Research

Growth factors, along with adhesion and other molecules, play critical roles in invasive cell growth taking place in the developing embryo. Invasive growth rarely occurs in adulthood, but malignancy often harnesses growth factors, or their downstream signaling pathways, to enhance tumor aggressiveness and metastasis.

The keys for understanding growth factor action in cancer are their surface receptors: a group of transmembrane glycoproteins whose cytoplasmic tyrosine kinase function is stimulated upon growth factor binding to the extracellular receptor’s part, and induction of dimer formation. An example is provided by the ErbB family of receptor tyrosine kinases (RTKs), which bind a large family of growth factors sharing an epidermal growth factor- (EGF-) like domain.

These receptors instigate a variety of intracellular pathways, which are schematically presented in Figure 1¹. The generic pathway entails a cascade of cytoplasmic proteins culminating in transcriptional regulation. Self-production of specific growth factors, expression of mutant forms of ErbB-1/EGFR or overexpression of either ErbB-1 or ErbB-2/HER2 characterizes a large variety of tumors of epithelial and glial origin. Moreover, two classes of pharmacological drugs, namely: monoclonal anti-receptor antibodies and low molecular weight tyrosine kinase inhibitors, effectively intercept growth factor signaling in clinical settings².

ErbB-2/HER2 is one of the most potent oncoproteins, but unlike other family members it binds no soluble growth factor. Likewise, ErbB-3 binds several growth factors, but unlike its family members the intrinsic kinase domain of ErbB-3 is catalytically inactive. For these and other reasons, signaling by ErbB and other RTK families is best described in terms of highly interconnected, layered signaling networks. The fail-safe (robust) ability of the ErbB network to decode and integrate extracellular signals is attributed to its modular structure, as well as to a dense array of feedback regulatory loops, collectively establishing system control as exemplified in Figure 2³.

Our research within the realm of system control within the ErbB family has established over the past few years several general groups of regulatory mechanisms, along with a few examples, which are described below with an emphasis on their collapse in human cancer.

Figure 1 – The epidermal growth factor receptor (EGFR/ErbB) pathway plays pivotal roles in cell-cell communication in both vertebrate and invertebrates. The four EGFR orthologs in vertebrates form a layered signaling network that participates in specification of cell fate and coordinates cell proliferation. Mutations in components of the pathway are commonly involved in human cancer.

Figure 2 – A systems perspective of the ERBB network. A reductionist view of the bow-tie-architectured signaling network is represented. The heart of the system is a core process, a collection of biochemical interactions, which are tightly coupled to each other and interface with two sets of components: three input modules, each comprising an ERBB receptor tyrosine kinase; and a large group of partly redundant ligand growth factors. The output of the core process is translated to gene expression through multiple transcription factors. Depending on the exact combination of transcription factors and the cellular context, the output of the network regulates cell behaviour. The system maintains two steady states (bistability), for which inter-conversions depend on ligand binding. The fail-safe (robustness) action of the system is conferred by structural modularity and functional redundancy, along with rich and stringent system controls.