SurveyThe role of ephrins and Eph receptors in cancer
Introduction
Eph receptors were originally identified in the late 1980s in a human cDNA library screen for homologous sequences to the tyrosine kinase domain of the viral oncogene v-fps [1]. The Eph receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. RTKs are transmembrane proteins with an extracellular domain capable of recognizing signals from the cells’ environment and can influence the growth and survival of cells by acting directly on gene transcription or indirectly on the production of second messengers. Eph/ephrin signaling is an indirect way of modulating a variety of biological activities, including cell–cell interaction and cell migration. One of the important consequences of Eph receptors and ephrins is their role in tumorigenesis and metastatic potential as related to tumor growth and survival. Elevated Eph/ephrin expression is associated with angiogenesis and tumor vasculature in many types of human cancers, including breast, lung, and prostate cancers, melanoma, and leukemia. Eph receptors and their ephrin ligands have also been implicated in diverse developmental and neurological functions, including hindbrain development in vertebrates and tissue patterning. Recent data suggest that Eph/ephrin signaling could play an important role in the development of novel inhibition strategies and cancer treatments to potentially target this receptor tyrosine kinase and/or its ligand. This review will discuss Eph receptors and ephrins, focusing on their role in cancer, but is in no way meant to be a comprehensive source. We have referenced original and review articles where possible, and apologize in advance to our colleagues that we have not referenced all of the original literature that exists on this topic due to space constraints.
Section snippets
Structure
Receptor tyrosine kinases (RTKs) are transmembrane spanning receptor proteins which contain an extracellular ligand binding domain and a cytosolic domain with inherent tyrosine kinase activity. They include the receptors for several growth factors (such as EGF, PDGF, and FGF) and insulin and contain over 50 different members organized into at least 14 different subgroups based on their structural organization. Ligand binding to a receptor tyrosine kinase induces receptor autophosphorylation of
Bi-directional signaling
A special feature of ephrins and Eph receptors is the concept of bi-directional—reverse and forward—signaling. An Eph receptor can act as a ligand in the same way that an ephrin ligand can act as a receptor. Ephrin ligand binding induces Eph receptor ‘forward’ signaling, usually requiring tyrosine kinase domain activation and transduction of the signal into the receptor-expressing cell [6]. But ephrins can also result in ‘reverse’ signal transduction into the ephrin-expressing cell. For
Biological functions
The cellular responses to Eph receptor stimulation by their ephrin ligands are important in mediating a wide range of biological activities, including angiogenesis, cell segregation, and cell attachment, shape, and motility. As several of these processes are know to go awry during tumorigenesis and metastasis, Eph/ephrin signaling has been identified to play a role in many human cancers, such as lung, breast, and prostate cancers, as well as melanoma, and leukemia. Besides their proposed role
Amplification and alteration in cancer
Posttranslational phosphorylation of proteins is an important regulatory mechanism in cell function and interaction. Its modification and consequent receptor/ligand alteration is thus one of the many factors that might result in the transformation of normal cells into an invasive or metastatic tumor. Eph receptors and ephrins have been found to be both over- and under-expressed in various tumor types. Upon the identification of the first member of the Eph family, EphA1, breast, liver, lung, and
Lung cancer
According to the American Cancer Society, an estimated 173,770 new cases of lung and bronchus cancer are expected in 2004 and account for approximately 13% of all cancer diagnoses. Lung cancer continues to be the leading cause of cancer death in the United States (approximately 28%), with an estimated 160,440 deaths in 2004 [69]. Thus, it is critical to further study possible novel therapeutic approaches for this devastating illness. The role of Eph receptors and their ephrin ligands in lung
Therapeutic approaches to inhibiting the eph/ephrin axis
In order to further advance novel cancer treatment methods, studies have been directed toward investigating new opportunities for therapeutic molecular targeting. In order to inhibit the transformation of a healthy cell with normal Eph/ephrin expression into a primary tumor and consequently into a metastatic/invasive tumor, investigators have focused on cell growth, viability, and apoptosis, as well as various cytoskeletal signaling pathways leading to cell motility and proliferation as
Conclusion
We are still in the process of understanding the cellular and molecular mechanisms involved in Eph and ephrin interaction and signaling. Since their functions include such processes as angiogenesis in tumor tissue, we can introduce the prospect of these molecules becoming candidates for tumor prognostic markers and potential targets for therapeutic intervention in cancer. The current challenge is to fully understand the mechanisms that govern the functional effects of Eph receptors and ephrins
Acknowledgments
Patrick C. Ma is supported by the American Association for Cancer Research (AACR)-AstraZeneca-Cancer Research and Prevention Foundation Fellowship in Translational Lung Cancer Research; and American Cancer Society Institutional Research Grant (ACS IRG-58-004-44). Ravi Salgia is supported by Research Scholar Grant awarded by the American Cancer Society (RSG-02-244-02-CCE), NIH/NCI R01 Grant (R01 CA100750-01A1), and Institutional V-Foundation Award.
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