Toll‑like receptor 4 and its associated proteins as prognostic factors for HCC treated by post‑radiotherapy surgery

Abstract

Locally advanced hepatocellular carcinoma (HCC) treated by radiotherapy (RT) may be suited for further treatment with surgery. As a critical mediator of the post-RT immune response, Toll-like receptor 4 (TLR4) and its associated proteins may serve as prognostic factors for patients with HCC treated by post-RT surgery. In the present study, a total of 20 patients with HCC treated by post-RT surgery were enrolled. Resected tumor and peritumoral liver tissues were used to construct tissue microarrays that were assessed with immunohistochemical staining for the expression levels of TLR4, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and vascular endothelial growth factor receptor 2 (VEGFR2). The overall (OS) and disease-free (DFS) survival outcomes for each patient were assessed, and the severity of radiation-induced liver diseases (RILDs) was detected. The patients with low TLR4 or TRAIL expression exhibited significantly better OS times than those with high TLR4 (P=0.003) or TRAIL (P=0.007) expression, whereas the median DFS times for patients with low VEGFR2 or TRAIL were significantly longer than those with high VEGFR2 (P=0.003) or TRAIL (P=0.008) expression. No significant differences in OS or DFS times were identified according to the expression of TLR4, VEGFR2 or TRAIL in peritumoral liver tissue, although more severe RILDs were identified in patients with the high expression of these factors in the peritumoral liver tissue post-RT (P<0.05). Therefore, the expression levels of TLR4 and its associated proteins in HCC tumors may be suitable as prognostic factors for patients with HCC treated by post-RT surgery. The inhibition of TLR4, VEGFR2 and TRAIL expression in HCC and non-tumor liver tissue may lessen the severity of RILDs and improve survival outcomes in the future.

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects

“…TLR4 signaling plays a prominent role in the development of both the acute and chronic damaging effects resulting from the pro-inflammatory activity of immunocytes and tumor cells under stress conditions such as bacterial infection and anticancer radiation and chemotherapy [4,6]. In fact, the expression and signaling of TLR4 correlated with the deleterious effects of anticancer radiation and chemotherapy [7,57]. Our work supports combining anticancer therapies with entolimod https://doi.org/10.1371/journal.pone.0227940.g005 treatment to regulate inflammation and minimize the risk of septic shock and acute and delayed therapy-associated toxicity caused by pro-inflammatory cytokines such as TNF.…”

Interplay of Extracellular Vesicles and TLR4 Signaling in Hepatocellular Carcinoma Pathophysiology and Therapeutics

“…However, patients with a high expression of these factors in peritumoral liver tissue post-RT showed more severe RILDs (p < 0.05). Thus, the expression levels of TLR4 and its associated proteins in HCC tumors could serve as prognostic factors for patients undergoing post-RT surgery, while the inhibition of TLR4, VEGFR2, and TRAIL expression in HCC and non-tumor liver tissue could potentially reduce the severity of RILDs and improve survival outcomes in the future [97]. Finally, the inflammatory processes initiated by acute liver graft injury orchestrated tumor recurrence, which is the primary hurdle when expanding LT for patients with HCC.…”