Whereas a role of PLXND1 in vessel patterning during development is well established, the functional consequences view more of PLXND1 expression on tumor cells and vessels are less clear. We recently demonstrated that PLXND1 expression is correlated with tumor invasion and metastasis in a human melanoma progression series. Inhibitors,Modulators,Libraries However, the PLXND1 ligands Semaphorin 3E and 4A inhibit, rather than promote, angiogenesis. Moreover, Semaphorin 3E even exhibits anti tumor and anti meta static properties. Here we show that PLXND1 is expressed at high levels on activated established tumor vasculature in a variety of pri mary and metastatic human malignancies, whereas in non tumor related tissues PLXND1 expression is restricted to a subset of, presumably activated, fibroblasts and mac rophages.

These results are in agreement with our previ ous observations in clinical brain tumors of different origin and a series Inhibitors,Modulators,Libraries of cutaneous melanocytic lesions representing different stages of melanoma progression. So, for subsets of tumor types in which vessel activa tion has occurred, PLXND1 may be a valuable candidate protein for vascular targeting approaches. Indeed, the anti PLXND1 single domain antibody A12 homes to and accumulates in tumor vessels. Successful vascular targeting has also been achieved with agents directed against molecules of which expression is restricted to vessels in early stages of angiogenesis. Exam ples are the L19 single chain antibody, directed against Inhibitors,Modulators,Libraries the ED B fragment of fibronectin which targets vasculature in actively growing tumors, whereas this single chain antibody is unable to detect quiescent endothelium in low grade malignancies.

Targeted radiotherapy with radiolabeled RGD peptides, recognizing integrin v 3 on newly formed endothelial cells, led to reduced growth of xenografts in mouse models of cancer. Further more, chimeric proteins, consisting of antibodies against the tumor vessel marker vascular cell adhesion molecule Inhibitors,Modulators,Libraries 1, fused to soluble Tissue Factor, induced tumor specific blood clotting, tumor necrosis and growth delay in different xenograft models. Due to vessel heterogeneity in tumors it is unlikely that one single marker will behave as a targetable pan tumor endothelial antigen, but appropriate mixtures of different tumor vessel targeting agents, including anti PLXND1 antibodies, may allow specific targeting of the majority of tumor vessels.

For instance, to effectively starve tumors like low grade gliomas, which thrive on quiescent vasculature, targeting agents that rec ognize co opted vessels in infiltrative tumor areas need to be developed. It remains to be seen whether such targets can Inhibitors,Modulators,Libraries be identified and, selleck catalog if so, whether such strategy holds promise for treatment of brain tumors, as it will include some toxicity for interspersed normal brain in infiltrative tumor areas.