Vascular targeting effect of combretastatin A-4 phosphate dominates the inherent angiogenesis inhibitory activity.

The current research aimed to define hypothesis-based anti-angiogenic properties of the vascular targeting agent combretastatin A-4 phosphate (combreAp). The in vitro wound assay indicated that combreAp potently inhibited migration of endothelial cells (EC). A significant inhibition of migration could already be measured after 2 hr of treatment. In a three-dimensional (3D) tube formation assay, combreAp inhibited sprout formation at concentrations that did not inhibit the proliferation of EC. At sub-ng concentrations the half-maximal response was reached. Interestingly, although combreAp is considered a vascular targeting agent, the human tumor cell lines tested were found to be 20–30 times more sensitive for combreAp than the human umbilical vein endothelial cells (HUVEC). A similar response difference between rat EC and R1 rat rhabdomyosarcoma tumor cells was observed. The growth inhibition in EC was only in part mediated by induction of apoptosis. The growth delay results obtained with the in vivo rodent tumor models involving repeat dosing of combreAp can partly be explained by anti-angiogenic activity of the compound. The results obtained with the various in vitro and in vivo assays substantiate an anti-angiogenic profile of combreAp, largely at the level of EC migration. This mechanism may operate to a different extent in different tumor types

Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia

A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis

3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry

Extracellular matrix plays a central role in driving cancer development. Here the authors using an in vitro approach show that confining collagen architectures induce fast and persistent cell migration and the formation of multicellular network structures linked to vascular mimicry observed in tumours from patients