Date Published: January 29, 2008
Publisher: Public Library of Science
Author(s): Rakesh K Jain, Johanna Lahdenranta, Dai Fukumura
Abstract: The authors discuss a new study of a paracrine regulatory circuit centered on PDGF receptor signaling in cancer-associated fibroblasts and pericytes of a mouse model of cervical carcinoma.
Partial Text: Cervical cancer is one of the most prevalent malignancies in women worldwide and is the leading cause of cancer death for women in developing countries . While early detection via the Pap test as well as treatment by surgery and chemoradiotherapy has reduced mortality from this disease, the prognosis is poor if the disease is detected at an advanced stage . Thus new treatment strategies for cervical cancer are needed.
The present study builds on previous work by this group and others where targeting PDGF signaling has been based primarily on the presence of PDGF receptors on the pericytes and endothelial cells of tumors. Targeting PDGF receptors on tumor pericytes can destabilize tumor blood vessels, making them more vulnerable to anti-vascular endothelial growth factor (VEGF) therapies . Targeting PDGF receptors on the tumor’s endothelial cells can have direct anti-vascular effects . In the new study, Pietras and colleagues offer evidence that targeting PDGF signaling in the carcinoma-associated fibroblasts plays a central role in the tumor response to PDGF receptor (PDGFR) blockade.
Originally developed as a bcr-abl kinase inhibitor, imatinib has served as a poster child for targeted therapy. Based on its dramatic effects on chronic myelogenous leukemia (CML), it was approved in 2001 by the FDA for CML and hailed as a “magic bullet” . Later it was shown to be effective against gastrointestinal stromal tumors because of its activity against c-kit and PDGFRa expressed in cancer cells in this disease . However, as a single agent, imatinib has not yet proven efficacious in PDGFR-expressing common solid tumors in any phase II clinical trials. Furthermore, although a small fraction of patients with glioblastoma multiforme (GBM) responded to imatinib, there was no correlation between patient survival and the tumor cell expression of the molecular targets of imatinib . PDGFRs are also expressed on the vascular endothelium of glioblastomas . Thus it is possible that imatinib might have led to a direct anti-vascular effect on these vessels in GBMs in addition to the indirect effect through FGF2 downregulation demonstrated in Pietras and colleagues’ study.