Solving the Puzzle of Metastasis: The Evolution of Cell Migration in Neoplasms

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.

Life history trade-offs in cancer evolution

“…Organisms that evolve under fast life history selection tend to reproduce early and rapidly, overexploit their local environment, migrate (to escape competition, depleted local environments and to find new regions where they can proliferate 19, 20 ), invest little in their own somatic maintenance, competitive capacity or their offspring, and die young 21 . There are exceptions to the general pattern of the tradeoff between survival and reproduction, but this is typically because of tradeoffs with other traits or other constraints (e.g., body size 22 , dispersal constraints 23 , age-dependent predation/mortality 24 , age dependent competition 25 etc.…”

“…Blood flow and nutrients in tumors change over seconds to hours 38, 39 . These temporal variations in resources should select for cells that proliferate quickly, over-exploit their environments and have higher rates of dispersal 19, 20 . The coexistence of both stable and fluctuating microenvironments should both select for and permit the coexistence of both fast and slow life history phenotypes within the same tumor 36 .…”

Simulation-based optimization of radiotherapy: Agent-based modeling and reinforcement learning

“…Our simulation model also considers the tumor in early vascular stage when it has less than 2 mm diameter. We model angiogenesis process and also oxygen diffusion based on Chen et al [7] methodology. In radiotherapy part, O'neil considers conformal radiotherapy, which irradiates tumor by circular domain surrounding tumor.…”

Can oncology recapitulate paleontology? Lessons from species extinctions

“…Furthermore, normalizing resource delivery across a tumour should reduce genetic diversity in the tumour and decrease the selective pressures that drive the evolution of cell migration and metastasis. 98, 99 …”