NFκB activation important in pluripotency and MET progression. TGF-β has been also shown to modulate the activities of the small GTPase proteins Rho, Rac, and Cdc42, responsible for the regulation of gene expression and cytoskeleton organization. TGF-β-activated RhoA can activate its downstream targets ROCK and LIM kinase influencing metastasis. TGF-β also induces PI3K/Akt which plays an important role in cell survival, growth, migration, and invasion. Moreover, PI3K/Akt signaling led to phosphorylation and activation of TWIST, thus promoting CSC-like phenotype, survival, and invasion of cancer cells. The reciprocal, potentiating interactions between HGFR-, EGFR-, and TGF-βR-activated pathways have been proposed. TGF-β mediates the migration, proliferation, and differentiation of stem cells into myofibroblasts recruited into the tumor bed. TGF-β is also able to stimulate EndMT and FMyoT. Red asterisk denotes the factors stimulated or released by activated fibroblasts/CAFs during Hp infection