ErbB receptors in the biology and pathology of the aerodigestive tract.

The most common sites of malignancies in the aerodigestive tract include the lung, head and neck and the esophagus. Esophageal adenocarcinomas (EA), esophageal squamous cell carcinomas (ESCC), and squamous cell carcinomas of the head and neck (SCCHN) are the primary focus of this review. Traditional treatment for aerodigestive tract cancers includes primary chemoradiotherapy (CRT) or surgical resection followed by radiation (or CRT). Recent developments in treatment have focused increasingly on molecular targeting strategies including cetuximab (a monoclonal antibody against epidermal growth factor receptor (EGFR)). Cetuximab was FDA approved in 2006 for treatment of SCCHN, underscoring the importance of understanding the biology of these malignancies. EGFR is a member of the ErbB family of growth factor receptor tyrosine kinases. The major pathways activated by ErbB receptors include Ras/Raf/MAPK; PI3K/AKT; PLCgamma and STATs, all of which lead to the transcription of target genes that may contribute to aerodigestive tumor progression. This review explores the expression of ErbB receptors in EA, ESCC and SCCHN and the signaling pathways of EGFR in SCCHN.

The role of the EGF family of ligands and receptors in renal development, physiology and pathophysiology.

Mammalian kidney expresses all of the members of the ErbB family of receptors and their respective ligands. Studies support a role for ErbB family receptor activation in kidney development and differentiation. Under physiologic conditions, EGFR activation appears to play an important role in the regulation of renal hemodynamics and electrolyte handling by the kidney, while in different pathophysiologic states, EGFR activation may mediate either beneficial or detrimental effects to the kidney. This article provides an overview of the expression profile of the ErbB family of ligands and receptors in the mammalian kidney and summarizes known physiological and pathophysiological roles of EGFR activation in the organ.

ErbB receptors and the development of the nervous system.

Tyrosine kinase receptors and their ligands allow communication between cells in the developing and adult organism. An extensive line of research has revealed that 'neuregulins', a family of EGF-like factors that signal via ErbB receptors, are used frequently for cell communication during nervous system development, and control a spectacular spectrum of developmental processes. For instance, during development of the peripheral nervous system, Schwann cells require neuronally-produced neuregulin (Nrg1) for growth, migration and myelination, neural crest cells rely on mesenchymally-generated Nrg1 signals for migration, while muscle requires neuronally-produced Nrg1 for the differentiation of a muscle spindle. In the central nervous system, neuregulin signals allow cells to act as guideposts or as barriers for axons during pathfinding. Neuregulin signals are also important in other organs, but the nervous system functions have received recently considerable attention due to the finding that particular haplotypes of Nrg1 and ErbB4 predispose to schizophrenia. Understanding the neuregulin signaling system can thus contribute to define causes of this devastating mental disorder.

Mechanistic aspects of crosstalk between GH and PRL and ErbB receptor family signaling.

Growth hormone (GH) and prolactin (PRL) are anterior pituitary hormones that have multiple roles in growth and metabolism. Both hormones are important in mammary development and breast cancer. The epidermal growth factor (EGF) family of peptides and the receptors that they activate (the ErbB family) are also major players in mammary biology and pathophysiology. Recent studies in signal transduction have highlighted the interplay between signaling pathways referred to as crosstalk. In this review, cell biological and signaling studies related to crosstalk between GH and PRL and the ErbB family are discussed. In particular, the role of GH- and PRL-induced phosphorylation of ErbB receptors in regulating EGF responsiveness is highlighted with attention to potential pathophysiological relevance.

Transgenic models to study actions of prolactin in mammary neoplasia.

Transgenic models to explore the role of prolactin and its interactions with other factors in mammary oncogenesis have begun to reveal the dynamic contributions of prolactin to the development and progression of this disease. Targeting prolactin to mammary epithelial cells mimics the local production of this hormone that is prominent in women, and permits studies in the absence of effects on the ovarian steroid milieu. These models have demonstrated that local production of prolactin is sufficient to induce mammary tumors after a long latency. Prolactin also can potentiate actions of other oncogenic stimuli, decreasing tumor latency and increasing incidence in several models. Augmented proliferation, without alteration of apoptosis, is a consistent feature. Pathways in addition to the well-characterized Jak2-Stat5 pathway, including ERK1/2 and Akt1/2, are implicated in these actions. These studies have also revealed a complex relationship with estrogen; while prolactin increases ERalpha expression, it does not require estrogenic ligand for lesion development, and indeed, in combination with the EGFR ligand, TGFalpha, prolactin can contribute to estrogen insensitivity. These studies highlight the utility of these models to decipher the interplay between prolactin and other oncogenic factors in breast cancer, with implications for preventative and therapeutic strategies.

