Whereas VEGF-A is predominantly required during the initial steps of angiogenesis (formation of the endothelial plexus) subsequent steps, involving recruitment and vessel coverage by pericytes and smooth muscle cells, appear to be dependent on other soluble factors, e.g., PDGF PDGF-B acts as a pericyte and smooth muscle cell chemoattractant whereas TGF-b has been implicated in vessel stabilization.269,270 Microscopic examination indicates that tumor capillaries possess mural cells; however, unlike normal vessels in which pericytes are well organized and closely associated with the endothelial compartment, tumor pericytes were present at a lower density and appeared more loosely attached.271 Positive immunohistochemical staining for PDGFR-B, originating from associated pericytes, was observed in tumors.194 Experimental manipulation of PDGF levels has demonstrated that release of PDGF from both endothelial and tumor cells can impinge on pericyte recruitment to tumor vessels.272 Activation of the intrinsic PDGF-R kinase domain, as well as the phosphatidylinositol-3-kinase (PI3K) signaling pathway, has been shown to be important in this process. Increased pericyte abundance, observed upon overexpression of PDGF, leads to increased tumor growth but does not increase microvessel density in a murine melanoma model, suggesting that it modulates the efficiency rather than number of vessels.273
Investigation of the clinically proven activity of VEGF-A antagonists suggest that they target immature vessels and that pericyte coverage renders vessels resistant to their actions. The hypothesis that a combination of PDGF and VEGF-A inhibitors would provide therapeutic benefit has been experimentally validated. Administration of SU6668, a joint PDGFR/VEGFR inhibitor, resulted in blocking a tumor growth, while SU5416, a more specific VEGFR inhibitor, was not effective.274
Glivec has been used to demonstrate the functionality of PDGFR expression on endothelial cells. Normally occurring at low levels, PDGFR was observed to be specifically unregulated in hyperproliferative endothelium and endothelial cells found within bone metastasis.275 Enhanced antitumor activity, observed upon combination of Glivec with chemotherapeutic agents, was associated with increased endothelial cell apoptosis, indicating that PDGF signaling may transmit prosurvival signals in these tumors.276,277
In addition to endothelial cells, PDGFR expression has been documented in other tumor-associated stromal cells. Manipulation of PDGF levels enhances stroma recruitment, decreases tumor necrosis, and reduces the latency time to formation of tumors in vivo. One functional consequence of stromal recruitment is the high interstitial fluid pressure that characterizes many tumors. Reduction of this pressure would be therapeutically beneficial as it would increase the penetration and effectiveness of pharmacological agents. A role for PDGF in control of interstitial fluid pressure in normal tissue has been documented, while decreased tumor interstitial fluid pressure, observed upon administration of Glivec, is associated with enhanced uptake and antitumor activity of coadministered chemotherapeutic agents.
Was this article helpful?