Primary and metastatic tumor dormancy as a result of population heterogeneity

Existence of tumor dormancy, or cancer without disease, is supported both by autopsy studies that indicate presence of microscopic tumors in men and women who die of trauma (primary dormancy), and by long periods of latency between excision of primary tumors and disease recurrence (metastatic dormancy). Within dormant tumors, two general mechanisms underlying the dynamics are recognized, namely, the population existing at limited carrying capacity (tumor mass dormancy), and solitary cell dormancy, characterized by long periods of quiescence marked by cell cycle arrest. Here we focus on mechanisms that precede the avascular tumor reaching its carrying capacity, and propose that dynamics consistent with tumor dormancy and subsequent escape from it can be accounted for with simple models that take into account population heterogeneity. We evaluate parametrically heterogeneous Malthusian, logistic and Allee growth models and show that 1) time to escape from tumor dormancy is driven by the initial distribution of cell clones in the population and 2) escape from dormancy is accompanied by a large increase in variance, as well as the expected value of fitness-determining parameters. Based on our results, we propose that parametrically heterogeneous logistic model would be most likely to account for primary tumor dormancy, while distributed Allee model would be most appropriate for metastatic dormancy. We conclude with a discussion of dormancy as a stage within a larger context of cancer as a systemic disease. Reviewers: This article was reviewed by Heiko Enderling and Marek Kimmel.