Research Article: Combined Anti-Angiogenic Therapy Targeting PDGF and VEGF Receptors Lowers the Interstitial Fluid Pressure in a Murine Experimental Carcinoma

Date Published: December 4, 2009

Publisher: Public Library of Science

Author(s): Agnieszka Kłosowska-Wardęga, Yoko Hasumi, Mikhail Burmakin, Aive Åhgren, Linda Stuhr, Ingrid Moen, Rolf K. Reed, Kristofer Rubin, Carina Hellberg, Carl-Henrik Heldin, Yihai Cao.

Abstract: Elevation of the interstitial fluid pressure (IFP) of carcinoma is an obstacle in treatment of tumors by chemotherapy and correlates with poor drug uptake. Previous studies have shown that treatment with inhibitors of platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) signaling lowers the IFP of tumors and improve chemotherapy. In this study, we investigated whether the combination of PDGFR and VEGFR inhibitors could further reduce the IFP of KAT-4 human carcinoma tumors. The tumor IFP was measured using the wick-in-needle technique. The combination of STI571 and PTK/ZK gave an additive effect on the lowering of the IFP of KAT-4 tumors, but the timing of the treatment was crucial. The lowering of IFP following combination therapy was accompanied by vascular remodeling and decreased vascular leakiness. The effects of the inhibitors on the therapeutic efficiency of Taxol were investigated. Whereas the anti-PDGF and anti-VEGF treatment did not significantly inhibit tumor growth, the inhibitors enhanced the effect of chemotherapy. Despite having an additive effect in decreasing tumor IFP, the combination therapy did not further enhance the effect of chemotherapy. Simultaneous targeting of VEGFR and PDGFR kinase activity may be a useful strategy to decrease tumor IFP, but the timing of the inhibitors should be carefully determined.

Partial Text: The development of tissue stroma is controlled by several growth factors and cytokines. Platelet-derived growth factor (PDGF) is particularly important for proliferation and chemotaxis of connective tissue cells (reviewed in [1]). PDGF is a family of homo- and hetero-dimeric molecules of structurally related A-, B-, C- and D-polypeptide chains, which exert their cellular effects by binding to α- and β-tyrosine kinase receptors. Vascular endothelial growth factor (VEGF) is the prototype of a five-membered family which control angiogenesis and lymphangiogenesis; the VEGF isoforms also act via tyrosine kinase receptors, i.e. the VEGF receptor 1, 2 and 3 [2].

Previous studies have shown that anti-PDGF treatment lowers the IFP of tumors [6] and improves the effect of chemotherapy [11]. Since both STI571 and the more specific PDGF aptamers exerted similar effects in KAT-4 tumors on regulation of IFP and Taxol treatment efficiency [11], the observed effects of STI571 are likely to be mediated by inhibition of PDGFR. The effect is presumably mediated by a relaxation of connective tissue cells, which participate in the control of tissue IFP by integrin-mediated contacts with extracellular matrix fibers [8]. It is also possible that anti-PDGF treatment results in a rebuilding of the extracellular matrix of the stroma into a less dense structure allowing a reduction of IFP [15]. However, STI571 inhibits also other kinases such as the stem cell factor receptor, Abl, Arg [16] and DDR1 [17]; therefore, although unlikely, one cannot exclude the possibility that inhibition of these pathways contributed to the lowering of the IFP. In addition, anti-VEGF treatment has also been shown to lower tumor IFP [5], [9], [10]. Since VEGF has a well-characterized vascular permeability effect, it is likely that anti-VEGF lowers tumor IFP by lowering vessel leakiness and thereby lowering the colloid osmotic pressure of the interstitium of tumors.



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