Matrix metalloproteinase‐9 interplays with the IGFBP2–IGFII complex to promote cell growth and motility in astrocytomas

Abstract Insulin‐like growth factor II (IGFII) acts as a potent mitogen for several tumor types and has been reported to positively influence astrocytoma cell growth and motility. In the central nervous system, IGFII bioavailability is mainly modulated by insulin‐like growth factor binding protein 2 (IGFBP2), which sequestrates IGFII and therefore prevents its interaction with the type‐1 IGF receptor (IGF‐IR). Proteolysis of IGFBP2 is the predominant mechanism recognized to reduce the binding affinity of IGFBP2 for IGFII, thus favoring dissociation of IGFII from the IGFBP2–IGFII complex. It is known that certain proteases involved in astrocytoma malignancy, such as matrix metalloproteinase‐7 (MMP‐7), plasmin, and cathepsin D, are able to proteolyze IGFBP2 in vitro . The present study aims to investigate whether other proteases expressed by astrocytomas, specifically MMP‐2, MMP‐9, and membrane‐type 1 matrix metalloprotease (MT1‐MMP), are able to proteolyze the IGFBP2–IGFII complex. Our results show the following: (i) MMP‐9 proteolyzes the IGFBP2–IGFII complex in vitro , while MMP‐2 and MT1‐MMP do not; (ii) this MMP‐9‐induced IGFBP2–IGFII complex proteolysis releases free IGFII, which contributes to enhance the motility and the growth of LN229 astrocytoma cells. Furthermore, this study also highlights that the formation of the IGFBP2–IGFII complex inhibits IGFBP2's cell motility promoting effect by reducing the pool of free IGFBP2. In conclusion, MMP‐9‐induced IGFBP2 proteolysis may be regarded as an important post‐translational event involved in astrocytoma aggressiveness. These new findings support drug targeting of MMP‐9 as an interesting approach in the treatment of astrocytoma. © 2008 Wiley‐Liss, Inc.