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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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Fluorescence micrograph of a breast tumor stained to visualize carcinoma cells (phospho-p53, green) surrounded by macrophages (CD11b, red) (a).Nuclei appear blue (DAPI). Image courtesy of Michael Graham Espey, PhD, National Cancer Institute, NIH (private communication). (b) Representative pictures of dormant and fast-growing tumors and their vascular structure. Reprinted from Cancer Letters, 294, Almog N, Molecular mechanisms underlying tumor dormancy, 139–146, Copyright (2010), with permission from Elsevier.
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pone-0109934-g001: Fluorescence micrograph of a breast tumor stained to visualize carcinoma cells (phospho-p53, green) surrounded by macrophages (CD11b, red) (a).Nuclei appear blue (DAPI). Image courtesy of Michael Graham Espey, PhD, National Cancer Institute, NIH (private communication). (b) Representative pictures of dormant and fast-growing tumors and their vascular structure. Reprinted from Cancer Letters, 294, Almog N, Molecular mechanisms underlying tumor dormancy, 139–146, Copyright (2010), with permission from Elsevier.

Mentions: Extensive studies over years have revealed three major cancer dormancy mechanisms: cellular dormancy, angiogenic dormancy and immunosurveillance [1], [2]. On the cellular level, a tumor cell could be arrested at a certain stage of the cell cycle and unable to complete the cell division process successfully, resulting in a dormant solitary cell [9]–[11]. On the cell population level, when the population does not gain enough ability to recruit blood vessels and promote neovascularization, the tumor cannot obtain sufficient nutrients necessary for its proliferation and as a result, angiogenic dormancy occurs [12], [13]. On other hand, immunosurveillance operates when the immune system suppresses the proliferation of tumor cell population and leads to the dormancy of the tumor [14]–[18]. Figure 1(a) shows an image of tumor tissue surrounded by immune cells. Figure 1(b) compares the morphology and vascular structure of dormant and fast-growing tumors.


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

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

Fluorescence micrograph of a breast tumor stained to visualize carcinoma cells (phospho-p53, green) surrounded by macrophages (CD11b, red) (a).Nuclei appear blue (DAPI). Image courtesy of Michael Graham Espey, PhD, National Cancer Institute, NIH (private communication). (b) Representative pictures of dormant and fast-growing tumors and their vascular structure. Reprinted from Cancer Letters, 294, Almog N, Molecular mechanisms underlying tumor dormancy, 139–146, Copyright (2010), with permission from Elsevier.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0109934-g001: Fluorescence micrograph of a breast tumor stained to visualize carcinoma cells (phospho-p53, green) surrounded by macrophages (CD11b, red) (a).Nuclei appear blue (DAPI). Image courtesy of Michael Graham Espey, PhD, National Cancer Institute, NIH (private communication). (b) Representative pictures of dormant and fast-growing tumors and their vascular structure. Reprinted from Cancer Letters, 294, Almog N, Molecular mechanisms underlying tumor dormancy, 139–146, Copyright (2010), with permission from Elsevier.
Mentions: Extensive studies over years have revealed three major cancer dormancy mechanisms: cellular dormancy, angiogenic dormancy and immunosurveillance [1], [2]. On the cellular level, a tumor cell could be arrested at a certain stage of the cell cycle and unable to complete the cell division process successfully, resulting in a dormant solitary cell [9]–[11]. On the cell population level, when the population does not gain enough ability to recruit blood vessels and promote neovascularization, the tumor cannot obtain sufficient nutrients necessary for its proliferation and as a result, angiogenic dormancy occurs [12], [13]. On other hand, immunosurveillance operates when the immune system suppresses the proliferation of tumor cell population and leads to the dormancy of the tumor [14]–[18]. Figure 1(a) shows an image of tumor tissue surrounded by immune cells. Figure 1(b) compares the morphology and vascular structure of dormant and fast-growing tumors.

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