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.
Highlights
Cancer stem cells (CSCs) are resistant to conventional therapeutic approaches [1,2,3]
We tested the ability of graphene oxide (GO) to affect CSC proliferation, using MCF7 cells, a well-established ER(+) breast cancer cell line
We show that treatment with GO is sufficient to inhibit tumor-sphere formation in six independent cancer cell lines, across multiple tumor types (breast, ovarian, prostate, lung, and pancreatic cancer, as well glioblastoma)
Summary
Cancer stem cells (CSCs) are resistant to conventional therapeutic approaches [1,2,3] As a consequence, they have been directly implicated in the disease pathogenesis of tumor recurrence and distant metastasis [4, 5]. A particular distinguishing characteristic of CSCs is their ability to initiate tumors and to undergo anchorageindependent growth, when cultured in suspension [11]. Under these particular cell culture conditions, CSCs proliferate and form 3D-spheroid-like structures, containing CSCs and progenitor cells, which are known as “tumor-spheres” or “onco-spheres” [12, 13]. The CSC population is resistant to DNA-damage, and shows lower levels of ROS production, as well [14, 15]. 3D-tumor-spheres derived from breast cancer cells are known as mammo-spheres [12, 13]
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