There were 9,365 new cases of brain cancer (4,650 in med and 4,715 in women) registered in 2010 in the UK, leading to 4,975 deaths 1. The brain cancer with the highest aggressive behaviour is the glioblastoma. Glioblastoma has a rapidly growth, invasiveness and recurrence aspect 2. The Celldex Therapeutics researchers have been developing a new treatment using a vaccine that targets a mutated molecule involved in the activation of signaling pathways that control the cell proliferation, migration and survival. This molecule is called EGFRvIII (epidermal growth factor receptor variant III) and is the most common mutation in EGFR in this condition 2. The RAS-MAPK pathway is related to glioblastoma and is crutial regulated by the IQGAP1 protein 3.
RAS-MAPK pathway transduces the signal from outside of the cell to the nucleus culminating in the expression of the target gene. It involves RAS, RAF (MAPKKK), MEK (MAPKK), ERK (MAPK) proteins which is likely to be activated by the interaction of EGF to its receptor EGFR. However, the activation of this MAP kinase cascade requires a scaffold protein, IQGAP1, which is capable of interacting to form a complex with them. Also IQGAP1 is part of the GTPase family that acts stimulating the GTPase activity of G proteins and switching off its activity by changing GTP to GDP.
EGF receptors are found attached to the cell surface, and they are associated with normal cell growth and oncogenesis. EGFRvIII has the ability to enhance the tumorigenicity behaviour of a cell, stimulating its proliferation and angiogenesis 2. The cell migration process requires a few steps, such as cell proliferation and angiogenesis. The interaction of IQGAP1 with EGFRvIII, vascular endothelial growth factor receptor 2 (VEGFR2), and proteins that regulate the epithelial-mesenchymal transition (EMT) are important for these processes. The scaffold protein is phosphorylated on its tyrosine residue and then bound to VEGFR2, both by the c-Src proto-oncogene adaptor participation 5 in order to make the cell go through these steps. After phosphorylated, IQGAP1 activates b-Raf that will end up with expression of cell proliferation genes.
Metastasis is a multi-step process that a cancer cell needs to follow with the aim of colonizing a different organ from its native. It increases tumor aggressiveness and mortality rate, although glioblastoma does not perfom. The invasiveness process is more complex and demands a series of changes in human body physiology, where in most of them IQGAP1 participates: (i) cell rearrangement and is promoted by Ca2+-calmodulin binding on IQGAP1’s IQ motif in response to the increased Ca2+ levels, which dissociates CDC42 from calmodulin 7, (ii) loss of cell:cell adhesion is accomplished because while IQGAP1 concentration at the membrane is high, the expression of junction proteins was seen to be low 8, (iii) EMT is essential to the cell gain motility and invade the bloodstream. Tumor cells still need the formation of...