Associations of circulating mediators of inflammation, cell regulation and immune response with esophageal squamous cell carcinoma

J Cancer Res Clin Oncol. 2021 Oct;147(10):2885-2892. doi: 10.1007/s00432-021-03687-3. Epub 2021 Jun 14.


Background: Esophageal squamous cell carcinoma (ESCC) is the most common histologic subtype of esophageal cancer globally. The development of squamous cell carcinoma has important inflammatory influences and effects. We, therefore, examined circulating levels of inflammation- and immune-related proteins for associations with ESCC.

Methods: We used pre-treatment EDTA plasma from 80 ESCC patients (44% clinical stages I and II) and 80 cancer-free control individuals within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 184 biomarkers were measured by high-throughput multiplexed proximity extension assays using Olink's Proseek Cell Regulation and Immuno-Oncology Panels. ESCC odds ratios (OR) per quantile (based on two to four categories) of each biomarker were calculated by unconditional logistic regression models, adjusted for age, sex, cigarette smoking and alcohol consumption. Correlations among continuous biomarker levels were assessed by Spearman's rank correlation. All statistical tests were two-sided with p values < 0.05 considered as significant. Given the exploratory nature of the study, we did not adjust for multiple comparisons.

Results: Seven proteins were undetectable in nearly all samples. Of the remaining 177 evaluable biomarkers, levels of cluster of differentiation 40 (CD40, per quartile OR 1.64; p trend = 0.018), syntaxin 16 (STX16, per quartile OR 1.63; p trend = 0.008), heme oxygenase 1 (per quartile OR 1.59; p trend = 0.014), and γ-secretase activating protein (GSAP, per quartile OR 1.47; p trend = 0.036) were significantly associated with ESCC. Amongst these significant markers, levels of CD40, STX16, and GSPA were moderately correlated (Rho coefficients 0.46-0.55; p < 0.05).

Conclusion: Our case-control study expands the range of inflammation and immune molecules associated with ESCC. These novel findings warrant replication and functional characterization.

Keywords: ESCC; HERPACC; Inflammation.

MeSH terms

  • Aged
  • Alcohol Drinking / adverse effects*
  • Biomarkers, Tumor / blood
  • Case-Control Studies
  • Cigarette Smoking / adverse effects*
  • Esophageal Neoplasms / blood
  • Esophageal Neoplasms / etiology
  • Esophageal Neoplasms / pathology*
  • Esophageal Squamous Cell Carcinoma / blood
  • Esophageal Squamous Cell Carcinoma / etiology
  • Esophageal Squamous Cell Carcinoma / pathology*
  • Female
  • Follow-Up Studies
  • Humans
  • Immunity / immunology*
  • Inflammation / complications*
  • Inflammation Mediators / blood*
  • Male
  • Prognosis
  • Risk Factors


  • Biomarkers, Tumor
  • Inflammation Mediators