L238	Platelet-derived growth factor signalling.
C-H.Heldin
Ludwig Institute for Cancer Research, Uppsala, SE.

Platelet-derived growth factor (PDGF) is a family if isoforms (PDGF-AA, -AB, -BB, -CC and -DD) which stimulate the growth, survival and migration of connective tissue cells and other cells. PDGF isoforms exert their cellular effects via binding to α- and β-tyrosine kinase receptors. They have important functions during the embryonal development and in wound healing. Overactivity of PDGF signaling pathways has been linked to certain types of malignancies, and to other diseases characterized by excessive cell growth, e.g. atherosclerosis and fibrotic conditions. We have investigated the mechanisms involved in regulation of the kinase activity of PDGF receptors. In the absence of ligand stimulation, the kinase of the monomeric receptor is kept inactive through several mechanisms involving interactions with epitopes in the juxtamembrane domain, activation loop, as well as in the C-terminal tail of the receptor. After ligand-induced dimerization, the receptor is activated by autophosphorylation in trans between the receptors in the dimer, accompanied by a conformational change in the cytoplasmic part of the receptor. We have also explored the use of PDGF antagonists in preclinical tumor models. In a mouse model for the rare human tumor dermatofibrosarcoma protuberans (DFSP), which is characterized by the production of large quantities of a collagen-PDGF-BB fusion protein which acts in an autocrine manner, PDGF antagonists cause a decrease in tumor growth by induction of apoptosis. Moreover, PDGF is produced by many cancer cells that do not themselves respond to PDGF; in such cases, PDGF may stimulate normal cells in the tumor in a paracrine manner. Such paracrine PDGF stimulation is involved in the increased interstitial fluid pressure of solid tumors, and for the maturation of newly formed blood vessels. We have observed that PDGF antagonists lower the interstitial fluid pressure in tumors, and affect the pericytes of blood vessels. The aim of these studies is to explore the possible clinical utility of PDGF antagonists.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.