Ephs in cancer progression: complexity and context-dependent nature in signaling, angiogenesis and immunity

Abstract

Eph receptors constitute the largest family of receptor tyrosine kinases, comprising 14 distinct members classified into two subgroups: EphAs and EphBs.. Despite their essential functions in normal physiological processes, accumulating evidence suggests that the involvement of the Eph family in cancer is characterized by a dual and often contradictory nature. Research indicates that Eph/ephrin bidirectional signaling influences cell-cell communication, subsequently regulating cell migration, adhesion, differentiation and proliferation. The contradictory functionalities may arise from the diversity of Eph signaling pathways and the heterogeneity of different cancer microenvironment. In this review, we aim to discuss the dual role of the Eph receptors in tumor development, attempting to elucidate the paradoxical functionality through an exploration of Eph receptor signaling pathways, angiogenesis, immune responses, and more. Our objective is to provide a comprehensive understanding of the molecular mechanisms underlying tumor development. Additionally, we will explore the evolving landscape of utilizing Eph receptors as potential targets for tumor therapy and diagnostic tools.

Keywords: Eph/ephrin; Immune; Pain; Tumor; Vascular.

Fig. 1

The Hazard Ratio of survival events associated with Eph receptor expressions across different cancer types. The TISCH2 database (http://tisch.compgenomics.org/), containing scRNA-seq data from more than 50 cancer types, was utilized to analyze the association of Eph receptor expression and HR of survival. An HR > 1 indicates a high risk of death, while an HR < 1 indicates a low risk of death. A HR of patient survival according to the expression of EphA2 in distinct cancer types from datasets. B HR of patient survival according to the expression of EphB1 in distinct cancer types from datasets. C HR of patient survival according to the expression of EphB4 in distinct cancer types from datasets

Fig. 2

The molecular structure of Ephrin-Eph and signaling pathway. A The molecular structures of ephrinA and ephrinB are different, while their receptors are similar. B, C The EphA and EphB receptor can bind to the ligands present on the same cell with the receptor, known as cis signaling, activating downstream signals. D, E The EphA and EphB receptor can bind to ligands located on neighboring cells, referred to as trans signaling, activating downstream signals. F Ephrin-Eph signaling engages in crosstalk with other RTKs such as EGFR and GFR, involving ERK, Ras and other downstream molecules

Fig. 3

Working models of Eph receptors and their ligands in physiological functions. A Ephrin-Eph signaling contains reverse signal and forward signal, leading to the phosphorylation of downstream molecules. The forward signal influences the expression of additional downstream molecules, thereby impacting processes such as angiogenesis, cell proliferation, cell adhesion, and migration. B Ephrin-Eph signaling engages in cross talk with other RTKs, such as VEGFR, exerting regulatory effects that can either suppress or promote tumor development

Fig. 4

The expression of EphB1 in various cell types. The expression of EphB1 in various cell types was analyzed in publicly accessible single-cell RNA-seq (scRNA seq) dataset of colorectal cancer tissues (EMTAB8107). A UMAP plot with cell type annotations displayed at the top of the tab. B UMAP plot shows the expression level of EphB1 in different cell types. C Pie plot shows the cell number distribution of each cell type. D Violin plot reflects the distribution of EphB1 gene expression in various cell types

Fig. 5

Average expression of Eph receptors. The TISCH2 database (http://tisch.compgenomics.org/), containing scRNA-seq data from more than 50 cancer types, was utilized to analyze the expression of Eph receptors. A The expression of EphA2 across datasets in different cell types. B The expression of EphB1 across datasets in different cell types. C The expression of EphB4 across datasets in different cell types

Fig. 6

Therapeutic strategies targeting Eph receptors. These strategies can inhibit tumor progression through various approaches and also impact pain behaviors