The neuro-neoplastic synapse: does it exist?

Since the pioneering work of Judah Folkman and colleagues in the 1970s on tumor neoangiogenesis, we learned more and more about the heterogeneity of the cellular, subcellular and stromal architecture within a tumor mass. The research on neoangiogenesis has lead to novel molecular entities (vascular endothelial growth factor, platelet-derived growth factor, acidic fibroblast growth factor, basic fibroblast growth factor, transforming growth factor-Beta, tumor necrosis factor-alpha, interleukin-8), which can be targeted within the framework of tumor neoangiogenesis inhibition. Accepting the paradigm of anti-angiogenic therapy, a new class of drugs could be developed some of which already obtained clinical approval. As blood vessels and nerves often follow parallel trajectories within a tumor tissue, it was consequent to argue that tumor cells for their growth advantage and survival and metastases formation use common cues that induce vascularization and innervation. Autocrine, paracrine or endocrine interactions between a resident tumor cell type with neurocrine cell types and their signaling molecules can be regarded as a neuro-neoplastic synapse. That cross-talk molecules are equally interesting molecules as selectable anti-tumor targets as it turned out to be in the past for tumor angiogenesis factors. An extended model of human tumor dormancy as well as metastasis formation is provided assuming an angiogenic and neurogenic switch from the non-angiogenic and non-neurogenic phenotype.