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A recent review paper on metastatic spread brings to the fore one of the most important questions that needs to be addressed in the creation of a physics of cancer. The basic issue is, why do the cells in the primary tumor develop the genetic and epigenetic properties that enable them to migrate through the body and establish successful (from the tumor’s perspective) metastatic outposts. It is hard to believe that these properties are selected for by direct evolutionary pressure, as the probability of success is extremely small and cells acting independently would have a huge advantage if they just stayed put. An answer to this puzzle could inform treatments that deter metastatic spread, which after all is the cause of death in a vast majority of cases.
Before proceeding to possible resolutions, it is important to point out that metastatic growth seems to be difficult even for cells that have already done it once. One can take cells from a metastasis and implant them into fresh tissue (in a mouse model, of course) and determine the rate of successful colonization. One can then repeat the process several times to enrich for growth potential. It seems that even these cells can form secondary tumors with low probability (perhaps 1%). So, whatever the final bottleneck is in metastatic inefficiency, it does not appear that one can totally eliminate it by direct selection.
The simplest proposition to explain these observations would be to combine random genetic variation with the need for a minimum size of nucleation for tumors. The idea here is that as the primary tumor becomes more and more genetically unstable, clones emerge that are motile and that have a much reduced nucleation barrier. Exactly how long this would take to occur is impossible to estimate
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