The metastatic process. The initial steps of metastasis require proliferation of the primary tumor and invasion through adjacent tissues and basement membranes. This process continues until the tumor invades blood vessels or lymphatic channels, when individual tumor cells detach from the primary tumor mass and are carried via the blood or lymph to a distant target organ. Subsequently, tumor cells arrest in small vessels within the distant organ, extravasate into the surrounding tissue and proliferate at the secondary site. All of these steps must be performed while tumor cells avoid and survive apoptotic signals and host immune responses.

A number of models have been proposed to explain the biological complexities of metastasis. (a) Progression model. A primary neoplasm gains a progressively more metastatic phenotype through a stochastic accumulation of somatic mutations. (b) Transient compartment model. All viable cells in a tumor acquire metastatic capacity, but due to positional and/or random epigenetic events only a small fraction are capable of completing the process at a given moment in time. (c) Fusion model. To gain a fully metastatic phenotype, a tumor cell must acquire certain characteristics of lymphoid cells (for example, proteolytic degradation, the ability to intra- and extravasate). This phenotype is achieved by nuclear transduction with cells of myeloid origin. (d) Gene transfer model. A characteristic of malignancy is the presence of tumor DNA in the bloodstream. This DNA, carrying the somatic mutations associated with neoplasia, is carried to the secondary site. Subsequently, the tumor DNA is absorbed by stem cells at the distant organ, which endow the stem cell with malignant properties. (e) Early oncogenesis model. The metastatic potential of any primary tumor is set early in its evolution, presumably as a consequence of somatic mutation. This is why it is possible to accurately predict prognosis from bulk tumor tissue using microarray gene expression signatures. (f) Genetic predisposition model. The metastatic potential of any primary tumor is altered by the genetic background upon which it arises. That is, an individual will be more or less susceptible to tumor dissemination as a consequence of constitutional polymorphism. Such germline variations influence all aspects of the metastatic cascade, including the expression of pro-metastatic gene expression signatures within the primary tumor.