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Using a murine xenograft model system, Kuznetsov and colleagues show the existence of systemic interactions between a primary tumor and the growth of distal tumors in both homotypic and heterotypic tissues. Importantly, they show that the characteristics of the primary tumor govern the histologic features of the distal tumor through distinct pathways, thus providing novel opportunities for risk assessment, prognosis, prevention, and intervention. ©2012 AACR.