title: Graphene oxide selectively targets cancer stem cells, across multiple tumor types: implications for non-toxic cancer treatment, via "differentiation-based nano-therapy".
abstract: Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano-materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for "bulk" cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT-signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy.
authors.affiliation: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.|The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.|The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fiorillo
authors.affiliation: School of Materials and National Graphene Institute, University of Manchester, UK.
authors.forename: Andrea F
authors.initials: AF
authors.lastname: Verre
authors.affiliation: School of Materials and National Graphene Institute, University of Manchester, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Iliut
authors.affiliation: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.|The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Peiris-Pagés
authors.affiliation: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.|The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.
authors.forename: Bela
authors.initials: B
authors.lastname: Ozsvari
authors.affiliation: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.|The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gandara
authors.affiliation: The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cappello
authors.affiliation: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.|The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.affiliation: School of Materials and National Graphene Institute, University of Manchester, UK.
authors.forename: Aravind
authors.initials: A
authors.lastname: Vijayaraghavan
authors.affiliation: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.|The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006108:Graphite / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D050997:Nanomedicine / Q000379:methods; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010087:Oxides / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D010087:Oxides; D006108:Graphite