TLR4-Mediated Recognition of Mouse Polyomavirus Promotes Cancer-Associated Fibroblast-Like Phenotype and Cell Invasiveness.
Vaclav JanovecBoris RyabchenkoAneta GandalovičováKarolina StaflovaDaniel RöselJan BrabekJan WeberJitka ForstováIvan HirschSandra HuérfanoPublished in: Cancers (2021)
The tumorigenic potential of mouse polyomavirus (MPyV) has been studied for decades in cell culture models and has been mainly attributed to nonstructural middle T antigen (MT), which acts as a scaffold signal adaptor, activates Src tyrosine kinases, and possesses transforming ability. We hypothesized that MPyV could also transform mouse cells independent of MT via a Toll-like receptor 4 (TLR4)-mediated inflammatory mechanism. To this end, we investigated the interaction of MPyV with TLR4 in mouse embryonic fibroblasts (MEFs) and 3T6 cells, resulting in secretion of interleukin 6 (IL-6), independent of active viral replication. TLR4 colocalized with MPyV capsid protein VP1 in MEFs. Neither TLR4 activation nor recombinant IL-6 inhibited MPyV replication in MEFs and 3T6 cells. MPyV induced STAT3 phosphorylation through both direct and MT-dependent and indirect and TLR4/IL-6-dependent mechanisms. We demonstrate that uninfected mouse fibroblasts exposed to the cytokine environment from MPyV-infected fibroblasts upregulated the expressions of MCP-1, CCL-5, and α-SMA. Moreover, the cytokine microenvironment increased the invasiveness of MEFs and CT26 carcinoma cells. Collectively, TLR4 recognition of MPyV induces a cytokine environment that promotes the cancer-associated fibroblast (CAF)-like phenotype in noninfected fibroblasts and increases cell invasiveness.
Keyphrases
- toll like receptor
- inflammatory response
- nuclear factor
- immune response
- extracellular matrix
- stem cells
- magnetic resonance imaging
- sars cov
- induced apoptosis
- single cell
- cell proliferation
- cell therapy
- endoplasmic reticulum stress
- oxidative stress
- hiv infected
- magnetic resonance
- binding protein
- endothelial cells
- climate change
- contrast enhanced
- high glucose
- amino acid
- protein protein
- protein kinase
- dual energy
- positron emission tomography
- human health
- disease virus
- cell cycle arrest