Evolving Strategies for Therapeutically Targeting Cancer Stem Cells

Cancer is a multifactor and multistep process that is affected intrinsically by the genetic and epigenetic makeup of tumor cells and extrinsically by the host microenvironment and immune system. A key component of cancer involves a unique subpopulation of highly malignant cancerous cells referred to as cancer stem cells (CSCs). CSCs are positioned at the apex of the tumor hierarchy with an ability to both self-renew and also generate non-CSC/differentiated progeny, which contribute to the majority of the tumor mass. CSCs undergo functional changes and show plasticity that is stimulated by specific microenvironmental cues and interactions in the tumor niche, which contribute to the complexity and heterogeneity of the CSC population. The prognostic value of CSCs in the clinic is evident since there are many examples in which CSCs serve as markers for poor patient prognosis. CSCs are innately resistant to many standard therapies and they display anoikis resistance, immune evasion, tumor dormancy, and field cancerization, which may result in metastasis and relapse. Many academic laboratories and biotechnology companies are currently focusing on strategies that target CSCs. Combination therapies, epigenetic modifiers, stemness inhibitors, CSC surface marker-based therapies, and immunotherapy-based CSC-targeting drugs are currently undergoing clinical trials. Potential new targets/strategies in CSC-targeted therapy include MDA-9/Syntenin (SDCBP), Patched (PTCH), epigenetic targets, noncoding RNAs, and differentiation induction. Defining ways of targeting and destroying CSCs holds potential to impact significantly on cancer therapy, including prevention of metastasis and cancer recurrence.