Also, cancer cells were injected directly into the vascular system in these models, thus mimicking

only the final steps of metastasis. The clonal selection theory would not seem consistent with the observation that primary tumors are often phenotypically similar to the metastases they give rise to [19], as according to this model, metastases should represent selection of only a subpopulation in the primary tumor. RG7420 molecular weight Other observations, for example from gene expression profiling of primary tumors, also suggest that the clonal selection model may need to be re-evaluated [20]. These studies have defined molecular signatures in primary tumors that successfully predict patient prognosis. The majority of tumor cells in the primary tumor must express the signature for it to be detected, which does not seem to conform with the notion that a small subpopulation of tumor cells develop metastastic properties, as suggested by the clonal selection hypothesis. These data rather indicate that metastatic development is pre-defined by genetic changes acquired during the initial stages of tumor development. Consistently,

transcriptome analysis suggests that primary tumors are rather similar to their matched metastases, and are more similar with each other than with tumors from other individuals [21]. Nevertheless, a number of observations make it difficult to use transcriptome Benzocaine analysis to draw conclusions about the provenance of the tumor cells that seed metastases with confidence, as although transcriptomically similar, primary tumors and their matched metastases also display profound Y-27632 mouse differences in their gene expression profiles [8] and [22]. The different genetic backgrounds of individuals may account for the more extensive differences between individuals than between their metastases and their primary tumors. Moreover, recent studies suggest that primary tumors are composed of clonal areas, which would not be detected by studies that simply take total

tumor material for analysis [23]. Furthermore, the existence of a predictive ‘metastatic signature’ in primary tumors might not be inconsistent with the clonal selection theory, since metastatic tumor cells may self-seed back to the primary tumor and therefore ‘contaminate’ a primary tumor signature with a metastatic signature [24] and [25]. Self-seeding of the primary tumor with metastasis-derived cancer cells might also complicate the interpretation of the established relationship between primary tumor size and metastatic potential [26] and [27]. Variations on the clonal selection model have been proposed that help to resolve some of these issues. The clonal dominance model suggests that metastatically competent cells have a competitive advantage and therefore outgrow other subpopulations in the primary tumor [28].