Eph/Ephrin Signaling in the Tumor Microenvironment
The Eph/ephrin system plays a vital role in diverse physiological events such as neurogenesis, vasculogenesis, and cell adhesion. Expression analysis of mRNA and protein in clinical samples revealed the involvement of the Eph/ephrin system in tumorigenesi
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Eph/Ephrin Signaling in the Tumor Microenvironment Katsuaki Ieguchi and Yoshiro Maru
Abstract
Keywords
The Eph/ephrin system plays a vital role in diverse physiological events such as neurogenesis, vasculogenesis, and cell adhesion. Expression analysis of mRNA and protein in clinical samples revealed the involvement of the Eph/ephrin system in tumorigenesis, Alzheimer’s disease, and atherosclerosis. Therefore, the Eph/ephrin system is considered a promising therapeutic target. However, no molecularly targeted drug against Ephs and ephrins is being used in the clinic thus far. Tumors are composed of various types of cells, including fibroblasts, immune cells, and endothelial cells. Recent studies showed the contribution of these cells to tumor growth, tumor progression, drug resistance, and metastasis. In this chapter, we discuss the role of Eph/ephrin system in the tumor microenvironment and describe its functions in tumor initiation, angiogenesis, cancer stem cell, tumor immunity, and also the metastatic environment.
Eph · Ephrin · Angiogenesis · Metastasis · Prognosis · Breast cancer · Colon cancer · Tumor Progression · Immune therapy · PD-L1 · Cancer stem cell · ADAM · Ras · MAPK · RhoA
K. Ieguchi (*) · Y. Maru (*) Department of Pharmacology, Tokyo Women’s Medical University, Tokyo, Japan e-mail: [email protected]; maru.yoshiro@twmu. ac.jp
3.1
General Overview
EphA1 a putative oncogene was isolated from an erythropoietin-producing human hepatocellular carcinoma cell line ELT1 by Hirai et al. in 1987 [1]. The Eph receptors are the largest family of receptor tyrosine kinases and divided into two subgroups, EphAs (A1–A8, A10) and EphBs (B1–B4, B6), based on receptor-ligand preferences. The EphA and EphB structures share a similarity in cysteine-rich, two fibronectin type III repeat, transmembrane, tyrosine kinase, and SAM domains (Fig. 3.1) [2, 3]. A ligand for the EphA receptors termed as ephrin-A1 was identified initially as a soluble factor upregulated by TNFα stimulation [4]. Ephrins also comprise of two families, ephrin-As (A1–A6) and ephrin-Bs (B1–B3), based on their structure. Ephrin-A is a glycosylphosphatidylinositol (GPI)-anchored plasma membrane protein, and ephrin-B is a transmembrane protein (Fig. 3.1). An interaction
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 A. Birbrair (ed.), Tumor Microenvironment, Advances in Experimental Medicine and Biology 1270, https://doi.org/10.1007/978-3-030-47189-7_3
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Fig. 3.1 Eph/ephrin system activation mechanism in a juxtacrine fashion. The representative domain structure is shown. Eph binds to ephrin present on an adjacent cell. Ephs transmit downstream signal in an Eph-
expressing cell termed as “forward signal,” and ephrins transmit intracellular signals in an ephrin-expressing cell termed as “reverse signal” mediated by Src family kinases
between types A and B families was shown earlier. For instance, ephrin-B2 promiscuously binds to the EphA recep
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