The evolving paradigm of tissue-specific metastasis

Previous dogma suggested a genetic basis for breast cancer metastasis as an extension of the stepwise transformation model, whereby the accumulation of genetic mutations confers selective survival and proliferative advantages to reach a malignant state of growth. Indeed, it was thought that several additional genetic alterations after initial transformation were required to confer metastatic ability [2]. Recent evidence has challenged this notion by suggesting that the genetic events necessary for primary tumor growth may also mediate metastatic behavior [3]. However, it is difficult to reconcile how the same genetic alterations could confer growth both in the breast microenvironment and in other tissue microenvironments.Recent work has begun to shed some light on the molecular mechanisms that mediate tissue-specific metastasis and reconcile this conceptual conflict. However, whether the genes identified in these studies will elucidate the genetic and, hopefully, predicative underlying mechanism for metastasis, or rather represents an artifact of the model systems employed for gene candidate discovery remains uncertain.The widely accepted hypothesis first reported by Paget suggests that breast cancer cells must express and utilize specific migratory and adhesion molecules that cross-react with those expressed in distant tissues in order to intravasate, survive, and proliferate in that microenvironment. However, when combined with the accepted mutation hypothesis, it is difficult to conceive how breast cancer cells could be selected during the process of primary tumor growth in the breast stromal microenvironment also to express factors specific for other tissue microenvironments.There is an alternative explanation, which has received less attention owing to the difficulty of studying the process. It suggests that once cells extravasate out of the primary tissue they genetically/epigenetically express migratory and adhesion molecules as a consequence of genetic insta