Allelic diversity in the host genetic background may be an important determinant in tumor metastatic dissemination

Metastasis, the spread and growth of tumors at secondary sites, is an extremely important clinical event, since the majority of cancer mortality is associated with the metastatic tumors rather than the primary tumor. In spite of the importance of metastasis in the clinical setting, the actual process is extremely inefficient. Millions of tumor cells can be shed into the vasculature daily yet few secondary tumors are formed. To successfully colonize a distant site tumor cells must overcome a series of barriers. Failure to complete any single step in the metastatic cascade abrogates the ability to form a secondary lesion. A variety of theories have been proposed to explain the inefficiency of the metastatic process. The most commonly accepted, the progression theory, posits a series of random mutational occurs within a primary tumor to generate a small subpopulation that acquires full metastatic capability. While significant evidence supports this model, recent discoveries demonstrating the ability to predict metastatic propensity from gene expression profiles in bulk tumor tissue are not consistent with only a small subpopulation of cells in the primary tumor acquiring metastatic ability. A second theory of metastatic inefficiency, the transient compartment theory, is more consistent with the microarray data, but does not completely explain observations like metastasis associated loss-of-heterozygosity events. To reconcile the observed results additional variables need to be added to the model of metastatic inefficiency. One possible variable that might explain the discrepancies is genetic background effects. Studies have demonstrated that the genetic background a tumor arises on can have significant affects on the ability of the tumor to metastasize and on gene expression profiles. Thus the observations could be reconciled by combining the theories, with genetic background influencing both metastatic efficiency and predictive gene expression profiles, upon which subsequently occur metastasis-promoting mutational and epigenetic events. If the genetic background is an important determinant of metastatic efficiency it would have significant implications for the clinical prediction and treatment of metastatic disease, as well as for the design of potential prevention strategies.