Heterogeneity of Neoplastic Stem Cells: Theoretical, Functional, and Clinical Implications

Abstract

Accumulating evidence suggests that human cancers develop through a step-wise, but nonlinear process of cellular diversification and evolution. Recent mutational analyses indicate that this process is more complex and diverse than anticipated before whole-genome sequencing methods were readily available. Examples are also emerging now of genetically abnormal clones of cells that have acquired mutations with known oncogenic potential but, nevertheless, may show no manifestations of malignant change for many years. To accommodate these diverse realities, we suggest the term neoplastic refer to clones of cells that have any type of somatic aberrancy associated with an increased propensity to become malignant, and the derivative term neoplastic stem cell be adopted to identify the cells responsible for the long-term maintenance of such clones. Neoplastic clones would thus include those that never evolve further, as well as those that eventually give rise to fully malignant populations, and all stages in between. The term cancer stem cells would then be more appropriately restricted to cells generating subclones that have established malignant properties. More precise molecular understanding of the different stem cell states thus distinguished should contribute to the development of more effective prognostic and therapeutic tools for cancer diagnosis and treatment. Cancer Res; 73(3);

Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

“…Progression of the diseases from a neoplastic (precancerous) to an aggressive malignant (leukemia) stage is quite variable in rate and incidence, but forebodes a poor prognosis. The aim of current research is to define the neoplastic stem cells that are predicted to maintain the disease, and as such are important therapeutic targets, but also to understand the step-wise but nonlinear process leading to overt malignancy (3,4). Such endeavors are most advanced for chronic myeloid leukemia, the most common MPN that is characterized by the BCR/ABL translocation.…”

The Vienna Cancer Stem Cell Club (VCSCC): First 10 Years and Future Perspectives

“…In addition, more and more molecular lesions (aberrations), epigenetic changes and posttranslational modifications are acquired by CSC. As a result, CSC in an overt tumor is quite heterogeneous populations of cells, with varying combinations of molecular lesions and oncogenic pathways, resulting in a variable tumorigenic potential of CSC-subpopulations [31,[38][39][40][41][42][43]. Subclone formation is based on genomic instability and plasticity of CSC, patient-related factors (such as the immune system) and the increased rate of symmetrical cell divisions that lead to a continuous expansion and diversification of the CSC pool [38][39][40][41][42][43].…”

“…As a result, CSC in an overt tumor is quite heterogeneous populations of cells, with varying combinations of molecular lesions and oncogenic pathways, resulting in a variable tumorigenic potential of CSC-subpopulations [31,[38][39][40][41][42][43]. Subclone formation is based on genomic instability and plasticity of CSC, patient-related factors (such as the immune system) and the increased rate of symmetrical cell divisions that lead to a continuous expansion and diversification of the CSC pool [38][39][40][41][42][43]. Subclone formation is also considered to contribute essentially to acquired resistance against diverse types of drugs (multidrug resistance) [38][39][40][41][42][43].…”

“…Subclone formation is based on genomic instability and plasticity of CSC, patient-related factors (such as the immune system) and the increased rate of symmetrical cell divisions that lead to a continuous expansion and diversification of the CSC pool [38][39][40][41][42][43]. Subclone formation is also considered to contribute essentially to acquired resistance against diverse types of drugs (multidrug resistance) [38][39][40][41][42][43]. Notably, CSC often remain unresponsive to many different drugs because of "intrinsic" (natural) stem cell resistance combined with multiple (additional) mechanisms of "acquired (subclone-specific) resistance" [31,40].…”

Cancer Stem Cells: Understanding their Dynamics

“…However, with increasing age and diminished immunocompetence, this elimination process remains incomplete leading to accumulation of pro-angiogenic accumulative changes. During early phase of neoplastic clone development, the minimally acquired mutations have very little effect on morphologic, immunological and transcriptional features [5].…”