A few research groups have proposed the concept of cancer stem cell heterogeneity. For example, phenotypic plasticity of cancer stem cells (CSC) was demonstrated in melanoma and acute myelogenous leukemia. Yet another heterogeneity phenomenon – stochastic phenotypic switching of any cancer cell into CSC, was recently proposed:
… a recently proposed hypothesis states that phenotypes in a cancer cell population are not static but can switch stochastically. The idea underlying this phenotypic switching hypothesis is that any biological system is subject to a varying degree of noise in key signalling pathways that may lead to heritable changes in gene expression through epigenetic mechanisms.
Hence, if phenotypic switching is reversible, most cells should have the potential to adopt a stem cell like phenotype accounting for the high proportion of cells able to seed tumors in severely immunocompromise animals.
However, the recent study, published in Scientific Reports offers a new explanation of reversible markers expression by CSC:
Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.
The authors applied a mathematical model to explain heterogeneity in studies based of sorted CSC:
The operative identification of CSCs relies on stem cell markers, but their absolute accuracy is far from being guaranteed. Our proposal is to assume that putative CSC markers are imperfect and derive the experimental consequences of this assumption (See Fig. 1B). An imperfect marker yields a marker-positive subpopulation that is CSC rich, but does not allow to eliminate all CSCs from the marker-negative subpopulation. The few CSCs present in the marker-negative subpopulation will drive tumor growth and re-establish a marker-positive subpopulation in the tumor.
So, the authors challenges mainly Lander’s hypothesis. The study doesn’t exclude the possibility that CSC could have many different surface markers and switch their expression during cancer progression.
The authors argue that “imperfect marker model” explains heterogeneity of sorted CSC better than “phenotypic switching” or “sorting error” models.
Very interesting study, worth reading.