Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis

Abstract

BackgroundDying cells after irradiation could promote the repopulation of surviving cancer cells leading to tumor recurrence. We aim to define the role of dying cells in promoting pancreatic cancer cells metastasis following radiotherapy.MethodsUsing the transwell system as the in vitro co-culture model, a small number of untreated pancreatic cancer cells were seeded in the upper chamber, while a larger number of lethally treated pancreatic cancer cells were seeded in the lower chamber. A series of experiments were conducted to investigate the role of dying-cell-derived HMGB1 on the invasion of pancreatic cancer in vitro and cancer metastasis in vivo. We then designed shRNA knockdown and Western blot assays to detect signaling activity.ResultsWe found that dying pancreatic cancer cells significantly promote the invasion of pancreatic cancer cells in vitro and cancer metastasis in vivo. HMGB1 gene knockdown attenuated the migration-stimulating effect of irradiated, dying cells on living pancreatic cancer cells. Finally, we showed that dying-cell-derived HMGB1 functions in a paracrine manner to affect cancer-cell migration dependent on acquiring an epithelial-mesenchymal transition (EMT) phenotype and PI3K/pAkt activation. This process is mediated by the receptor for TLR2.ConclusionOur study indicates that, during radiotherapy, dying pancreatic cancer cells activate paracrine signaling events that promote the mobility of surviving tumor cells. We suggest a strategy to inhibit HMGB1 for preventing pancreatic carcinoma relapse and metastasis.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0726-2) contains supplementary material, which is available to authorized users.

Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis

“…Next, we went further to investigate how HCC cells polarized M2 macrophage via TLR2 signaling. HMGB1 is able to activate TLR2 signaling and has a potent ability to promote M2 macrophage polarization 14 , 15 . In addition, HMGB1 has been reported as a pathogenic factor in HCC 16 , and is upregulated in ML-1 4a cells compared with non-malignant mouse embryonic fibroblasts (MEF) cells (Supplementary Fig.…”

In-vivo and in-vitro impact of high-dose rate radiotherapy using flattening-filter-free beams on the anti-tumor immune response

“…The increase in HMGB1 secretion for doses up to 5 Gy seems congruent with the work of Chen and al. [30] on pancreatic cancer cells. However, even it is of substantial interest, the secretion of HMGB1 cannot be considered as the only marker of ICD and other criteria such as calreticulin translocation or ATP secretion will have to be the field for further explorations.…”

Natural display of nuclear-encoded RNA on the cell surface and its impact on cell interaction

“…The third class is the translocation of intracellular molecules onto the cell surface. In all the 3 classes, the molecule-producing cells can be dying cells [1,39,40]. In line with the third class of pathways, bacterial ribonucleoprotein complexes are comprised of both RNA and transmembrane proteins and the RNA is required for these complexes to localize to the cell membrane [4].…”