The central role of a two-way positive feedback pathway in molecular targeted therapies-mediated pyroptosis in anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive tumours. We previously confirmed that apatinib has potential therapeutic effects on ATC via regulated cell death (RCD). As a newly identified RCD, pyroptosis demonstrates direct antitumour activity different from apoptosis or autophagy. Therefore, the clinical significance, regulatory role and underlying mechanisms of pyroptosis in ATC were focused on in this study. METHODS: In a phase II trial, patients with anaplastic or poorly differentiated thyroid carcinoma received apatinib 500 mg once daily. Multiple assays were implemented to evaluate the antitumour efficacy of apatinib and/or melittin in vitro and in vivo. High-throughput sequencing was applied to analyse differential mRNAs expression in ATC cells treated by apatinib with or without melittin. In situ Hoechst 33342/PI double-staining, LDH release assay and enzyme-linked immunosorbent assay (ELISA) were employed to determine pyroptosis. In mechanism exploration, quantitative RT-PCR, Western blotting and si-RNA knocking down were executed. RESULTS: Seventeen patients were evaluable. Apatinib showed a promising therapeutic effect by a disease control rate (DCR) of 88.2%; however, treatment was terminated in 23.5% of patients due to intolerable toxicity. To reduce adverse events, a pyroptosis-mediated synergistic antitumour effect of apatinib and melittin was identified in treatment of ATC in vitro and in vivo. The caspase-1-gasdermin D (GSDMD) axis-mediated pyroptosis was the key to extra antitumour effect of the combination of apatinib and melittin. Moreover, caspase-3-gasdermin E (GSDME) pyroptosis pathway also functioned importantly in addition to caspase-1-GSDMD pathway. Evidenced by in vitro and in vivo study, a two-way positive feedback interaction was innovatively confirmed between caspase-1-GSDMD and caspase-3-GSDME axes. CONCLUSIONS: Through pyroptosis mediated by caspase-1-GSDMD and caspase-3-GSDME axes synchronically, low-dosage apatinib and melittin could synergistically achieve a comparable therapeutic potential with reduced AEs. More importantly, a two-way positive feedback interaction is innovatively proposed between these two axes, which provide a new prospect of targeted therapy.

Tumor aggressiveness risk factors in the differentiated thyroid carcinoma.

BACKGROUND: The differentiated thyroid carcinoma (DTC) is the most frequent malignancy in endocrinology (95%). Our aim was to retrospectively compare risk factors of tumor aggressiveness and history of thyroid disease in patients with conventional DTC and differentiated thyroid microcarcinoma (DTMC). METHODS: Retrospective analysis of 167 patients after total thyroidectomy with a histologically confirmed DTC, of which 83 patients with conventional DTC (> 1 cm) and 84 with DTMC (≤ 1 cm). The analyzed factors were tumor size, its aggressiveness (i.e. multifocal or bilateral occurrence, angioinvasion, extracapsular growth, presence of cervical lymph node metastases, distant metastases, and early local relapse) and medical history of thyroid diseases. RESULTS: In the DTMC group, there were 80/84 (95.2%) papillary carcinomas compared with 58/83 (69.9%) in the conventional DTC group (p=0.001). Patients with DTMC were significantly older than those with conventional DTC (p=0.006). In the conventional DTC group, there was a significantly higher occurrence of angioinvasion and extracapsular growth (p=0.001), cervical lymph node metastases (p=0.013), relapse (p=0.018), and distant metastases (p=0.007), compared with the DTMC group. CONCLUSION: In patients with DTMC, there was a significantly lower presence of risk factors of tumor aggressiveness, compared with the conventional DTC group (Tab. 2, Ref. 17).