Disruption of a Quorum Sensing mechanism triggers tumorigenesis: a simple discrete model corroborated by experiments in mammary cancer stem cells.
BACKGROUND
The balance between self-renewal and differentiation of stem cells is expected to be tightly controlled in order to maintain tissue homeostasis throughout life, also in the face of environmental hazards. Theory, predicting that homeostasis is maintained by a negative feedback on stem cell proliferation, implies a Quorum Sensing mechanism in higher vertebrates.


RESULTS
Application of this theory to a cellular automata model of stem cell development in disrupted environments shows a sharply dichotomous growth dynamics: maturation within 50-400 cell cycles, or immortalization. This dichotomy is mainly driven by intercellular communication, low intensity of which causes perpetual proliferation. Another driving force is the cells' kinetic parameters. Reduced tissue life span of differentiated cells results in uncontrolled proliferation. Model's analysis, showing that under the Quorum Sensing control, stem cell fraction within a steady state population is fixed, is corroborated by experiments in breast carcinoma cells. Experimental results show that the plating densities of CD44+ cells and of CD44+/24lo/ESA+ cells do not affect stem cell fraction near confluence.


CONCLUSIONS
This study suggests that stem cell immortalization may be triggered by reduced intercellular communication, rather than exclusively result from somatic evolution, and implies that stem cell proliferation can be attenuated by signal manipulation, or enhanced by cytotoxics targeted to differentiated cells. In vivo verification and identification of the Quorum Sensing mediating molecules will pave the way to a higher level control of stem cell proliferation in cancer and in tissue engineering.
Agur
Zvia
Z
Institute for Medical BioMathematics, 10 Hate'ena St, Bene Ataroth, Israel. agur@imbm.org
Kogan
Yuri
Y
Levi
Liora
L
Harrison
Hannah
H
Lamb
Rebecca
R
Kirnasovsky
Oleg U
OU
Clarke
Robert B
RB
D000818:Animals; D006801:Humans; D008962:Models, Theoretical; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D053038:Quorum Sensing / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
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