Modeling of cancer stem cells and the tumor microenvironment Via NT2/D1 cells to probe pathology and treatment for cancer and beyond

Abstract

Introduction: Unique from the other tumor cells, tumorigenic cancer stem cells (CSCs) manifest as a subpopulation of cells within the tumor that exhibit genetic and phenotypic features and signaling processes, which escape traditional anti-oncogenic treatments, thereby triggering metastases and relapses of cancers. Critical to cancer biology is the crosstalk between CSCs and tumor microenvironment (TME), implicating a CSC-based cancer immunotherapy. Cognizant of CSCs’ significant role in cancer pathology and treatment, finding a biological model that recapitulates CSCs and TME may allow a better understanding of tumor onset and progression for testing CSC-based therapies. In this review paper, we examined the CSC and TME characteristics of the human embryonal carcinoma NTERA-2 clonal cell line called NTERA-2 cl.D1 or NT2/D1 cells and discussed their potential utility for research and development of treatments for cancer and central nervous system (CNS) disorders. Methods: To probe our hypotheses that NT2/D1 cells display CSC and TME properties key to tumor development, which can serve as a screening platform to test cancer and CNS therapeutics, we conducted a literature review over a 10-year period (2014–2024), focusing on PUBMED and Science Direct published articles on cellular models of cancer, with emphasis on milestone research discoveries on NT2/D1 cells relevant to CSCs and TME. We categorized the studies under pre-clinical and clinical investigations in supporting the existence of CSC and TME features in NT2/D1 cells and providing a laboratory-to-clinic translational basis for cancer and CNS therapeutics. Conclusions: NT2/D1 cells stand as a feasible biological model that recapitulates the crosstalk of CSCs and TME, which may critically contribute to our understanding of cancer and CNS biology and therapeutics. Designing therapeutics against CSCs' distinct self-renewal and differentiation capacities within the TME opens new avenues for treating cancers and CNS disorders.