Molecular Origins of the Metastatic Phenotype

The biologic process by which a primary tumor escapes the vicinity of its original environment and colonizes remote destinations is complex, involving a cascade of pathophysiologic events. Such events, it has been suggested, occur through a sequence of stochastic genetic alterations12 fostered by an inherent genetic instability.13-15 These mutations are perpetuated by a mechanism of evolutionary selection, which confers a survival advantage on the metastasizing cell.16-18 In contrast to the idea of random molecular occurrences spawning the metastatic phenotype, some investigators have proposed that metastasis derives from activation of preexisting genetic scripts, for example, RAS- and/or MYC-mediated mechanisms,19,20 that promote metastasis. Alternately, cells may acquire the ability to metastasize via the silencing of metasta-tic suppressor genes.21,22 The first metastatic suppressor was identified as the "non-metastatic clone 23" (NM23) gene,23 whose suppressive effects are believed to be mediated via influences upon ERK-MAPK signaling.24 Subsequently, additional metastatic suppressor genes have been characterized, including, among others, KAI-1,25 KISS-1,26 tissue inhibitors of metalloproteinases (TIMPs),27 MKK4,28'29 BRMS1,30 SSeCKs,31 RhoGD12,32 and Drg-1.33 This collection of metastasis suppressor genes are unified mechanistically insofar as they inhibit the spread of primary tumors via modulation of cellular growth and adhesion properties and cytoskeletal architecture.29 Whether the metastatic phe-notype ultimately develops from a series of random mutations, activation of preprogrammed genetic scripts, or inhibition of suppressive mechanisms, further investigations of the molecular origins of this phenotype may yield important insights into the specific targeting and/or control of cancer metastases.

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