High expression of the cachexia-related protein Fn14 in esophageal squamous cell carcinoma correlates with poor chemotherapy response and anti-Fn14 therapy decreases chemotherapeutic resistance.

Background: In cancer cachexia, cytokine release by tumours causes weight loss, decreased therapeutic efficacy, and worsened prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast inducible factor 14 (Fn14) are cancer cachexia-related proteins; however, their expression in oesophageal squamous cell carcinoma (ESCC) and association with therapeutic resistance remain unclear.

Methods: We evaluated how Fn14 knockdown and overexpression in ESCC lines (TE6 and TE10) contributed to proliferation, migration, and chemotherapy resistance in vitro and in vivo. In 135 ESCC patients who underwent esophagectomy after neoadjuvant chemotherapy, tumour expression of TWEAK and Fn14 was evaluated immunohistochemically to assess the association with clinicopathological factors and prognosis, including chemotherapeutic efficacy.

Results: Proliferation, migration, and chemotherapy resistance of ESCC cell lines were decreased by Fn14 knockdown but increased by Fn14 overexpression. Patients with Fn14-overexpressing ESCC had a decreased response rate to neoadjuvant chemotherapy and significantly lower rates of overall and recurrence-free survival, while concurrent expression of TWEAK and Fn14 was associated with further reductions in the response rate to chemotherapy and the rates of overall and recurrence-free survival.

Conclusions: TWEAK and Fn14 expression was associated with treatment resistance and prognosis in ESCC. Inhibiting the TWEAK/Fn14 axis may reduce treatment resistance and improve prognosis.