Elsevier

Gene

Volume 366, Issue 1, 17 January 2006, Pages 2-16
Gene

Review
Epidermal growth factor receptor (EGFR) signaling in cancer

https://doi.org/10.1016/j.gene.2005.10.018Get rights and content

Abstract

The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTK). These trans-membrane proteins are activated following binding with peptide growth factors of the EGF-family of proteins. Evidence suggests that the EGFR is involved in the pathogenesis and progression of different carcinoma types. The EGFR and EGF-like peptides are often over-expressed in human carcinomas, and in vivo and in vitro studies have shown that these proteins are able to induce cell transformation. Amplification of the EGFR gene and mutations of the EGFR tyrosine kinase domain have been recently demonstrated to occur in carcinoma patients. Interestingly, both these genetic alterations of the EGFR are correlated with high probability to respond to anti-EGFR agents. However, ErbB proteins and their ligands form a complex system in which the interactions occurring between receptors and ligands affect the type and the duration of the intracellular signals that derive from receptor activation. In fact, proteins of the ErbB family form either homo- or hetero-dimers following ligand binding, each dimer showing different affinity for ligands and different signaling properties. In this regard, evidence suggests that cooperation of multiple ErbB receptors and cognate ligands is necessary to induce cell transformation. In particular, the growth and the survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. This phenomenon is also important for therapeutic approaches, since the response to anti-EGFR agents might depend on the total level of expression of ErbB receptors and ligands in tumor cells.

Introduction

The role of growth factors-driven signaling in the pathogenesis of human cancer has been long established. Almost twenty years ago Mike Sporn and Anita Roberts (Sporn and Roberts, 1985), following the seminal observations of Joseph deLarco and George Todaro (De Larco and Todaro, 1978), elaborated the theory of autocrine secretion: cancer cells generally exhibit a reduced requirement for exogenously supplied growth factors to maintain a high rate of proliferation. This relaxation in growth factor dependency is due in part to the ability of tumor cells to produce high levels of peptide growth factors. Since this seminal observation, an enormous amount of literature has confirmed the role of growth factor driven signaling in the pathogenesis of human cancer. It has been recognized that different mechanisms might contribute to amplify the signal driven by growth factors. For example, expression of a high number of receptors on the surface of tumor cells can increase their sensitivity to low concentrations of host- or tumor-derived growth factors. A direct correlation also exists between growth factors and cellular proto-oncogenes (Aaronson, 1991, Goustin et al., 1986). In fact, several proto-oncogenes code for proteins that are either growth factors, or growth factor receptors, or proteins that are involved in the intracellular signal transduction pathway for growth factors. In addition, activated cellular proto-oncogenes may also control the endogenous production and/or the response of tumor cells to peptide growth factors. More recently, the involvement of growth factors in sustaining the survival of cancer cells and in promoting tumor-induced angiogenesis has been demonstrated, suggesting that growth factors contribute to tumor progression through different mechanisms.

Different families of growth factors and growth factor receptors have been shown to be involved in the autonomous growth of cancer cells. Among these, the epidermal growth factor receptor (EGFR) and the EGF-family of peptide growth factor have a central role in the pathogenesis and progression of different carcinoma types (Salomon et al., 1995, Normanno et al., 2001). The EGF ligand/receptor system is also involved in early embryonic development and in the renewal of stem cells in normal tissues such as the skin, liver and gut (Salomon et al., 1990, Campbell and Bork, 1993). However, it is important to emphasize that the EGFR belongs to a family of receptors that encompasses three additional proteins, ErbB-2, ErbB-3 and ErbB-4. These proteins and the growth factors of the EGF-family form an integrated system in which a signal that hits an individual receptor type is often transmitted to other receptors of the same family. This mechanism leads to amplification and diversification of the initial signal, a phenomenon that is important for cell transformation, as we will discuss later. Therefore, the role of EGFR signaling cannot be discussed without taking in account the complex interactions existing within the ErbB family of receptors and growth factors. Such interactions might also be important to develop more efficient therapeutic approaches aimed to block EGFR signaling in cancer patients.

Several different review articles have been published on the role of EGFR in the pathogenesis of human carcinoma. In the present article, we will describe the role of EGFR signaling in cancer with a special focus on the cooperation between different ErbB receptors in cancer pathogenesis and progression. Furthermore, we will revise the most recent knowledge on the mechanisms involved in EGFR activation in different types of cancer, and their relevance to novel therapeutic approaches.

Section snippets

The ErbB receptors and their cognate ligands

The ErbB family of receptor tyrosine kinases (RTK) comprises four distinct receptors: the EGFR (also known as ErbB-1/HER1), ErbB-2 (neu, HER2), ErbB-3 (HER3) and ErbB-4 (HER4) (Ferguson et al., 2003, Yarden, 2001). All proteins of this family have an extracellular ligand-binding domain, a single hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase-containing domain (Olayioye et al., 2000). The intracellular tyrosine kinase domain of ErbB receptors is highly conserved although the

Role of ErbB receptors in development

Observations made in knockout animal models have demonstrated the importance of ErbB receptors for the development of different organs (Table 2). Genetically engineered mice with mutations in genes that encode ErbB receptors develop multiorgan failure leading to embryonic or perinatal death. Null mutations for EGFR cause developmental defects in the epithelial structures of the skin, lung, pancreas, gastrointestinal tract and central nervous system (Miettinen et al., 1995, Sibilia and Wagner,

The ErbB receptors and their ligands are transforming genes in vitro and in vivo

Different studies have shown that overexpression of either EGFR or ErbB-2 leads to in vitro transformation of mouse NIH-3T3 cells. Transformation of these cells by EGFR is dependent on exogenous EGF that is required to activate the receptor, whereas ErbB-2-induced transformation is directly related to the levels of expression of the oncogene (Di Fiore et al., 1987a, Di Fiore et al., 1987b). Overexpression of the EGFR ligand TGF-α also transformed Rat-1 and NRK fibroblasts, as assayed by colony

The ErbB receptors and their ligands are frequently expressed in human carcinoma

The role of ErbB receptors and their ligands in the pathogenesis of human carcinomas is confirmed by a number of studies that have shown overexpression of these proteins in the majority of solid neoplasms. Our group has previously published exhaustive reviews on the expression of the ErbB receptors and their cognate ligands in human carcinomas, and this is beyond the purpose of this review article (Salomon et al., 1995, Normanno et al., 2003a, Normanno et al., 2005a). Briefly, expression of

Conclusions

The findings described in this review article strongly support the hypothesis that a network formed by the ErbB receptors and their cognate ligands is involved in tumor pathogenesis and progression. In fact, these proteins function as an integrated system that is able to regulate cellular functions that are important for tumor development, such as growth, differentiation, survival and angiogenesis. The type and the amount of receptors and ligands expressed on tumor cells and within the tumor

Acknowledgments

This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.) (national and regional grants), and from Ministero della Salute (Grant 110/FSN2004) to N. Normanno.

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