Novel mechanisms of endothelial-epithelial interactions underlying cancer metastasis

Abstract

Elucidation of molecular mechanisms underlying metastasis is the final frontier in cancer biology research. Identifying individual pathways in the metastatic cascade could lead to development of metastasis-specific therapeutics; however, current in vivo metastasis model systems are not efficient tools for isolating a single molecular event from the network of complex biological pathways. In response to these needs, we have developed a 3D in vitro co-culture system that isolates molecular and physical interactions between metastatic cells and the endothelium, which are prerequisite for invasive spread. We have used this model to identify key mediators of epithelial-endothelial cell interactions, to screen metastasis specific therapeutics, and most significantly, to elucidate a novel form of intercellular communication through thin cytoskeletal projections called nanoChannels (nCs) that is involved in pathological angiogenesis and that may prime metastatic spread. Metastatic cells preferentially form nCs with the endothelium, enabling rapid and directed transfer of intracellular contents. Proteins, small cytoplasmic dyes, nanoparticles, and most interestingly, functional microRNAs (miRNAs) are transported through these structures. Communication of miRNAs through nCs presents a novel mechanism of pathological angiogenesis and the angiogenic switch. NanoChannel-mediated communication introduces a new paradigm of cancer progression in which tumor cells can directly transform surrounding cell populations in order to facilitate cancer pathogenesis.