Tryptophan Metabolites as Biomarkers for Esophageal Cancer Susceptibility, Metastasis, and Prognosis

Yun Chen; Jianliang Chen; Dainian Guo; Peixuan Yang; Shuang Chen; Chengkuan Zhao; Chengcheng Xu; Qiuzhen Zhang; Chaoxian Lin; Shilong Zhong; Shuyao Zhang

doi:10.3389/fonc.2022.800291

Tryptophan Metabolites as Biomarkers for Esophageal Cancer Susceptibility, Metastasis, and Prognosis

Front Oncol. 2022 Feb 28:12:800291. doi: 10.3389/fonc.2022.800291. eCollection 2022.

Authors

Yun Chen¹, Jianliang Chen², Dainian Guo³, Peixuan Yang⁴, Shuang Chen⁵, Chengkuan Zhao^{1

5}, Chengcheng Xu^{1

5}, Qiuzhen Zhang^{1

5}, Chaoxian Lin⁶, Shilong Zhong^{5

7}, Shuyao Zhang¹

Affiliations

¹ Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China.
² Clinical Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, China.
³ Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, China.
⁴ Health Management Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
⁵ Department of Pharmacology, Shantou University Medical College, Shantou, China.
⁶ Department of Pharmacology, Shantou Chaonan Minsheng Hospital, Shantou, China.
⁷ Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

Abstract

Background: Perturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism.

Method: A total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients.

Results: Levels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case-control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, p = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, p = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, p = 0.0080 and HR: 0.42, p = 0.0031, respectively).

Conclusion: This study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention.

Keywords: circulating biomarker; esophageal cancer; metastasis; prognosis; susceptibility; tryptophan metabolism.