Abstract
BackgroundMetastasis represents one of the most clinically important transitions in neoplastic progression. The evolution of metastasis is a puzzle because a metastatic clone is at a disadvantage in competition for space and resources with non-metastatic clones in the primary tumor. Metastatic clones waste some of their reproductive potential on emigrating cells with little chance of establishing metastases. We suggest that resource heterogeneity within primary tumors selects for cell migration, and that cell emigration is a by-product of that selection.Methods and FindingsWe developed an agent-based model to simulate the evolution of neoplastic cell migration. We simulated the essential dynamics of neoangiogenesis and blood vessel occlusion that lead to resource heterogeneity in neoplasms. We observed the probability and speed of cell migration that evolves with changes in parameters that control the degree of spatial and temporal resource heterogeneity. Across a broad range of realistic parameter values, increasing degrees of spatial and temporal heterogeneity select for the evolution of increased cell migration and emigration.ConclusionsWe showed that variability in resources within a neoplasm (e.g. oxygen and nutrients provided by angiogenesis) is sufficient to select for cells with high motility. These cells are also more likely to emigrate from the tumor, which is the first step in metastasis and the key to the puzzle of metastasis. Thus, we have identified a novel potential solution to the puzzle of metastasis.
Highlights
The evolution of metastasis is one of the most important transitions in neoplastic progression
We showed that variability in resources within a neoplasm is sufficient to select for cells with high motility
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 [4]
Summary
The evolution of metastasis is one of the most important transitions in neoplastic progression. Evidence suggests that 106–107 cells emigrate from a neoplasm every day yet rarely establish a growing metastasis in a new location in the body [6]. 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?. The evolution of metastasis is a puzzle because a metastatic clone is at a disadvantage in competition for space and resources with nonmetastatic clones in the primary tumor. Metastatic clones waste some of their reproductive potential on emigrating cells with little chance of establishing metastases. We suggest that resource heterogeneity within primary tumors selects for cell migration, and that cell emigration is a by-product of that selection
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