Colorectal Cancer-Associated Myofibroblasts Exhibit Enhanced Angiogenin Expression and Signaling via the PLXNB2 Receptor

Abstract

Introduction: Dynamic cell-cell interactions shape the tumor microenvironment to regulate tumor growth and invasiveness. Myofibroblasts are gastrointestinal stromal cells that are upregulated in the setting of colorectal cancer (CRC) and may play an important role in tumor-stromal cell communication. Angiogenin is a 14-kDa ribonuclease that regulates myofibroblast function and has been implicated in myofibroblast-CRC cell communication in mouse models. However, its role in human patients has not been well established.

Methods: Open access, annotated single-cell RNA sequencing data of paired normal human colon and CRC tissue were available in the National Center for Biotechnology Information Gene Expression Omnibus Database. We supplemented and verified these data by analyzing scRNA-seq data from an independent set of paired normal human colon and CRC tissue. CellChat was used to quantitatively infer biologically meaningful cell-cell communication networks from scRNA-seq data. PLXNB2 and α-2 actin (ACTA2) are cell surface angiogenin receptors that regulate angiogenin signaling. Ligand-receptor interactions involving angiogenin, PLXNB2, and ACTA2 were analyzed between cell populations in each sample.

Results: We found no difference in overall angiogenin expression comparing normal colon and CRC tissue. In normal colon tissue, myofibroblasts do not express angiogenin or the PLXNB2 receptor. In the presence of CRC, there was a striking increase in the number of myofibroblast cells within the surrounding stroma. CRC-associated myofibroblasts were characterized by a significant upregulation of both angiogenin and PLXNB2 receptor expression (P < 0.05), while no difference was seen in ACTA2. CRC cells not only use angiogenin for autocrine signaling but also communicate with myofibroblasts via the PLXNB2 receptor.

Conclusions: Compared to normal human colon tissue, CRC tissue is associated with an enrichment of myofibroblasts that exhibit upregulated expression of angiogenin and the angiogenin receptor PLXNB2. CRC cells engage in autocrine signaling via angiogenin and paracrine signaling with myofibroblasts via PLXNB2. Angiogenin appears to be directly involved in tumor-stromal cell communication in human CRC tissue and may play an important role in disease progression.

Keywords: Angiogenin; Colorectal cancer; Myofibroblast; Tumor microenvironment.