Cancer stem cells, cancer cell plasticity and radiation therapy

Abstract

Summary Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms.

3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.

“…In addition, new data suggest that longterm temozolomide treatment induces chromosomal instability, which in turn leads to potential increases in invasion and migration (38). Including such additional phenotypic changes in our model, as well as therapy-induced reprogramming of differentiated GBM cells to GSCs (35), would only add to the invasiveness we observed.…”

“…Here, we do not account for reprogramming of differentiated GBM cells to GSCs that could occur during treatment (see Discussion; ref. 35).…”

The changing paradigm of tumour response to irradiation

“…98 Particularly important in the context of radiation treatment is that back differentiation of progenitor cells into stem cells may be induced by radiation, although the extent of this phenomenon is currently uncertain. [99][100][101][102] However, comparisons of the radiation dose required to cure xenografted tumour cell lines in immune-deprived mice using single doses vs fractionated treatments have given a reasonably good correlation, suggesting that this effect may be limited. 74 Further studies are needed in this area, particularly with tumours directly from patients and early patient-derived xenograft (PDX) models.…”

Accelerated Senescence of Cancer Stem Cells: A Failure to Thrive or a Route to Survival?

“…Many gene modules of ESC are found active in various cancers [20], in turn, aggressive tumors express the markers of ESC or germ cells [21][22][23][24]. Third, tumors also acquire epigenetic proiles of ESC under genotoxic [25][26][27][28] or hypoxic conditions [29], in association with overcoming the tetraploidy barrier. So, epigenetically, CSCs of highly de-diferentiated tumors possess many features of ESC.…”