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Jeremy N. Rich, MD, MHSc
The Dynamic Complexity of Cancer Stem Cells
Chair, Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic; Professor, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University
2 Riverside Circle, Roanoke, VA 24016
Cancer research has rediscovered the complexity of nervous system cancers through the incorporation of cellular heterogeneity into tumor models with cellular subsets displaying stem cell characteristics. The cancer stem cell hypothesis posits that tumor cells are organized in a hierarchy with cancer stem cells at the apex and functionally defined by the ability to self renew and propagate tumors similar to the parental tumors from which they are derived.
Cancer stem cells remain controversial because of unresolved relationships with cell-of-origin, frequency, and defining universal markers but it has been nearly impossible to create absolute rules for even a single cancer type so it is likely that the cancer stem cell phenotype can be acquired through convergent evolution and may be governed by variable rules based on tumor type, grade, course, and therapeutic treatment.
Cancer stem cells have been studied in multiple cancer types, most heavily in leukemias, glioblastomas, and breast and colon cancers. Cancer stem cells also yield the non-tumorigenic tumor bulk cells that display a more differentiated phenotype. The ability to prospectively isolate and interrogate cancer stem cells is defining molecular mechanisms responsible for the tumor maintenance and growth. The clinical relevance of cancer stem cells has been supported by cancer stem cell resistance to cytotoxic therapies and promotion of tumor angiogenesis. Cancer stem cells reside in specific functional niches in perivascular and hypoxic niches that may offer the ability to disrupt tumor maintenance and therapeutic resistance through targeting the niche.
The cancer stem cell phenotype is regulated by both cell intrinsic and microenvironmental influences that may further increase the complexity of tumor modeling. Notably, cell lines and standard culture conditions used in preclinical studies fail to recapitulate the tumor heterogeneity and do not fully predict patient responses, supporting the development of improved tumor models.
The study of cellular heterogeneity and cancer stem cells has already yielded novel molecular targets and pathways that are amenable to therapeutic targeting, perhaps permitting attenuation of tumor resistance. The conventional pyramidal unidirectional differentiation cascade with cancer stem cells at the apex has been called into question by studies demonstrating plasticity of the cancer stem cell phenotype, thus suggesting that targeting only cancer stem cells will likely fail to cure patients and require simultaneous targeting of cancer stem cells and the bulk tumor. Although the field of cancer stem cell biology is relatively young, continued elucidation of the tumor hierarchy holds promise for the development of novel patient therapies.