Immunohistochemical analysis showed that hepatic metastases

in DDR2−/− mice had higher density of HSC-derived myofibroblasts (dual desmin/alpha-smooth muscle actin-expressing cells), neoangiogenic vessels (CD31-expressing cells) and proliferating cells (ki67-expressing) than in DDR2+/+ littermates. Consistent with in vivo findings, selleck kinase inhibitor secretion of endothelial cell adhesion- and migration-stimulating factors, and of MCA38 cell proliferation-stimulating factors significantly increased by 50% in the supernatants of DDR2−/− HSC primary cultures, compared to those from wild-type HSC. These secreted factors further increased by 20% in the supernatants of DDR2−/− HSC cultures pretreated with MCA38 cell-conditioned media. Moreover, compared to wild-type HSC, gene profiling of DDR2−/− HSC showed increased expression of a cluster of genes, associated with inflammation and extracellular matrix remodeling, that have been clinically correlated with hepatic metastasis occurrence, such as IL-10, TGFbeta, syndecan-1, integrin-a2, thrombopoietin and BMP7. These results demonstrate that DDR-2 deficiency predisposes hepatic tissue to colon Target Selective Inhibitor Library carcinoma metastasis. The mechanism may depend on a special prometastatic microenvironment operating in the absence

of certain DDR2-dependent factors that prevent tumor cell adhesion and proliferation, and endothelial cell migration. Poster No. 220 Time-Dependent Effects these of Aflibercept (VEGF Trap) on Functional Vessels, Tumor Hypoxia, and Distribution of Doxorubicin in Tumor Xenografts Vithika Sivabalasundaram 1 , Krupa Patel1, Ian F. Tannock1 1 Division of Applied Molecular Oncology, Princess Margaret Hospital, Toronto, ON, Canada Background: Clinical experience has shown limited benefits when anti-angiogenic agents that target VEGF are used alone, but greater effects when combined with chemo-therapy. Transient vascular normalization has been proposed to explain this unexpected combination effect (Jain, Science 2005;307:58–62),

which involves reduced vascular permeability, destruction of immature vessels and increased pericyte recruitment at specific times following anti-VEGF therapy. The resulting improvement of tumor blood flow and oxygenation, and reduction in interstitial fluid pressure, might improve chemotherapy delivery. Evidence to support vessel normalization remains inconsistent. Here we evaluate the effect of aflibercept, a potent soluble receptor for VEGF (undergoing clinical trials), for its effect on vascular physiology and delivery of doxorubicin to solid tumors. Hypothesis: During a certain window of time, aflibercept will increase functional blood vessels, decrease hypoxia, and improve delivery and therapeutic effects of doxorubicin.