Biological significance of c-erbB family oncogenes in head and neck cancer.

Squamous cell carcinoma of the head and neck (SCCHN) tends to run an aggressive course and the prognosis has remained virtually unchanged in recent decades. The development of novel therapeutic strategies to improve patient outcome centres on the biology of the disease, namely the pivotal c-erbB family of growth factor receptors. c-erbB1 (or epidermal growth factor receptor, EGFR), is key to the pathogenesis of SCCHN and plays a central role in a complex network of downstream integrated signalling pathways. EGFR overexpression, detected in up to 90% of SCCHN, correlates with an increased risk of locoregional tumour relapse following primary therapy and relative resistance to treatment. The biological sequelae of erbB receptor activation are not simply cell proliferation, but also inhibition of apoptosis, enhanced migration, invasion, angiogenesis and metastasis: the 'hallmarks of cancer' [1]. As EGFR overexpression is associated with a poor clinical outcome in SCCHN, this receptor is attractive as a therapeutic target and the successful development of targeted therapies represents a paradigm shift in the medical approach to head and neck cancer. However, the extensive cross talk between signalling pathways, the multiple molecular aberrations and genetic plasticity in SCCHN all contribute to inherent and acquired resistance to both conventional and novel therapies. Understanding the cancer cell biology, in particular the significance of co-expression of c-erbB (and other) receptors, and the cell survival stimuli from (for example) activation of the phosphoinositide 3-kinase (PI3-kinase) cascade is fundamental to overcome current limitations in biologically targeted therapies.

Developmental profile of ErbB receptors in murine central nervous system: implications for functional interactions.

The ErbB family, ErbB1 (also known as the epidermal growth factor receptor EGFR), ErbB2, ErbB3, and ErbB4 comprise a group of receptor tyrosine kinases that interact with ligands from the epidermal growth factor (EGF) superfamily, subsequently dimerize, catalytically activate each other by cross-phosphorylation, and then stimulate various signaling pathways. To gain a better understanding of in vivo functions of ErbB receptors in the central nervous system, the current study examined their mRNA expression throughout development in the mouse brain via in situ hybridization. EGFR, ErbB2, and ErbB4 exhibited distinct but sometimes overlapping distributions in multiple cell types within germinal zones, cortex, striatum, and hippocampus in prenatal and postnatal development. In addition, a subpopulation of cells positive for ErbB4 mRNA in postnatal cortex and striatum coexpressed mRNA for either EGFR or GAD67, a marker for gamma-aminobutyric acid (GABA)ergic interneurons, suggesting that both ErbB4 and EGFR are coexpressed in GABAergic interneurons. In contrast, ErbB3 mRNA was not detected within the brain during development and only appeared in white matter tracts in adulthood. Together, these findings suggest that ErbB receptors might mediate multiple functions in central nervous system development, some of which may be initiated by EGFR/ErbB4 heterodimers in vivo.

Small molecule inhibitors of the class 1 receptor tyrosine kinase family.

This review covers literature describing research progress in erbB family tyrosine kinase inhibition over the last year. Excellent recent reviews are available, thus we have focussed on current developments of leading small molecule drug candidates as well as their erbB family inhibition profile. The most advanced erbB family tyrosine kinase (TK) inhibitors are demonstrating promising anti-cancer activity in clinical trials and are discussed. Several inhibition strategies are emerging: EGFR TK selective, irreversible TK inhibition and dual EGFR/erbB2 TK inhibitors. While small structural differences are seen in the leading compounds, the variations in their inhibition profiles and compound properties suggest that biological systems judge structural diversity differently. The readers' attention is drawn to common issues of selectivity and potency generally encountered with kinase inhibitors.