Exosomal circular RNAs in tumor microenvironment: An emphasis on signaling pathways and clinical opportunities

Abstract

Exosomes can regulate the malignant progression of tumors by carrying a variety of genetic information and transmitting it to target cells. Recent studies indicate that exosomal circular RNAs (circRNAs) regulate multiple biological processes in carcinogenesis, such as tumor growth, metastasis, epithelial-mesenchymal transition, drug resistance, autophagy, metabolism, angiogenesis, and immune escape. In the tumor microenvironment (TME), exosomal circRNAs can be transferred among tumor cells, endothelial cells, cancer-associated fibroblasts, immune cells, and microbiota, affecting tumor initiation and progression. Due to the high stability and widespread presence of exosomal circRNAs, they hold promise as biomarkers for tumor diagnosis and prognosis prediction in blood and urine. In addition, designing nanoparticles targeting exosomal circRNAs and utilizing exosomal circRNAs derived from immune cells or stem cells provide new strategies for cancer therapy. In this review, we examined the crucial role of exosomal circRNAs in regulating tumor-related signaling pathways and summarized the transmission of exosomal circRNAs between various types of cells and their impact on the TME. Finally, our review highlights the potential of exosomal circRNAs as diagnostic and prognostic prediction biomarkers, as well as suggesting new strategies for clinical therapy.

Keywords: biomarker; circRNA; exosome; tumor microenvironment; tumor therapy.

FIGURE 1

JAK/STAT3 signaling pathway regulated by circRNAs. Circ‐0009092 inhibits tumor progression by regulating the JAK/STAT3 pathway, while circSEPT9, circHIPK3, and circKIF4A activate STAT3 and promote cancer progression.

FIGURE 2

Exosomal circRNAs in different types of cancer. The exosomal circRNAs are differentially expressed in many types of tumors, including glioma, pituitary adenoma, esophageal squamous cell carcinoma, breast cancer, liver cancer, colorectal cancer, bladder cancer, osteosarcoma, oral squamous cancer, lung cancer, gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, cervical cancer, and prostate cancer.

FIGURE 3

Function of exosomal circRNAs in tumorigenesis. Exosomal circRNAs can regulate the activity of downstream target genes and signaling pathways, subsequently affecting various tumor‐related biological processes, including proliferation, metastasis, EMT progression, angiogenesis, glycolysis, autophagy, and drug resistance.

FIGURE 4

Exosomal circRNAs facilitate communication in various cells of the tumor microenvironment. The cell types in the tumor microenvironment mainly include tumor cells, CAFs, endothelial cells, T cells, Treg cells, macrophages, MDSCs, NK cells, and neutrophils. Multiple cells reshape the immune microenvironment and affect tumor progression by transmitting exosomal circRNAs. In addition, a few gut microbiota can influence the synthesis of exosomal circRNAs in tumor cells, thereby regulating tumor development.

FIGURE 5

The clinical application strategies of exosomal circRNAs. Exosomal circRNAs can be regarded as biomarkers for cancer diagnosis, prognosis prediction and drug efficacy prediction. Meanwhile, exosomal circRNAs are promising therapeutic targets, significantly impacting chemical synthesis and nanoparticle delivery therapies.