title: Modeling boundary conditions for balanced proliferation in metastatic latency.
abstract: OBJECTIVE
  Nearly half of cancer metastases become clinically evident five or more years after primary tumor treatment; thus, metastatic cells survived without emerging for extended periods. This dormancy has been explained by at least two countervailing scenarios: cellular quiescence and balanced proliferation; these entail dichotomous mechanistic etiologies. To examine the boundary parameters for balanced proliferation, we conducted in silico modeling.
  
  
  METHODS
  To illuminate the balanced proliferation hypothesis, we explored the specific boundary probabilities under which proliferating micrometastases would remain dormant. A two-state Markov chain Monte Carlo model simulated micrometastatic proliferation and death according to stochastic survival probabilities. We varied these probabilities across 100 simulated patients each with 1,000 metastatic deposits and documented whether the micrometastases exceeded one million cells, died out, or remained dormant (survived 1,218 generations).
  
  
  RESULTS
  The simulations revealed a narrow survival probability window (49.7-50.8%) that allowed for dormancy across a range of starting cell numbers, and even then for only a small fraction of micrometastases. The majority of micrometastases died out quickly even at survival probabilities that led to rapid emergence of a subset of micrometastases. Within dormant metastases, cell populations depended sensitively on small survival probability increments.
  
  
  CONCLUSIONS
  Metastatic dormancy as explained solely by balanced proliferation is bounded by very tight survival probabilities. Considering the far larger survival variability thought to attend fluxing microenvironments, it is more probable that these micrometastatic nodules undergo at least periods of quiescence rather than exclusively being controlled by balanced proliferation.
authors: Department of Bioengineering, University of Pittsburgh and Taylor Allderdice High School, Pittsburgh, Pennsylvania 15261, USA.
authors: Donald P
authors: DP
authors: Taylor
authors: Jakob Z
authors: JZ
authors: Wells
authors: Andrej
authors: A
authors: Savol
authors: Chakra
authors: C
authors: Chennubhotla
authors: Alan
authors: A
authors: Wells
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003198:Computer Simulation; D006801:Humans; D008390:Markov Chains; D008954:Models, Biological; D009010:Monte Carlo Method; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*