EGFR(s) in aging and carcinogenesis of the gastrointestinal tract

Abstract

Cells of the gastrointestinal (GI) mucosa are subject to a constant process of renewal which, in normal adults, reflects a balance between the rates of cell production and cell loss. Detailed knowledge of these events is, therefore, essential for a better understanding of the normal aging processes as well as many GI diseases, particularly malignancy, that represent disorders of tissue growth. In general, many GI dysfunctions, including malignancy, increase with advancing age, and aging itself is associated with alterations in structural and functional integrity of the GI tract. Although the regulatory mechanisms for age-related increase in the incidence of GI-cancers are yet to be fully delineated, recent evidence suggests a role for epidermal growth family receptors and its family members {referred to as EGFR(s)} in the development and progression of carcinogenesis during aging. The present communication discusses the involvement of EGFR(s) in regulating events of GI cancers during advancing age and summarizes the current available therapeutics targeting these receptors. The current review also describes the effectiveness of ErbB inhibitors as well as combination therapies. Additionally, the involvement of GI stem cells in the development of the age-related rise in GI cancers is emphasized.

Fig. (1)

Schematic representation of architecture and signaling in the small intestinal mucosa. A) In the epithelial lining of the normal intestinal mucosa, stem cells are located at the bottom of crypts and divide asymmetrically to give rise to different lineage of cells. The daughter cells undergoing differentiation migrate upwards to give rise to transit amplifying and terminally differentiated cells. The latter are programmed for cell death and are shed into the lumen. B) Intestinal stem cells give rise to a lineage of differentiated epithelial cells. The proliferation and differentiation of stem cells is tightly regulated by distinct signaling pathways.

Fig. (2)

Schematic representation of ErbB family members showing extracellular ligand binding, transmembrane and cytoplasmic domains. The numbers depict percentage homology of each domain relative to EGFR/ErbB-1. ErbB family has 10 ligands with specific affinity for each receptor. EGFR: Epidermal growth factor receptor; HER: Human Epidermal growth factor Receptor; EGF: Epidermal growth factor; TGF-α: Transformation growth factor α; HB-EGF: heparin binding-EGF; AR: amphiregulin; BTC: betacellulin; EPR: epiregulin; NRG: neuregulin; ErbB-2 has no known ligands and ErbB-3 lacks tyrosine kinase activity due to point mutation.

Fig. (3)

Schematic representation of ErbBs/EGFR(s) signaling pathways. Ligand binding to ectodomain of EGFR(s) leads to dimerization of the receptor and subsequent activation of tyrosine kinase domain. Complexity of ErbB signaling is regulated by ligand specific binding, leading to different combinations of homo/ -hetero dimerization of the receptors. Depending on the type of homo/-hetero dimer formed, a distinct intracellular pathway is activated. These pathways are involved in several processes of cellular homeostasis. PI3K: Phospholinositide-3-Kinase; Akt: phospho kinase B (PKB); JAK: Janus Kinase; STAT: Signal Transducer and Activator of Transcription; ERK: Extracellular Signal Regulated Protein Kinase; MAPK: Mitogen Activated Protein Kinase.

Fig. (4)

Schematic representation of different strategies to inhibit EGFR(s). Inhibition of EGFRs can be achieved by targeting extracellular ligand binding domain and/or intracellular tyrosine kinase domain of the receptor. Among the available strategies, mAbs that target the ligand binding domain and TKIs that target intracellular tyrosine kinase activity have been shown to be more successful. mAbs: monoclonal antibodies; siRNA: small interfering ribonucleic acid.