Disruption of a Quorum Sensing mechanism triggers tumorigenesis: a simple discrete model corroborated by experiments in mammary cancer stem cells

Abstract

BackgroundThe 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.ResultsApplication 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.ConclusionsThis 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.ReviewersThis article was reviewed by Glenn Webb and Marek Kimmel.

IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells

“…Quorum sensing is a form of intercellular communication which allows unicellular prokaryotic organisms to respond synchronously to alterations in microenvironment, almost as if they were a multicellular organism [24, 25]. The involvement of quorum-sensing mechanisms in human tumor cell biology and metastasis has been hypothesized [26, 27]. …”

Embryonic stem cells growing in 3-dimensions shift from reliance on the substrate to each other for mechanical support

“…Inter-cellular interactions effects are beyond strictly mechanical. Inter-cellular communication has been shown, for example, to maintain homeostasis in cells, where reduction of cell-cell signals could trigger stem cell immortalization and proliferation resulting in tumorigenesis (Agur et al, 2010). These studies reveal importance of the cell-cell interactions in developmental events such as differentiation, to expose dependence of pluripotent stem cells on their biophysical environment as they gain specificity and functionality.…”

Using an adaptive gene network model for self-organizing multicellular behavior

“…For instance, a hypothesis that cancer cells may use a quorum-sensing mechanism to regulate multicellular functions and control steps in metastatic colonization has been proposed [33]. It has also been reported that disruption of a quorum-sensing mechanism triggers tumorigenesis in mammary cancer stem cells [34]. These studies indicate that computationally modeling self-organization using adaptive networks may lead to useful insights in diverse biological fields.…”