e most important transitions in neoplastic progression. Prior to metastasis, most neoplasms can be cured surgically, and 5-year survival rates are often above 90%. However, once a neoplasm has spread to distant sites, some form of systemic therapy is necessary, and 5year survival rates often fall below 15%. Understanding and preventing metastasis would have a dramatic impact on the management and burden of the disease. Bernards and Weinberg focused attention on a paradox in our understanding of the evolution of metastasis. Within a neoplasm, cells compete for space and resources. genetic instability generates new mutant clones, and those with a survival or reproductive advantage tend to spread within the neoplasm. If a cell acquires a mutation that 910232-84-7 web increases the chances that its offspring will emigrate from the neoplasm, that clone should be at a disadvantage within the primary neoplasm, because some of its reproductive potential is lost to emigration. Clones that do not emigrate will have a net growth advantage over the emigrating clone, which should be quickly driven extinct. However, evidence suggests 15963531 that 10607 cells emigrate from a neoplasm every day yet rarely establish a growing metastasis in a new location in the body. Thus the evolution of cell emigration from the primary neoplasm does not seem to be a rate limiting step in metastasis. How could a metastatic clone ever grow large enough to produce the millions of emigrating cells necessary to overcome the low probability of establishing a metastasis Four possible, non-mutually exclusive, solutions for the puzzle of metastasis have been proposed previously. First, a mutation that provides the potential to metastasize might have other effects that increases the survival or reproductive potential of the clone and so compensates for the fitness penalty of cell emigration. In a theoretical exploration of the first solution, Dingli and colleagues suggested a second solution: there may be so many cells in a neoplasm that millions of de novo metastatic April 2011 | Volume 6 | Issue 4 | e17933 Evolution of Cell Migration in Neoplasms mutants may be produced every cell generation. Even if each metastatic clone is at a competitive disadvantage and tends to go extinct, new metastatic clones may continually replace them. Third, the potential to metastasize might only be triggered late in progression, by a change in the tumor microenvironment, allowing the clone to expand, without the fitness penalty of emigration, before the change in the microenvironment. Fourth, an early mutation might confer the potential to metastasize, but that potential may only be activated by a later mutation. However, this is not actually a solution because the later mutation leads to a fitness disadvantage for the metastatic clone and that clone with both mutations should not expand, which mirrors the original framing of the problem. Recently, we identified a fifth alternative based on dispersal theory in ecology, the ��resource heterogeneity��solution. Dispersal theory predicts that resource heterogeneity in both space and time selects for migration in organisms because organisms that move to locate regions with more resources than their current location will leave more offspring than sedentary organisms. We 10188977 apply dispersal theory to cancer to solve the paradox of the evolution of metastasis. There is microenvironmental variability in neoplasms – regions within a neoplasm can become transiently hypoxic due to poorle most important transitions in neoplastic progression. Prior to metastasis, most neoplasms can be cured surgically, and 5-year survival rates are often above 90%. However, once a neoplasm has spread to distant sites, some form of systemic therapy is necessary, and 
5year survival rates often fall below 15%. Understanding and preventing metastasis would have a dramatic impact on the management and burden of the disease. Bernards and Weinberg focused attention on a paradox in our understanding of the evolution of metastasis. Within a neoplasm, cells compete for space and resources. genetic instability generates new mutant clones, and those with a survival or reproductive advantage tend to spread within the neoplasm. If a cell acquires a mutation that increases the chances that its offspring will emigrate from the neoplasm, that clone should be at a disadvantage within the primary neoplasm, because some of its reproductive potential is lost to emigration. Clones that do not emigrate will have a net growth advantage over the emigrating clone, which should be quickly driven extinct. However, evidence suggests that 10607 cells emigrate from a neoplasm every day yet rarely establish a growing metastasis in a new location in the body. Thus the evolution of cell emigration from the primary neoplasm does not seem to be a rate limiting step in metastasis. How could a metastatic clone ever grow large enough to produce the millions of emigrating cells necessary to overcome the low probability of establishing a metastasis Four possible, non-mutually exclusive, solutions for the puzzle of metastasis have been proposed previously. First, a mutation that provides the potential to 10555746 metastasize might have other effects that increases the survival or reproductive potential of the clone and so compensates for the fitness penalty of cell emigration. In a theoretical exploration of the first solution, Dingli and colleagues suggested a second solution: there may be so many cells in a neoplasm that millions of de novo metastatic April 2011 | Volume 6 | Issue 4 | e17933 Evolution of Cell Migration in Neoplasms mutants may be produced every cell generation. Even if each metastatic clone is at a competitive disadvantage and tends to go extinct, new metastatic clones may continually replace them. Third, the potential to metastasize might only be triggered late in progression, by a change in the tumor microenvironment, allowing the clone to expand, without the fitness penalty of emigration, before the change in the microenvironment. Fourth, an early mutation might confer the potential to metastasize, but that potential may only be activated by a later mutation. However, this is not actually a solution because the later mutation leads to a fitness disadvantage for the metastatic clone and that clone with both mutations should not expand, which mirrors the original framing of the problem. Recently, we identified a fifth alternative based on dispersal theory in ecology, the ��resource heterogeneity��solution. Dispersal theory predicts that resource heterogeneity in both space and time selects for migration in organisms because organisms that move to locate regions with more resources than their current location will leave more offspring than sedentary organisms. We apply dispersal theory to cancer to solve the paradox of the evolution of metastasis. There is microenvironmental variability in neoplasms – regions within a neoplasm can become transiently hypoxic due to poorl
