The perturbation and conscription of normal cellular signaling processes is one of the defining features in the development of cancer (Hanahan and Weinberg, 2011). A major challenge in the development of therapeutics against signaling networks is the ability to target these perturbations without interfering with the ability of normal cells and tissues to receive and respond to extracellular signals. The ability to respond to extracellular signals is essential to our ability to respond to our physical or chemical environment, and to initiate the necessary modifications of cell metabolism, morphology, movement, and proliferation. These responses are brought about by elaborate networks of intracellular signals transmitted by changes in protein phosphorylation and enzymatic activity, localization, and the formation of protein-protein complexes. In turn, cellular responses are triggered by the recognition of extracellular signals at the cell surface, resulting in the activation of cytoplasmic enzymes that trigger biochemical cascades in the cytoplasm and nucleus. These signal transduction networks are critical to numerous cellular processes that range from the generalized control of cell proliferation and survival, to specialized functions such as the immune response and angiogenesis. This chapter will focus on how the dysregulation of networks involved in normal growth, adhesion, and development contribute to malignant transformation in human cells, and how these perturbations can be exploited to develop new cancer therapeutics.
6.2 GROWTH FACTOR SIGNALING
6.2.1 Extracellular Growth Factors and Receptor Tyrosine Kinases
Cells communicate with the external environment in myriad ways that include binding of small molecules to the cell surface, antigen stimulation through their interaction with immune cells, or via interactions with other cells and the extracellular matrix. In this chapter, the focus is on secreted polypeptide molecules called growth factors or cytokines, and how their recognition by membrane-bound receptors results in intracellular biochemical signaling responses that control cellular properties including cell proliferation.
There are at least 7 types of growth factor receptors with known roles in cancer development (Fig. 6–1). These receptor “families” are composed of a polypeptide (often monomeric or dimeric) that contains a transmembrane domain and an associated intracellular kinase domain. These receptors can be grouped according to the types of polypeptides that bind to them, and by the architecture of the receptor itself; for example, transmembrane-spanning polypeptides that contain a ligand-binding domain and an intracellular tyrosine kinase domain (eg, epidermal growth factor receptor [EGFR]), or serine/threonine kinase domain (eg, transforming growth factor–β receptor [TGFβRI/II]), tyrosine kinase receptors that are linked to extracellular “alpha-chain” extracellular ligand-binding domains (eg, insulin growth factor receptor 1 [IGF1R]), or tyrosine kinase–associated polypeptides whose extracellular domain contains 3, 5, or up to 7 Ig-like ligand-binding domains, for example, vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor (PDGFRα/β), or fibroblast growth factor receptor (FGFR1-4), respectively (Tiash and Chowdhury, 2015).
The receptor protein tyrosine kinases. Representative molecules from ...