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A cellular automaton model for tumor dormancy: emergence of a proliferative switch.

Chen D, Jiao Y, Torquato S - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, United States of America; Physical Science in Oncology Center, Princeton University, Princeton, New Jersey, United States of America.

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.

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Upper panel: statistics of a simulated noninvasive tumor growing in the ECM with  and microenvironmental suppression factors, as predicted by the “CA dormancy model”.(a) Tumor area AT normalized by the area A0 of the growth permitting region. (b) Areas of different cell populations normalized by the area A0 of the growth permitting region. Lower panel: statistics of a simulated noninvasive tumor growing in the ECM with  without suppression. (c) Tumor area AT normalized by the area A0 of the growth permitting region. (d) Areas of different cell populations normalized by the area A0 of the growth permitting region.
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pone-0109934-g002: Upper panel: statistics of a simulated noninvasive tumor growing in the ECM with and microenvironmental suppression factors, as predicted by the “CA dormancy model”.(a) Tumor area AT normalized by the area A0 of the growth permitting region. (b) Areas of different cell populations normalized by the area A0 of the growth permitting region. Lower panel: statistics of a simulated noninvasive tumor growing in the ECM with without suppression. (c) Tumor area AT normalized by the area A0 of the growth permitting region. (d) Areas of different cell populations normalized by the area A0 of the growth permitting region.

Mentions: Here we consider the growth of a proliferative tumor in a confined space with . As shown in Figure 2(a), with the interactions between the tumor and the microenvironmental suppression factors incorporated, there exists a period of dormancy in the tumor's growth. Specifically, for the initial approximate 900 days, the tumor stays in a dormant state. Suddenly at approximately day 900, the tumor switches its behavior and begins rapid proliferation. The virtual patient would die 100 days after this critical point in time. Figure 2(b) shows the areas A of different populations normalized by the area of the growth-permitting area A0. For purposes of comparison, Figure 2(c) and Figure 2(d) show the statistics of the tumor growth without the suppression of microenvironmental factors. Moreover, by comparing Figure 2(a) and Figure 2(c), it is seen that the interactions between the tumor and the microenvironmental suppression factors lead to the existence of a dormancy period and a subsequent emergent “switch” behavior of the tumor from a dormant state to a proliferative state. Also, from the comparison of Figure 2(b) and Figure 2(d), one can see that the additional interaction rules alter the fractions of necrotic cell population and proliferative cell population within the tumor. When suppression of the tumor growth is present, the necrotic region decreases and the proliferative region increases relatively; the area of the quiescent region remains almost unchanged.


A cellular automaton model for tumor dormancy: emergence of a proliferative switch.

Chen D, Jiao Y, Torquato S - PLoS ONE (2014)

Upper panel: statistics of a simulated noninvasive tumor growing in the ECM with  and microenvironmental suppression factors, as predicted by the “CA dormancy model”.(a) Tumor area AT normalized by the area A0 of the growth permitting region. (b) Areas of different cell populations normalized by the area A0 of the growth permitting region. Lower panel: statistics of a simulated noninvasive tumor growing in the ECM with  without suppression. (c) Tumor area AT normalized by the area A0 of the growth permitting region. (d) Areas of different cell populations normalized by the area A0 of the growth permitting region.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199683&req=5

pone-0109934-g002: Upper panel: statistics of a simulated noninvasive tumor growing in the ECM with and microenvironmental suppression factors, as predicted by the “CA dormancy model”.(a) Tumor area AT normalized by the area A0 of the growth permitting region. (b) Areas of different cell populations normalized by the area A0 of the growth permitting region. Lower panel: statistics of a simulated noninvasive tumor growing in the ECM with without suppression. (c) Tumor area AT normalized by the area A0 of the growth permitting region. (d) Areas of different cell populations normalized by the area A0 of the growth permitting region.
Mentions: Here we consider the growth of a proliferative tumor in a confined space with . As shown in Figure 2(a), with the interactions between the tumor and the microenvironmental suppression factors incorporated, there exists a period of dormancy in the tumor's growth. Specifically, for the initial approximate 900 days, the tumor stays in a dormant state. Suddenly at approximately day 900, the tumor switches its behavior and begins rapid proliferation. The virtual patient would die 100 days after this critical point in time. Figure 2(b) shows the areas A of different populations normalized by the area of the growth-permitting area A0. For purposes of comparison, Figure 2(c) and Figure 2(d) show the statistics of the tumor growth without the suppression of microenvironmental factors. Moreover, by comparing Figure 2(a) and Figure 2(c), it is seen that the interactions between the tumor and the microenvironmental suppression factors lead to the existence of a dormancy period and a subsequent emergent “switch” behavior of the tumor from a dormant state to a proliferative state. Also, from the comparison of Figure 2(b) and Figure 2(d), one can see that the additional interaction rules alter the fractions of necrotic cell population and proliferative cell population within the tumor. When suppression of the tumor growth is present, the necrotic region decreases and the proliferative region increases relatively; the area of the quiescent region remains almost unchanged.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, United States of America; Physical Science in Oncology Center, Princeton University, Princeton, New Jersey, United States of America.

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.

Show MeSH
Related in: MedlinePlus