Seed, soil, and beyond: The basic biology of brain metastasis.

First invoked by Paget, the seed and soil hypothesis suggests that the successful growth of metastatic cells depends on the interactions and properties of cancer cells (seeds) and their potential target organs (soil). In the context of the seed and soil hypothesis this review examines recent advances in the understanding of molecular and cellular features that permit transformed epithelial cells to gain access to the blood stream (intravasation), survive their journey through the blood stream, and ultimately traverse through the microvasculature of target organs (extravsation) to deposit, survive, and grow in a foreign tissue environment. In addition to a review of the clinical and experimental evidence supporting the seed and soil theory to cancer metastasis, additional concepts highlighted include: (i) The role of cancer stem-like cells as putative cells of metastatic origin (the "seeds"); (ii) the mechanism of epithelial to mesenchymal transition (EMT) in driving epithelial cell conthose molecules do no blood stream to avoid anoikis, or anchorage independent cell death; and (iv) the reverse process of EMT, or mesenchymal to epithelial transition (MET), which promotes conversion back to the parent cell morphology and growth of macrometastsis in the target organ. The unique biology of metastases once established in the brain, and in particular the "sanctuary" role that the brain microenvironment plays in promoting metastatic growth and treatment resistance, will also be examined. These issues are of more than academic interest since as systemic therapies gradually improve local tumor control, the relative impact of brain metastasis will inexorably play a proportionally greater role in determining patient morbidity and mortality.