Models of Functional Heterogeneity and Targeting Strategies for Cancer Stem Cells

Introduction: Functional heterogeneity, defined as variations between and within tumours, is the underlying cause for malignant tumour processes such as tumour progression, metastasis and treatment resistance. In particular, cancer stem cells (CSCs) could be important contributors to functional heterogeneity within tumours, as CSCs can differentiate into different tumorous cells. This study aims to identify models for the genesis of functional heterogeneity among cancer cells and strategies for targeting CSCs. Methods: Using an integrated review process, various models for functional heterogeneity genesis in cancer and cancer stem cell treatments were explored. Papers that explicitly focused on either explaining a model for the genesis of functional heterogeneity in cancer or on describing targeting strategies for CSCs were included. To conduct our search the following databases were used: PubMed, OVID (Medline), and Web of Science. Results: Several prominent models for genesis of cancer functional heterogeneity were identified, including the hierarchy model, stochastic model, and plasticity model. There is no definitive model as different types of cancer may follow different models of functional heterogeneity. However, multiple models suggest that CSCs, tumor cells with acquired or innate multipotency, are responsible for enhancing tumour progression. Hence, many therapeutic methods have been explored to target CSCs including: interfering with signalling pathways, targeting biomarkers, exerting transcriptional control, damaging quiescence, disrupting the microenvironment and immunotherapy. Discussion: This study identified a gap in current literature to be the lack of clinical studies, with the majority of experiments being conducted on mice models or in vitro. As such the applicability of the findings on a human in vivo level are unclear. Strengths of this paper include the extensive scope of literature reviewed, while limitations include the lack of a quality assessment stage. Conclusion: This study suggests that CSCs are involved in the development of functional heterogeneity in tumours and identifies some preliminary strategies to target them. However, more clinical trials are needed to further validate current proposed treatments. By developing CSC-specific therapies, functional heterogeneity amongst cancer cells can be decreased, which will prevent cancer cells from continuing to progress. As a result, these treatments will be more likely to effectively treat cancer.