ReviewEpidermal growth factor receptor (EGFR) signaling in cancer
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.
References (179)
Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo
J. Biol. Chem.
(2003)EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations
Mod. Pathol.
(2005)- et al.
c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function
J. Biol. Chem.
(1999) - et al.
Epidermal growth factor-like modules
Curr. Opin. Struct. Biol.
(1993) ErbB-4: mechanism of action and biology
Exp. Cell. Res.
(2003)- et al.
The role of individual SH2 domains in mediating association of phospholipase C-gamma1 with the activated EGF receptor
J. Biol. Chem.
(1999) - et al.
The deaf and the dumb: the biology of ErbB-2 and ErbB-3
Exp. Cell. Res.
(2003) - et al.
HER4-mediated biological and biochemical properties in NIH 3T3 cells, Evidence for HER1-HER4 heterodimers
J. Biol. Chem.
(1996) - et al.
Induction of c-fos and c-myc proto-oncogene expression by epidermal growth factor and transforming growth factor alpha is calcium-independent
J. Biol. Chem.
(1989) Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells
Cell
(1987)
EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization
Mol. Cell
Intracellular trafficking of epidermal growth factor family ligands is directly influenced by the pH sensitivity of the receptor/ligand interaction
J. Biol. Chem.
Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha
Cell
The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors
Mol. Cell
Behavioral characteristics of a nervous system-specific erbB4 knock-out mouse
Behav. Brain Res.
Activated neu induces rapid tumor progression
J. Biol. Chem.
TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas
Cell
Epidermal growth factor receptor: mechanisms of activation and signalling
Exp. Cell. Res.
Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts
Cell
Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery
Eur. J. Cancer
Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1
Mol. Cell
TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice
Cell
Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation
Cell
Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice
Cell
Growth factors and cancer
Science
Lack of expression of EGF and TGF-alpha in the fetal mouse alters formation of prostatic epithelial buds and influences the response to TCDD
Toxicol. Sci.
Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma
Br. J. Cancer
Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas
Oncogene
ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells
Clin. Cancer Res.
A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway
EMBO J.
Epidermal growth factor-induced nuclear factor kappa B activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells
Proc. Natl. Acad. Sci. U. S. A.
A null mutation in TGF-alpha leads to a reduction in midbrain dopaminergic neurons in the substantia nigra
Nat. Neurosci.
Severe follicular hyperplasia and spontaneous papilloma formation in transgenic mice expressing the neu oncogene under the control of the bovine keratin 5 promoter
Mol. Carcinog.
Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival
Clin. Cancer Res.
Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation
Oncogene
Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (‘Iressa') is independent of EGFR expression level
J. Cell. Physiol.
Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer
J. Natl. Cancer Inst.
EGF receptor transactivation mediated by the proteolytic production of EGF-like agonists
Sci. STKE 2000
Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases
Nature
Ligands for ErbB-family receptors encoded by a neuregulin-like gene
Nature
Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth
Cancer Res.
Structure of the extracellular region of HER3 reveals an interdomain tether
Science
Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab
Nature
Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer
Clin. Cancer Res.
Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder
Clin. Cancer Res.
NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer
Cancer Res.
Transforming growth factor-alpha expression is enhanced in human mammary epithelial cells transformed by an activated c-Ha-ras protooncogene but not by the c-neu protooncogene, and overexpression of the transforming growth factor-alpha complementary DNA leads to transformation
Cell. Growth Differ.
Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells
EMBO Rep.
Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer
Clin. Cancer Res.
Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype
J. Clin. Invest.
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