We tested the hypothesis that circulatory PMN-MDSCs can directly interact with CTCs affecting their biology, thus “priming” CTCs as cluster-mediated, self-perpetrating cycle: the induction of pro-survival signaling pathways in CTCs via PMN-MDSC-generated ROS and the activation of Notch signaling pathway could be reciprocated by CTCs promoting PMN-MDSC pro-tumor functions via the secretion of CTC Nodal protein interacting with PMN-MDSC Nodal receptor Cripto and signaling. Here, CRIPTO is linked to neoplasm.