Expression Patterns of Microenvironmental Factors and Tenascin-C at the Invasive Front of Stage II and III Colorectal Cancer: Novel Tumor Prognostic Markers.

Mai Hashimoto,Akira Sasaki,Yoshiki Kajiwara,Noriyuki Uesugi,Mitsumasa Osakabe,Tamotsu Sugai,Naoki Yanagawa,Hideki Ueno,Koki Otsuka

doi:10.3389/fonc.2021.690816

Abstract

BackgroundBiological markers expressed in cancer cells and the surrounding cancer-associated fibroblasts (CAF) can be used for prediction of patient prognosis in colorectal cancer (CRC). Here, we used immunohistochemical techniques to evaluate cancer cells’ expression of specific biomarkers that are closely associated with neoplastic progression.MethodsImmunohistochemical markers included Ki-67, p53, β-catenin, MMP7, E-cadherin and HIF1-α. We also characterized microenvironmental markers expressed by CAF, including expression of α-smooth muscle actin, CD10, podoplanin, fibroblast specific protein 1, platelet derived growth factor β, fibroblast association protein, tenascin-C (TNC), ZEB1 and TWIST1. The study population consisted of 286 CRC patients with stage II and III disease. Stage II and III CRC were divided into a first and a second cohort (for validation). The CRCs were stratified using cluster analysis. To identify the utility of prognostic markers in stage II and III CRC, univariate and multivariate analyses were performed in both cohorts.ResultsStage II and III CRCs were stratified into 3 subgroups. Specific subgroups were significantly correlated to disease-free survival using univariate and multivariate analyses in the first cohort. High expression of TNC was identified as a single prognostic marker in both cohorts by univariate and multivariate analyses.ConclusionsWe suggest that the presence of a specific subgroup defined by multiple markers can be used for prediction of CRC outcome in stages II and III. In addition, we showed that high expression of TNC was correlated with a poorer prognosis in stages II and III of CRC.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women in the United States [1]
We propose that identification of protein expression patterns in cancer cells and cancerassociated fibroblasts (CAF) could provide new biological insights and guide the development of new therapies for CRC [12, 13]
We performed hierarchical clustering based on marker scores to evaluate differences in expression patterns of cancer cell, CAF

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women in the United States [1]. A pronounced desmoplastic stromal reaction in the microenvironment involves complex cellular interactions at the invasive front [10] This theory posits that cooperation between cancer cells and cancer associated fibroblasts (CAFs) present within the tumor microenvironment is necessary to support tumor growth and progression [10, 11]. The microenvironment itself plays an important role in neoplastic progression and metastasis in CRC [10, 11] Whereas such histological findings are widely used as markers for establishing a patient’s prognosis, they do not explain the underlying cellular processes that promote tumor growth and metastasis [12, 13]. We used immunohistochemical techniques to evaluate cancer cells’ expression of specific biomarkers that are closely associated with neoplastic progression

Methods

Results

Discussion

Conclusion