Phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. Some cancers also contain a hierarchy in which tumorigenic cancer stem cells differentiate into non-tumorigenic progeny. However, it remains unclear what fraction of cancers follow the stem-cell model and what clinical behaviours the model explains. Studies using lineage tracing and deep sequencing could have implications for the cancer stem-cell model and may help to determine the extent to which it accounts for therapy resistance and disease progression.

Tumour heterogeneity and cancer cell plasticity

Multicellular tumor spheroids: an underestimated tool is catching up again

Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.

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Cancer stem cells in glioblastoma

Cancer stem cells: current status and evolving complexities.

Cancer Stem Cells: Impact, Heterogeneity, and Uncertainty

Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens.

Subpopulations of tumorigenic cells have been identified in many human tumors, although these cells may not be very rare in some types of cancer. Here, we report that medulloblastomas arising from Patched-1-deficient mice contain a subpopulation of cells that show a neural precursor phenotype, clonogenic and multilineage differentiation capacity, activated Hedgehog signaling, wild-type Patched-1 expression, and the ability to initiate tumors following allogeneic orthotopic transplantation. The normal neural stem cell surface antigen CD15 enriches for the in vitro proliferative and in vivo tumorigenic potential from uncultured medulloblastomas, supporting the existence of a cancer stem cell hierarchy in this clinically relevant mouse model of cancer.

http://cancerres.aacrjournals.org/content/canres/69/11/4682.full.pdf

Koichi Yoshikawa

Papers

Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens.

Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma.