Subtype-Based Analysis of Cell-in-Cell Structures in Esophageal Squamous Cell Carcinoma

Yuqi Wang; Zubiao Niu; Lulin Zhou; Yongan Zhou; Qunfeng Ma; Yichao Zhu; Mengzhe Liu; Yinan Shi; Yanhong Tai; Qiuju Shao; Jianlin Ge; Jilei Hua; Lihua Gao; Hongyan Huang; Hong Jiang; Qiang Sun

doi:10.3389/fonc.2021.670051

Subtype-Based Analysis of Cell-in-Cell Structures in Esophageal Squamous Cell Carcinoma

Front Oncol. 2021 Jun 11:11:670051. doi: 10.3389/fonc.2021.670051. eCollection 2021.

Authors

Yuqi Wang^{1

2}, Zubiao Niu², Lulin Zhou^{2

3}, Yongan Zhou⁴, Qunfeng Ma⁵, Yichao Zhu², Mengzhe Liu¹, Yinan Shi^{1

6}, Yanhong Tai⁷, Qiuju Shao⁸, Jianlin Ge¹, Jilei Hua¹, Lihua Gao², Hongyan Huang⁹, Hong Jiang¹, Qiang Sun²

Affiliations

¹ College of Life Science and Bioengineering, School of Science, Beijing Jiaotong University, Beijing, China.
² Research Unit of Cell Death Mechanism, Institute of Biotechnology, Chinese Academy of Medical Science, Beijing, China.
³ School of Medicine, Nankai University, Tianjin, China.
⁴ Department of Thoracic Surgery, The Second Affiliated Hospital of Air Force Military Medical University, Xi'an, China.
⁵ Department of Thoracic Surgery, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
⁶ Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China.
⁷ Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
⁸ Department of Radiotherapy, The Second Affiliated Hospital of Air Force Military Medical University, Xi'an, China.
⁹ Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, Beijing, China.

Abstract

Cell-in-cell (CIC) structures are defined as the special structures with one or more cells enclosed inside another one. Increasing data indicated that CIC structures were functional surrogates of complicated cell behaviors and prognosis predictor in heterogeneous cancers. However, the CIC structure profiling and its prognostic value have not been reported in human esophageal squamous cell Carcinoma (ESCC). We conducted the analysis of subtyped CIC-based profiling in ESCC using "epithelium-macrophage-leukocyte" (EML) multiplex staining and examined the prognostic value of CIC structure profiling through Kaplan-Meier plotting and Cox regression model. Totally, five CIC structure subtypes were identified in ESCC tissue and the majority of them was homotypic CIC (hoCIC) with tumor cells inside tumor cells (TiT). By univariate and multivariate analyses, TiT was shown to be an independent prognostic factor for resectable ESCC, and patients with higher density of TiT tended to have longer post-operational survival time. Furthermore, in subpopulation analysis stratified by TNM stage, high TiT density was associated with longer overall survival (OS) in patients of TNM stages III and IV as compared with patients with low TiT density (mean OS: 51 vs 15 months, P = 0.04) and T3 stage (mean OS: 57 vs 17 months, P=0.024). Together, we reported the first CIC structure profiling in ESCC and explored the prognostic value of subtyped CIC structures, which supported the notion that functional pathology with CIC structure profiling is an emerging prognostic factor for human cancers, such as ESCC.

Keywords: EML staining; cell-in-cell structures; entosis; esophageal squamous cell carcinoma; functional pathology; multiplex staining; prognosis; subtype.