Growth Factors in Oncology

Cell proliferation and cell growth are tightly regulated by a fine balance between growth-promoting and growth-inhibiting factors. To sensor extracellular growth stimuli, cells express on their surface transmembrane receptor proteins, which after binding of the ligand molecule transfer the message into the cell. Complex networks of signaling pathways translate the signal into cellular processes as cell proliferation, differentiation or survival. Disturbances in this balance were shown to trigger uncontrolled cell growth and malignancy.
Various aspects of cancer biology are influenced by changes to growth factor/receptor pathways including the epidermal growth factor (EGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF) signaling cascades.

One of the most studied growth signal pathways in oncology involves the epidermal growth factor and its receptor EGFR. EGFR (or ErbB-1) forms together with Her 2/neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4) a family of closely related receptors. The structure of these receptors resembles other growth factor receptor molecules and consists of an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Upon binding of a ligand molecule, the EGFR tyrosine kinase is activated by dimerization of two receptor proteins of the ErbB family.

Heightened activity at the EGF receptor, mostly due to increased receptor number was identified in a wide variety of solid tumors including non-small cell lung cancer, prostate cancer, breast cancer, gastric cancer, bladder cancer, and tumors of the head and neck.
Furthermore, excessive activation of EGFR on the cancer cell surface was found to be associated with advanced disease, the development of a metastatic phenotype or poor prognosis in cancer patients.

Many studies showed that increased EGFR-mediated signalling within a cancer cell can either directly or indirectly promote tumor cell growth, block apoptosis, stimulate angiogenesis and formation of metastasis.

Therefore, interference with heightened EGFR activity is considered a very exciting option in cancer therapy. Different approaches, as blocking of the ligand-binding domain with monoclonal antibodies or blocking the intracellular tyrosine kinase activity with small inhibitory molecules, were successfully developed and recently made their way into the clinic.