Abstract
Malignant cancers that lead to fatal outcomes for patients may remain dormant for very long periods of time. Although individual mechanisms such as cellular dormancy, angiogenic dormancy and immunosurveillance have been proposed, a comprehensive understanding of cancer dormancy and the “switch” from a dormant to a proliferative state still needs to be strengthened from both a basic and clinical point of view. Computational modeling enables one to explore a variety of scenarios for possible but realistic microscopic dormancy mechanisms and their predicted outcomes. The aim of this paper is to devise such a predictive computational model of dormancy with an emergent “switch” behavior. Specifically, we generalize a previous cellular automaton (CA) model for proliferative growth of solid tumor that now incorporates a variety of cell-level tumor-host interactions and different mechanisms for tumor dormancy, for example the effects of the immune system. Our new CA rules induce a natural “competition” between the tumor and tumor suppression factors in the microenvironment. This competition either results in a “stalemate” for a period of time in which the tumor either eventually wins (spontaneously emerges) or is eradicated; or it leads to a situation in which the tumor is eradicated before such a “stalemate” could ever develop. We also predict that if the number of actively dividing cells within the proliferative rim of the tumor reaches a critical, yet low level, the dormant tumor has a high probability to resume rapid growth. Our findings may shed light on the fundamental understanding of cancer dormancy.
Highlights
Cancer dormancy, the phenomena that the tumor’s volume or the number of tumor cells stays at a very low level for a certain period of time before the tumor begins to grow rapidly, has been an outstanding issue in cancer research for many years [1,2]
We generalized a two-dimensional cellular automaton (CA) model previously developed for proliferative growth of avascular solid tumors to investigate tumor dormancy and evasion from dormancy to proliferation
Our CA dormancy model incorporates a variety of cell-level tumor-host interactions, including those between the tumor and the suppression factors in the microenvironment, for example the immune system
Summary
The phenomena that the tumor’s volume or the number of tumor cells stays at a very low level for a certain period of time before the tumor begins to grow rapidly, has been an outstanding issue in cancer research for many years [1,2]. The mechanisms responsible for the ‘‘switch’’ from a dormant state to a rapid growth state for different tumors are not well understood, it is well known that such a ‘‘switch’’ in secondary metastatic tumors can be triggered by the removal of the primary tumor This could eventually lead to failure of tumor treatment and fatal outcomes for the patient. In some cases of pancreatic cancer, the tumor can remain in a benign dormant state for about 20 years [3] During this time, it is undetectable by conventional clinical methods, and it is only afterwards that the tumor becomes highly malignant and grows aggressively with highly fatal outcomes after about a year. Recurrence has been observed in brain tumors, which indicates the existence of a large number of micrometastases that are dormant in the presence of the primary tumor [7,8]
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