Whether it is possible to predict if antiangiogenic treat ment can improve vascular function in a specific tumor is currently unknown. The effect of antiangiogenic treatment on tumor vasculature Nutlin and on tumor oxygenation should thus be monitored closely if antiangiogenic treatment is considered as neoadjuvant therapy. Conclusions Sunitinib treatment reduced vessel density but did not improve vascular function in A 07 GFP and R 18 GFP human melanoma xenografts. The sunitinib treatment increased hypoxic fractions and, consequently, sunitinib used as neoadjuvant therapy may reduce the effect of ionizing radiation or chemotherapy in clinical tumors similar to the A 07 GFP and R 18 GFP human mela noma xenografts.
Background The majority of gastrointestinal stromal tumors harbor gain of function mutations in KIT or PDGFRA, resulting in the activation of the down stream pathways PI3K AKT, Ras MAPK, and JAK STAT3, and playing a crucial role in tumorigenesis. A subset of GIST lack specific KIT or PDGFRA mutations and form a heterogeneous group, including NF1, Carney Triad, Carney Stratakis Syndrome, pediatric and young adult GIST, and a small proportion of sporadic adult GIST. The mechanisms involved in the tumorigenesis of GIST lacking KIT or PDGFRA mutations are still poorly understood. A subgroup of these GISTs forms a unique clinicopathological entity, defined by nega tive staining for SDHB in addition to exhibiting dis tinct morphologic and clinical features. Indeed, such SDH deficient GISTs account for 5 7. 5% of all gastric GISTs in unselected populations and include the great majority of pediatric GISTs.
They are characterized by defects in cellular respiration and ac tivation of pseudohypoxia signalling pathways. The succinate dehydrogenase protein complex II catalyzes the oxidation of succinate. SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD. Loss of SDHB expression results in inhib ition of the degradation of Hypoxia Inducing Factors, which in turn impairs apoptosis, and induces angiogenesis and glycolysis. Loss of SDHB ex pression was first identified in GIST occurring in the context of Carney triad and in a subset of pediatric and adult GISTs with similar characteristics. Loss of SDHB is also seen in WT GIST occuring in the context of CSS with genlius mutation of SDHB or SDHC.
However, such mutations were also found in about 10% of sporadic GIST lacking KIT or PDGFRA mutation. The mechanisms involved in loss of SDHB expression in SDH deficient GIST with out an associated SDHB or SDHC mutations remain unclear. One possible explanation is loss of function mutations in the SDHA gene, which have been re cently identified in four patients with sporadic GIST lacking KIT or PDGFRA mutations.